KR20080068108A - Identification and characterization of function-blocking anti-ed-b-fibronectin antibodies - Google Patents

Abstract

The invention relates to recombinant polypeptides, in particular antibodies or antibody fragments, which are able to bind the ED-B isoform of fibronectin and block the function thereof. Further diagnostic and pharmaceutical application of the polypeptides of the invention is also disclosed.

Description

IDENTIFICATION AND CHARACTERIZATION OF FUNCTION-BLOCKING ANTI-ED-B-FIBRONECTIN ANTIBODIES

This application claims the benefit of the filing date of US Provisional Serial No. 60 / 697,565, filed July 11, 2005, which is incorporated herein by reference.

The present invention relates to recombinant polypeptides, in particular antibodies or antibody fragments, which can bind to and block the action of the ED-B- homolog of fibronectin. In addition, diagnostic and pharmaceutical applications of the polypeptides according to the invention are also disclosed.

During tumor development and progression, the extracellular matrix on which the tumor grows (ECM) is modified by proteolytic degradation of existing ECM. This process produces tumor-inducing substrates that are distinct from those of ECM occurring in normal tissues. 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 existing blood vessels. This process requires proteolysis of ECM, targeted growth and differentiation of endothelial cells in new vascular structures, which is essential for further tumor growth (5).

Fibronectin is an important substrate-glycoprotein class. The primary role is to promote the attachment of cells to many different extracellular substrates. Not only the presence of fibronectin on the surface of non-transformed cells in culture, but also in the case of transformed cells makes it possible to identify important adhesion proteins. It interacts with a number of other different molecules such as collagen, heparan sulfate proteoglycan and fibrin to regulate cell morphology and cytoskeletal formation. In addition, it causes cell migration and cell differentiation during embryonic development. In addition, fibronectin is also important for wound healing, enabling the formation of blood clots by allowing macrophages and other immune cells to migrate to the area and allow platelets to attach to damaged areas of blood vessels.

Fibronectin is a dimer consisting of two similar peptides, each chain approximately 60-70 nm in length. More than 20 different fibronectin chains have been identified, all of which are produced through selective splicing of RNA transcripts from a single fibronectin gene.

Fibronectin is a polymer-mediated glycoprotein that plays an important role in vascular development. In addition, fibronectin chemotactically affects endothelial cells upon angiogenesis, regulates the action of growth factors and supports linear growth of endothelial cells (6-9). Proteolytic fibronectin-cleavage analysis showed that the polypeptide consists of six largely folded domains, each domain containing a so-called repeating sequence ("repeat"), and their amino acid sequence similarity. According to three types (Type I, II and III). The central region of both chains of the dimer consists of a region called a type III repeat, consisting of a region on average 90 amino acids in length (10). Structural studies have found that each type III repeat consists of seven beta-strands, which are folded into two sheets parallel in opposite directions, exposing short loop regions as potential protein-protein-interaction sites ( 11).

Fibronectin can act as an adhesion molecule that interacts with cell surface molecules called “integrins” through these type III repeats. The term “integrin” was first described in 1987 (12) to describe a related group of heterodimeric cell surface molecules that act as mediators between the extracellular matrix and the intracellular cytoskeleton to induce cell attachment and migration. Was used. These heterodimeric receptors "integrate" or mediate signals from the extracellular environment with specific cellular functions. To date, 17 beta-subunits are known which can specifically interact without covalently binding to more than 20 alpha-subunits, in particular forming 20 different families (13) . In particular, the sequence RGDS found in the tenth repeat (III-10) of type III fibronectin mediates the interaction between fibronectin and at least eight different integrins. In addition, it has been shown that four or more integrins can specifically interact with fibronectin in a manner that does not depend on RGDS (13). In addition to the III7-, III8-, III9- and III10 sequences, the repeat sequence group of type III also includes EIIIB and EIIIA (ED-B and ED-A) repeats.

ED-B-fibronectin cannot be detected in normal adult tissues (the only exception: proliferative endometrium), but is strongly expressed in fetal tissue and tumor growth in addition to the interstitial local expression of ED-B. In addition, ED-B-fibronectin is localized around newly formed blood vessels upon angiogenesis. For this reason, ED-B-fibronectin is a marker protein specific for the (tumor) angiogenesis process (14).

The ED-B domain is a highly conserved, complete type III homology component of 91 amino acids. The degree of homology between humans and rats is 100%, and the degree of homology between humans and chickens is 96%. Little is known about the action of the ED-B domain in the literature. Some publications (15-17) speculate on general attachment-mediated action on various cells. To date, no specific action has been shown on endothelial cells.

In WO 02/20563, recombinant ED-B is characterized in that (i) the proliferation of bFGF-stimulated human dermal microvascular endothelial cells (HDMVEc) is promoted by recombinant ED-B, and (ii) the protein mediates the attachment of HDMVEC. And (iii) recombinant ED-B has been shown to exhibit specific pro-angiogenic activity in vitro that stimulates infiltration and differentiation (tube formation) of HDMVEC in collagen gels.

In addition, these ED-B-mediated effects can be specifically blocked by synthetic peptides derived from the ED-B domain. Thus, peptide sequences represent binding regions for ED-B-specific receptors on the endothelial cell surface, identified as α ₂ β ₁ -integrins by means of affinity chromatography. Specific interactions between α ₂ β ₁ -integrins and ED-B domains have not been described in previous literature.

WO 02/20563 also discloses a protein specifically regulated by the ED-B-fibronectin domain, including α ₂ β ₁ -integrin, topical attachment kinase, CD6 ligand (ALCAM), alpha chain of vitronectin receptor, integrated alpha-8 Disclosed are proteins comprising precursors of subunits or follistatin related proteins.

Many integrin receptors with partially overlapping properties are expressed by endothelial cells (DG Stupack and D. A. Cheresh, SciSTKE, 2002 February 12; 2002). This pattern of expression is related to endothelial cells, where different integrins (eg, alphavbeta3 and alpha5beta1) mediate similar biological phenomena (attachment, migration, and survival), protecting their behavior and survival. Show duplicate systems. Previously, alpha2beta1 has been known to interact with its natural ligand, collagen. Blocking these interactions can lead to anti-angiogenic effects [Y. Funahashi et al. Cancer Res. 62: 6116-6123, 2002.

Therefore, it was an object of the present invention to prepare antibodies that specifically block receptor-binding sites of action-blocking binding molecules such as the ED-B domain. Such binding molecules have anti-angiogenic action on (tumor) endothelial cells. Unlike the relatively broadly expressed α ₂ β ₁ -integrin, the ED-B domain is an ideal and specific target molecule for such binding molecules.

Thus, ED-B structure makes monoclonal and polyclonal antibody development difficult because ED-B can be predicted to have low immunogenicity in vivo. Thus, antibody BC-1 [J. reacts. Cell Biol. 108 (1989), 1139-1148, react with the latent epitope of fibronectin, which is present only in the presence of ED-B and therefore does not react directly with ED-B. Antibody L19 (Tarli et al. Blood 94 (1999), 192-198 and WO 01/62800) produced using recombinant ED-B as an immunogen is biologically inactive, i.e., the cells are directed to ED-B. You may not notice much of what is attached.

Surprisingly enough, current action-blocking ED-B-binding molecules such as ED-B-action-blocking antibody MOR03255 can be produced, which significantly inhibits the attachment of cells to ED-B and in vivo It has been found to significantly reduce tumor growth in. The blockade of ED-B caused by the binding molecule according to the invention is clearly not able to be compensated by the compensation mechanism of collagen-integrin.

For example, a library comprising 1.6 × 10E10 different antibodies in a Fab-fragment format, generated starting from a HuCAL-common sequence by diversification corresponding to the diversity of human antibodies in all six CDR regions (WO 97 / 08320; Knappik A, Ge L .; Honegger A .; Pack, P .; Fischer M .; Wellnhofer G .; Hoess A ,; Wolle, J .; Plunckthun A, and Virnekas B. (2000) J. Mol . Biol 296:. 57]) , by a careful review, HuCAL ^® gold library (HuCAL ^® gold library) which is subject to variation of the CysDisplay (01/05950 WO) of the phage display method as a means as a means, the test led to the present invention Action-blocking Fab-antibody fragments that selectively bind to the ED-B domain at were identified. The efficacy of these antibody fragments can be represented by in vitro adhesion tests that reflect specific interactions between recombinant ED-B and isolated HDMVEc. Binding affinity for the ED-B domain can be significantly improved by specifically changing the binding molecule. In vivo binding molecules have also been shown to be able to inhibit tumor growth in animal models.

Thus, the first aspect of the invention

(i) specifically binds to the ED-B domain of fibronectin,

(ii) a polypeptide that inhibits the interaction between an ED-B domain and its receptor.

Polypeptides according to the invention are preferably antibodies or antibody fragments. The term “antibody” in the context of the present invention refers to polyclonal, monoclonal, chimeric, humanized or human antibodies, as well as recombinant antibodies, eg single-chain antibodies, or antigen-binding antibody fragments, eg monovalent antibodies. Fragments such as Fab fragments or scFv fragments, or bivalent antibody fragments such as F (ab ') ₂ fragments.

In this regard, the antibody meets the above-mentioned requirements, that is, specifically binds to the ED-B domain and inhibits the interaction between the ED-B domain and its receptor, in particular its receptor on endothelial cells, It is essential to the present invention to contain one or more antigen binding sites. Such antigen binding properties are preferably achieved by the combination of the VH and VL regions, whereby these regions are directed to the CDR regions (VH regions) that mediate antigen binding, as well as to the framework regions referred to (FR1, FR2, FR3 and FR4). L-CDR1, L-CDR2, L-CDR3) for the H-CDR1, H-CDR2, H-CDR3 and VL regions.

Polypeptides according to the invention may be selected from the K _{D relative} to the ED-B domain. Has an affinity corresponding to the value ≦ 1 μm, preferably ≦ 100 nM, particularly preferably ≦ 10 nM, even more preferably ≦ 1 nM and most preferably ≦ 0.1 nM, with the affinity shown in the Examples as it can be determined by a test on a BIAcore ^® (BIAcore ^®) system.

Polypeptides according to the invention in particular bind to the ED-B domain of fibronectin, for example other fibronectin domains, in particular fibronectin domain 6 (FN6) and / or fibronectin domain 7-8-9 (7-8- For 9) they differ in that they bind with significantly lower affinity. In a preferred embodiment, the polypeptides and fibronectin ED-B domains according to the invention are at least twice as high as FN6 and / or 7-8-9, as can be measured, for example, by the binding test shown in the Examples. ,-In particular, at least 5 times, and particularly preferably at least 10 times higher affinity.

In another preferred embodiment, the polypeptides of the invention indicate in vitro inhibition of attachment of recombinant ED-B to HDMVEc cells, preferably at least 50% inhibition at each concentration of 10 μg / ml, and especially Preferably at least 75% inhibition.

In addition, it is preferred that the polypeptides of the present invention show inhibition of in vivo tumor growth produced by transplantation of F9-teratocarcinoma cells (ATCC CRL-1720) in test animals, such as hairless mice.

Polypeptides of the invention preferably

(a) (i) Nucleic acid sequence SEQ ID NO: 1 (MOR 02610), SEQ ID NO: 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: : At least one of the H-CDR1, H-CDR2 and / or H-CDR3 regions of the VH region, or one of the above-mentioned VH regions, encoded by 41 (MOR 02721), SEQ ID NO: 45 (MOR 02722), or

(ii) a VH region derived from the VH region according to (i) by a change in at least one H-CDR region, and / or

(b) (i) 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: : VL region encoded by 43 (MOR 02721), SEQ ID NO: 47 (MOR 02722), or at least one of the L-CDR1, L-CDR2 and / or L-CDR3 regions of one of the above-mentioned VL regions, or

(ii) is selected from antibodies and antibody fragments comprising a VL region derived from the 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, a polypeptide of the invention refers to a VL region derived from a VL region encoded by nucleic acid sequence SEQ ID NO: 27 (MOR 02619) or SEQ ID NO: 35 (MOR 02715).

(i) H-CDR1, H-CDR2 and / or H of the VH region, or one of the above-mentioned VH regions, encoded by nucleic acid sequence SEQ ID NO: 25 (MOR 02619) or SEQ ID NO: 33 (MOR 02715) At least one of the CDR3 regions, or

Particularly preferred are polypeptides comprising a VH region derived from the VH region according to (i) by (ii) a change in at least one H-CDR region.

The polypeptide preferably represents a VH region that is induced by a change in the H-CDR2 region and encoded by the VH region from nucleic acid sequence SEQ ID NO: 25 (MOR 02619) or SEQ ID NO: 33 (MOR 02715). In this case,

(a) (i) 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 the above-mentioned At least H-CDR2 in one of the VH regions, or

(ii) a VH region derived from the VH region according to (i) by a change in at least one H-CDR region, and / or

(b) (i) 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, MOR03253, MOR03255 and MOR03257), SEQ ID NO: 89 (MOR 03258), or at least one of the L-CDR1, L-CDR2 and / or L-CDR3 regions of one of the above-mentioned VL regions, or

Particularly preferred are polypeptides comprising a VL region derived from the VL region according to (i) by (ii) a change in at least one L-CDR region.

Specific examples of polypeptides of the invention are as follows:

VH region encoded by SEQ ID NO: 1 and VL region encoded by SEQ ID NO: 3 (MOR 02610), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 5 and VL region encoded by SEQ ID NO: 7 (MOR 02611), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 9 and VL region encoded by SEQ ID NO: 11 (MOR 02613), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 13 and VL region encoded by SEQ ID NO: 15 (MOR 02614), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 17 and VL region encoded by SEQ ID NO: 19 (MOR 02616), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 21 and VL region encoded by SEQ ID NO: 23 (MOR 02618), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 25 and VL region encoded by SEQ ID NO: 27 (MOR 02619), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 29 and VL region encoded by SEQ ID NO: 31 (MOR 02622), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 33 and VL region encoded by SEQ ID NO: 35 (MOR 02715), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 37 and VL region encoded by SEQ ID NO: 39 (MOR 02718), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 41 and VL region encoded by SEQ ID NO: 43 (MOR 02721), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 45 and VL region encoded by SEQ ID NO: 47 (MOR 02722), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 25 and VL region encoded by SEQ ID NO: 49 (MOR 03055), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 25 and VL region encoded by SEQ ID NO: 51 (MOR 03066), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 25 and VL region encoded by SEQ ID NO: 53 (MOR 03075), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 25 and VL region encoded by SEQ ID NO: 55 (MOR 03069), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 25 and VL region encoded by SEQ ID NO: 57 (MOR 03071), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 33 and VL region encoded by SEQ ID NO: 59 (MOR 03064), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 33 and VL region encoded by SEQ ID NO: 61 (MOR 03062), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 63 and VL region encoded by SEQ ID NO: 65 (MOR 03243), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 67 and VL region encoded by SEQ ID NO: 69 (MOR 03245), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 71 and VL region encoded by SEQ ID NO: 73 (MOR 03246), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 75 and VL region encoded by SEQ ID NO: 77 (MOR 03251), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 79 and VL region encoded by SEQ ID NO: 77 (MOR 03252), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 81 and VL region encoded by SEQ ID NO: 77 (MOR 03253), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 83 and VL region encoded by SEQ ID NO: 77 (MOR 03255), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 85 and VL region encoded by SEQ ID NO: 77 (MOR 03257), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH region encoded by SEQ ID NO: 87 and VL region encoded by SEQ ID NO: 89 (MOR 03258), or at least one H-CDR1, H-CDR2, H-CDR3, L-CDR1, L-CDR2 Or a polypeptide comprising an L-CDR3 region.

VH and VR chain formation of the polypeptides according to the invention are as follows:

VH chain:

Framework region 1 extends from nt 1-78 (ie 26 aa); The last codon (aa) of FR1 is always TCC (Cys).

▶ "CDR1 region" means two different lengths, 30 nt (10 aa) (in the possible VH1A, VH1B, 3, 4 and 5 series), or 36 nt (12 aa) (in the possible VH2, VH4 and VH6 series) Can be.

Framework region 2 always represents 33 nt (ie 11 aa); The first codon (aa) of FR2 is always TGG (Trp); The last two codons are always CTC.GAG (LeuGlu).

▶ “CDR2 region” means three different lengths, 57 nt (19 aa) (in the possible VH2 and VH4 series), 60 nt (20 aa) (in the possible VH1A, VH1B, 3 and 5 series), or 63 nt 21 aa) (in the possible VH6 family).

Framework region 3 always represents 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 AIa Arg).

▶ “CDR3 region” means several different lengths, 12-69 nt (4-23 aa) (in the possible VH2 and VH4 series), 60 nt (20 aa) (in the possible VH1A, VH1B, 3 and 5 series), or 63 nt (21 aa) (possibly in the VH6 family).

Framework region 4 always represents 33 nt (ie 11 aa) and is the same in all seven series: TGG.GGC.CAA.GGC.ACC.CTG.GTG.ACG.GTT.AGC.TCA

VL kappa chain:

Framework region 1 extends from nt 1-69 (ie, 23 aa); The last codon (aa) of FR1 is always TCC (Cys).

▶ “CDR1 regions” are four different lengths, 24 nt (8 aa) (in the possible Vκ1 and Vκ3 series), 27 nt (9 aa) (in the possible Vκ3 series), 39 nt (13 aa) (the possible Vκ2 series) ), Or 42 nt (14 aa) (in the possible Vκ4 family); The first codon (aa) is always AGA (Arg); The second codon (aa) at the end of the CDR1 region is always CTG (Leu).

Framework region 2 always represents 33 nt (ie 11 aa); The first two codons (aa) of FR2 are always TGG.TAC (Trp Tyr); The second codon at the end is always CCG (Pro).

“CDR2 region” always represents 33 nt (ie 11 aa); The first three codons (aa) are therefore always CTA.TTA.ATT (Leu Leu Ile).

Framework region 3 always represents 96 nt (ie, 32 aa); The first three codons (aa) of FR3 are always GGG.GTC.CCG (Gly Val Pro); The last three codons are always TAT.TAT.TGC (Tyr Tyr Cys).

“CDR3 region” always represents 24 nt (ie 8 aa); The second codon (aa) is thus always CAG (Gln).

Framework region 4 always represents 39 nt (ie 13 aa); The same in all four families: ACC.TTT.GGC.CAG.GGT.ACG.AAA.GTT.GAA.ATT.AAA.CGT.ACG.

VL Lambda Chains:

Framework region 1 extends from nt 1-66 (ie, 22 aa); The last codon (aa) of FR1 is always TGT (Cys).

▶ “CDR1 regions” are three different lengths, 33 nt (11 aa) (in the possible Vl3 family), 39 nt (13 aa) (in the possible Vl1 family), or 42 nt (14 aa) (possible Vl1 and Vl2 ) In the series.

Framework region 2 always represents 33 nt (ie 11 aa); The first two codons (aa) of FR2 are always TGG.TAC (Trp Tyr); The last third codon is always GCG (Ala).

“CDR2 region” always represents 33 nt (ie 11 aa); Thus the third codon (aa) is always ATT (Ile); The last three codons are always CGT.CCC.TCA (Arg Pro Ser).

Framework region 3 always represents 96 nt (ie, 32 aa); The first codon (aa) of FR3 is always GGC (Gly); The last four codons are always GAT.TAT.TAT.TGC (Asp Tyr Tyr Cys).

▶ “CDR3 regions” are three different lengths, 24 nt (8 aa); 27 nt (9 aa); Or 30 nt (10 aa).

Framework region 4 always represents 39 nt (ie 13 aa); The same in all three families: GTG.TTT.GGC.GGC.GGC.ACG.AAG.TTA.ACC.GTT.CTT.GGC.CAG.

For therapeutic or diagnostic purposes, for example, polypeptides of the invention can be used for in vitro or in vivo diagnosis.

For therapeutic applications, the polypeptides of the present invention may exist in the form of conjugates with therapeutically active ingredients selected from, for example, radiation therapy or chemotherapy agents such as small molecule or biological cell growth inhibitors or cytotoxic active ingredients. . Conjugation of a therapeutically active ingredient on a polypeptide is optionally homogeneous- or hetero-bifunctional, according to known methods, preferably via covalent bonds with reactive amino, carboxy, hydroxy and / or thiol groups of the protein according to known methods. This can be done by using a linker.

In addition, the polypeptide may also exist in the form of a fusion protein containing cytokines fused thereto, such as, for example, IL2, IL12 or TNFα-polypeptide, in addition to antibodies in the form of IgG molecules or fragments thereof. In addition, the fusion protein may be in the form of a bispecific antibody, whereby in addition to binding to the ED-B domain, it is preferred to bind to another antigen. Other antibody specificities of bispecific antibodies are diagnostically and therapeutically related radionuclides such as α-, β-, or γ-emitters, eg ⁹⁰ Y, diagnostic NIR (near infrared) -dyes, therapeutic As an effective dye, surface molecules on immunological effector cells (eg, NK cells, cytotoxic T cells, or NKT cells), binding domains for chelating agents for angiogenesis-related integrins, in particular, anti-VEGF-binding domains. Binding domains that inactivate and block their action while inactivating the binding domains for VEGF receptors 1, 2, and 3 (eg, α ₁ , β ₃ , α ₁ β ₃ , α ₂ β ₁ , α ₂ β ₂ )to be.

For diagnostic applications, the polypeptide may be in the form of a conjugate of a diagnostically detectable labeling group, such as a labeling group for in vitro or in vivo diagnosis. Examples of labeling groups are radiolabeling groups, NMR-, dye-, enzyme-, and fluorescence- (eg, fluorescence in the near infrared range) labeling groups.

For therapeutic applications, the polypeptide preferably contains the polypeptide of the invention as an active ingredient and optionally contains additional active ingredients, as well as pharmaceutical, pharmaceutically acceptable vehicles, adjuvants, and / or diluents. Formulated as a composition. The pharmaceutical composition contains the active ingredient in a therapeutically effective amount that can be determined by one skilled in the art in a simple manner by, for example, in vitro testing in a suitable cell culture, or animal model. Administration of the composition is preferably carried out by injection or infusion, although other types of administration are contemplated. Intravenous and / or subcutaneous administration is preferably performed. The dosage of the active ingredient administered depends on the type and severity of the disease as well as the condition of the patient to be treated. The therapeutic composition is preferably administered several times over a long period of time, for example, 2-4 weeks or more. In this regard, see, eg, 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] may be referred to known methods of administering antibodies or antibody conjugates, eg, pharmaceutical antibodies such as Rituximab, CAMPATH, Remicade, and the like. See current administration methods for.

Another subject of the invention is a diagnostic composition comprising a polypeptide of the invention as a diagnostic reagent. In addition, the diagnostic composition may also contain additional diagnostic conventional reagents, carriers, adjuvants and / or diluents. The diagnostic composition contains a polypeptide in an amount sufficient to enable diagnostic detection in each format, such as, for example, an in vivo or in vitro diagnostic format. In this regard, reference may be made to known in vivo and in vitro diagnostic methods using labeled antibodies.

Pharmaceutical and diagnostic compositions may be for the treatment and diagnosis of all diseases involving ED-B expression, eg, epilepsy and / or perivascular ED-B expression. Examples of such diseases include hyperproliferative diseases, such as those associated with angiogenesis, in particular cancers, fundus diseases, hypertrophic scars, etc., diseases associated with myofibroblast dysfunction, such as endometriosis, atherosclerotic plaques, or inflammation. Diseases such as psoriasis, Crohn's disease, rheumatoid arthritis or multiple sclerosis.

Pharmaceutical and diagnostic compositions according to the invention may contain one or more active polypeptides, such as combinations of polypeptides, which bind to other sites of the ED-B domain. The composition is suitable for use in human and veterinary medicine.

Another subject of the invention is a nucleic acid encoding a peptide or fusion polypeptide according to the invention. Such nucleic acids may be single-stranded or double-stranded DNA or RNA. The nucleic acid is preferably operably linked to an expression control sequence so that it can be expressed in a suitable host cell or in a suitable host organism. The nucleic acid may be present on a vector suitable for introduction into the host cell or host organism. The vector can be, for example, a prokaryotic vector suitable for prokaryotic cell introduction, such as a plasmid or bacteriophage. In contrast, the vector can also be a eukaryotic vector suitable for introduction into a eukaryotic host cell or host organism, such as a plasmid, artificial chromosome or viral vector. Suitable vectors include (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). As is known to those skilled in the art.

Still another subject of the invention are cells transformed with a nucleic acid according to the invention or a vector according to the invention, such as prokaryotic or eukaryotic cells, such as human cells. Another subject of the invention is an organism other than a human, such as a transgenic animal, transformed with a nucleic acid according to the invention or a vector according to the invention. In this regard, the term “transformation” within the scope of the present invention includes all possibilities of introducing the nucleic acid into a cell or organism, including transfection or infection.

The polypeptide of the present invention is cultured in a cell according to the present invention or an organism other than a human according to the present invention under conditions in which the polypeptide can be expressed, and then the expressed polypeptide is secreted, for example, in a cell, a culture medium, an organism or an organism. By obtaining from the product.

In addition, the invention will be explained through the following figures and examples:

1 depicts a graphical implementation of an inhibition test that identifies functionally active antibodies.

Human endothelial cells (human dermal microvascular endothelial cells, HDMVEc) obtained from skin microvessels were incubated with ED-B-specific Fab-antibody fragments. The number of bound cells is visually determined by crystal violet staining and measured with a photometer. High color intensity means there are many adherent cells and no binding-blocking antibodies. Low color intensity means little adhesion and the presence of binding-blocking antibodies.

2 shows a screening diagram to identify ED-B-fibronectin-acting-blocking antibodies by means of Fab-fragment display.

In the first step, a panning method is performed using recombinant ED-B. Antibody fragments obtained in this way are used for specificity tests (ELISA), functional adhesion tests, as well as immunohistochemical studies. Then, the affinity of the antibodies for performing these tests is determined. It is then changed in the CDR domain for affinity improvement, where affinity maturation 1 means a change in the L-CDR3 domain and affinity maturation 2 means a change in the H-CDR2 domain.

Once the antibody obtained by affinity maturation passes the above-mentioned test, it is tested for efficacy in vivo.

3 shows the results of specificity tests in ELISA format using antibody-Fab fragments produced by panning with recombinant ED-B.

ED-B means binding to recombinant ED-B, 6-FN means binding to recombinant fibronectin-domain 6, domains 7-8-9 are recombinant fibronectin domains 7-8-9 (ED-B Does not include), and domain 7-ED-B-8-9 means binding to recombinant fibronectin domain 7-8-9 including ED-B. The specificity of the antibody under study can be determined by the ratio of ED-B to 6-FN and / or 7-8-9. AAP-39 refers to a covalent dimer of biologically inactive anti-ED-B scFv antibody L19.

4 shows the adhesion test results using the antibody under study.

Attachment of HDMVEc cells to ED-B-coated plates was studied for inhibition by indicated Fab fragments at 25 μg / ml or 0.4 μg / ml Fab concentrations. The indication is the result of three measurements.

5 shows immunohistochemical response patterns of action-blocking anti-ED-B-Fab fragments as an example of MOR 02616. Figures 5A and 5C show results using a negative control (negative HuCAL Fab), Figures 5B and 5D show human neuroblastoma cell-IRM xenograft organs (Figures 5A and 5B) as well as murine F9-teratocarcinoma cells (Figures 5C and Results of using antibody MOR 02616 on 5D) are shown.

Frozen sections of cells (thickness: 10 μm) were air dried and then fixed in ice cold acetone for 10 minutes. Sections were then washed with PBS and incubated with 2 μg / ml of MOR 02616 or negative control for 60 minutes at room temperature. Peroxidase-labeled polyclonal goat anti-human F (ab) ₂ antiserum (diluted 1: 100 in PBS, Dianova) as secondary antibody, diaminobenzidine (Sigma Chemicals) as a chromogenic substrate (Sigma Chemicals)).

6 shows the results of specificity tests in ELISA format using antibody Fab fragments optimized by maturation.

The test method is as described in FIG. 3.

7 shows immune tissue of antibody Fab fragment MOR 03255 optimized by maturation on cryosections of F9-teratocarcinoma cells (FIG. 7A) and by maturation on hairless SKMEL-28 human-melanoma cell xenograft organs (7B). Chemical reaction patterns.

The test method is as described in FIG. 5.

8 shows the results of adhesion tests using antibody Fab fragments according to the invention as compared to comparative antibodies L19 and Ly6 0.3.

The test method is described very similarly in FIG. Antibody concentrations were 1 μl / ml, 10 μl / ml or 20 μl / ml.

9 shows the stability of the antibody-Fab fragments of the invention after incubation in human plasma or PBS for 4 hours at 37 ° C.

Immune reactivity was measured in the ELISA test using concentrations ranging from 0.039 to 5 μg / ml. The signal when 0.62 μg / ml in human plasma without incubation was defined as a 100% value.

10 shows the therapeutic efficacy of anti-ED-B-acting-blocking Fab-antibody fragments as an example of MOR 03255.

11 shows the nucleotide sequences encoding the VH and VL regions of antibodies according to the invention.

1. Materials and Methods

1.1 Proteins and Antibodies

Purified recombinant fibronectin domain ED-B (His) ₆ , fibronectin domain 6 (6FN), fibronectin domain 7-8-9 and domain 7-ED-B-8-9 were standard methods (eg, Sambrook et al., Molecular Cloning.A Laboratory Manual, Cold Spring Harbor Press].

Mouse Antibodies to Purified ED-B Receptors Also, according to standard methods, 50 μg of purified receptor in Freund's complete adjuvant was administered to mice and 25 μg of purified receptor in Freund's incomplete adjuvant three weeks later. And after three additional weeks all applications in Freund's incomplete adjuvant were administered intraperitoneally. Subsequently, blood was collected through orbital sinus 14 days after the third immunization.

Plasma fibronectin was ordered from Sigma.

1.2 ED -B specific phage selection

The selection was carried out according to the selected HuCAL ^® Gold phage (HuCAL ^® Gold phage) protocol. The HuCAL ^® Gold Library was subdivided into six framework-specific pools. ED-B-specific phages were concentrated by three consecutive selection of recombinant proteins immobilized on 96-hole plates (Maxisorb, Rochester Nunk, NY). For panning A it was coated plates at 37 ℃ for 2 hours with 1 ㎍ / hole _{ED-B (His 6) (} 10 ㎍ / ml of the ampu ^® (Ampuwa ^®)). Panning B MgCl in PBS (pH 7.2, 1 mmol in 4 ℃ overnight the plate to the _2/1 mmol of CaCl _2, And ED-B at the same concentration. Plates were blocked with 5% skim milk powder in PBS, 0.05% Tween20 (Sigma, St. Louis, MO) (blocking buffer) and with 1 x 10 ¹³ HuCAL ^® gold phage preincubated with large amount of blocking buffer. Incubate. Panning B was further preincubated with 0.5 μg / ml of fibronectin-domain 6 to reduce the selection of binding molecules specific for the conserved structure of the type 3 domain repeat of fibronectin. After incubation with phage for 2 hours at room temperature, washed 5 times with PBS, 0.05% Tween20 and 5 times with PBS. The remaining phage eluted with 20 mmol of dithiothreitol (DTT) in 10 mmol of Tris / HCl, pH 8.0 for 10 minutes. It was then incubated with E. Coli TG-1 (Stratagene, OD ₆₀₀ = 0.5) for infection. The hole was then incubated with E. coli TG-1 as an additional elution step.

1.3 Phagemid  Recovery, phage propagation and purification

HuCAL ^® gold phages were grown in 2xTY medium (2xTY-CG) containing 34 μg / ml chloramphenicol and 1% glucose. Infected with adjuvant phage (VCSM 13) at 37 ° C. with an OD ₆₀₀ of about 0.5, then centrifuged, resuspended in 2 × TY-CG / 50 μg / ml kanamycin, and induced cells with 0.25 mmol of IPTG, Incubate overnight at 22 ° C. Polyethylene glycol was used to precipitate phage from the supernatant and [Ausubel et al. (1998), Current Protocols of Microbiology), resuspended in PBS and used for selection of the next round.

1.4 selected Fab  Short Subcloning  And availability Fab  Expression of fragments

Fab-encoding inserts of selected HuCAL ^® gold phage were subcloned in the expression vector pMORPHx9-FS. Plasmid-DNA preparations of selected HuCAL ^® gold clones were digested with restriction enzymes XbalI / EcoRI to cut Fab-encoding inserts (ompA-VL and phoA-Fd). Fab molecules expressed in such vectors contain two C-terminal labels (FLAG ™ and Strep-tagII) for detection and purification.

1.5 E. In Coli Hucal ^®  Expression and Purification of Gold Antibodies

Expression of TG-1 F cells on pMORPHx9-FS-encoded Fab fragments in E. coli was performed in shake culture bottle cultures containing 0.75 L of 2xTY medium and 34 μg / ml chloramphenicol. After induction with 0.75 mmol IPTG, cells were incubated at 30 ° C. for 16 hours. As an alternative, Fab clones obtained from the second mature pool 2 were induced with 0.1 mmol IPTG and then cultured at 22 ° C. Was isolated by (IBA located at a Göttingen, Germany) taktin ^® (Strep-Tactin ^®) chromatography of the extracellular plasma membrane from the pellet extracts are prepared by the osmotic pressure shock, and Fab fragments streptavidin. The apparent molecular weight was determined by size-exclusion chromatography (SEC) with calibration criteria. Concentration was measured by UV spectroscopy.

1.6 ELISA On by ED -B combine Fab Short sympathy

96-hole-Maxisorb ELISA plates were coated overnight at 4 ° C. with 100 μl of ED-B solution (10 μg / ml in coating buffer (PBS pH 7.4, 1 mmol CaCl ₂ , 1 mmol MgCl ₂ )). Add crude lysate or purified Fab molecules; Non-binding Fab molecules were removed by washing five times with wash buffer (PBS pH 7.4, 0.05% Tween20). Fab fragments were detected by incubation with anti-human-Fab-antibody-peroxidase-conjugate (Dianova), run with soluble peroxidase substrate (Roche), and measured at 370 nm. Clones expressing ED-B-specific Fab molecules by positive ELISA signals on immobilized ED-B versus little or no signal at 6FN were identified.

1.7 ELISA Measurement of plasma stability under physiological temperature conditions

Essentially coated with ED-B (2.5 μg / ml) as described above. Fab fragments were incubated at 37 ° C. for 4 hours at a concentration of 50 μg / ml in human plasma (German Red Cross; Batch 9985550). After incubation, Fab molecules were measured at concentrations of 5.0, 2.5, 1.25, 0.62, 0.31, 0.156, 0.078 and 0.039 μg / ml in PBS containing 1% bovine serum albumin for ELISA testing to determine the linear range of signal intensity. Diluted. Functional Fab molecules were determined by developing with Attophos (Roche) and measuring at 535 nm using anti-flag M2 antibody (Sigma F3165) and a secondary anti-mouse-antibody-alkaline phosphatase conjugate.

1.8 HDMVEc  Cell culture and cell adhesion test

Human dermal microvascular endothelial cells (HDMVEc) isolated from pediatric foreskin contain 10% fetal bovine serum, 2 mmol glutamine, 20 μg / ml heparin and 3 ng / ml bFGF, and 0.1% gelatin (Sigma) Incubated in EGM-MV medium (Clonetics Inc.) coated with. For the adhesion test, cells that were not cultured at least 8 passages were used. ED-B (10 μg / ml) or plasma fibronectin (2.5 μg / ml) in PBS pH 7.4, 0.9 mmol CaCl ₂ , 0.5 mmol MgCl ₂ was fixed overnight at 4 ° C. in a 96-hole ELISA plate and for 1 hour. Blocked at 37 ° C. with 1% RSA in PBS pH 7.4, 0.9 mmol CaCl ₂ , 0.5 mmol MgCl ₂ . Cells were labeled with 0.15 μg / ml calcein at 37 ° C. for 30 minutes and washed once in adherent medium (MCDB 131, 2 mmol glutamine, 0.1% RSA, 20 μg / ml heparin). 1 × 10 ⁵ cells were incubated for 20 minutes at 37 ° C. with the antibody with the concentrations indicated in each case and diluted in adherent medium (final volume 100 μl). The cell suspension was added to ED-B-coated plates at 37 ° C. for 2 hours. After washing the cells twice in PBS pH 7.4, 0.9 mmol CaCl ₂ , 0.5 mmol MgCl ₂ , adherent cells were detected on a plate fluorimeter (excitation 485 nm; emission 530 nm).

As a control, cells bound to ligand-coated plates (A) were measured without the addition of specific antibodies, and (B) cell adhesion to the holes was measured without ligand coating, whereby the values obtained in the last mentioned control were determined in this test. It was defined as the minimum value of cell adhesion at.

1.9 step by step CDR  Selected by cassette exchange Fab  Affinity Maturation of Molecules

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

For this reason, Fab fragments from expression vector pMORPHx9 in phagemid vector pMORPH-23 were cloned using EcoRI / Xbal restriction sites. To optimize the affinity of the selected Fab fragments, two successive maturation steps were performed for each maturation pool. In a first step, an antibody fragment-phage library was prepared in which the L-CDR3 region of the starting clone was modified by 7 x 10 ⁸ (pool 1) and 3.8 x 10 ⁸ (pool 2) individual light chain-CDR sequence repertoires. . Derivatives with improved affinity from the first maturation stage were then exposed to second round maturation by the H-CDR2 region replaced by a library of diversified elements. In this way, two phage libraries with 1 x 10 ⁸ individual clones in each case were made.

Affinity maturation libraries were prepared by transformation with E. coli TOP10F. Phage were prepared as described above. Fab fragments with improved affinity were selected under stringent conditions three times in the first maturation and two times in the second stage.

1.10 surface Plasmon  Resonance ( Viacore ^® Affinity measurement by

Monomer fractions of Fab fragments (monomer content of 80% or higher as determined by analytical SEC (Superdex75, Amersham Pharmacia)) were used to determine K _D values. The F1-chip (Biacore, Sweden) was coated with about 200 RU ED-B (30 μg / ml, 10 mmol acetate buffer, pH 4.0) using standard EDC-NHS-amino-coupling chemistry, Reference flow cells were coated with the corresponding amount of human serum albumin (20 μg / ml, 10 mmol acetate buffer, pH 4.5). Antigen density decreased to about 100 RU for Fab characterization of the second maturation. Regeneration with 10 mmol HCl. All kinetics were measured in PBS buffer (136 mmol NaCl, 2.7 mmol KCl, 10 mmol Na ₂ HPO ₄ , 1.76 mmol KH ₂ PO ₄ pH 7.4) using a Fab concentration range of 1.5-500 nmol at a flow rate of 20 μl / min. It was. In each case the infusion period was 1 minute. All sensorgrams were evaluated using BIA evaluation software 3.1.

Abbreviation: EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, NHS: N-hydroxysuccinimide, RU: resonance unit

2. Results

2.1 Human ED Antibody Production Against -B

Two different panning assays were performed. It was coated with ED-B for the first assay (Panning A) according to conditions known from biological tests showing ED-B as confirmation that HDMVEc cells could attach to immobilized antigen. For the second panning (B), further phage was blocked by the addition of excess 6FN to prevent the selection of binding molecules that cross-react with fibronectin-domain 6.

In total, 23 different HuCAL-Fab molecules have been found that meet the conditions of binding to ED-B but not to 6FN from 1315 primary hits. In addition, antibodies were tested for their ability to bind recombinantly expressed fibronectin, including domains 7, 8, and 9, with or without the ED-B domain inserted in their natural arrangement (FIG. 3). All of the antibodies tested were shown to specifically recognize the 7-ED-B-8-9 construct, but did not react with the corresponding construct without the ED-B domain.

2.2 ED Functional phase of a -B specific binding molecule Characterization

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

Twelve of the 23 molecules described in section 2.1 have been shown to inhibit cell adhesion in immobilized ED-B. Representative selectivity of the six most effective Fab molecules is shown in FIG. 6. At concentrations of 25 μg / ml, cell adhesion was inhibited by 50% to almost 100%. At concentrations of 0.4 μg / ml only a few Fab molecules, for example MOR02610. Only MOR02616, MOR02715 and MOR02718 have been shown to reproducibly inhibit cell adhesion.

The action-blocking Fab-antibody fragments were characterized immunohistochemically in connection with their localization on F9-mouse-teratoma carcinoma cells and human IRM30 neuroblastoma-xenograft tracheotomy sections. All of the antibodies tested showed vascular localization on two tissue sections, while no blood vessels were stained on normal tissues (eg, colon and sclerotic liver and skin). 5B and 5D, MOR 02616 shows staining of the abdominal area in the lumen perivascular of blood vessels, indicating proliferation of endothelial and tumor stroma. Except for normal blood vessels, ED-B collections around the neovascular structure of exponentially growing tumors can be detected. No staining was observed for negative control antibodies against the same concentration of lysozyme (FIGS. 5A and 5C).

The properties of the 12 selected binding molecules were determined by Biacore analysis (see Table 1). Affinity (K _on ) ranged from 15 to 50 nmol. The affinity of the bivalent L19 derivative AP39 (comparative antibody biologically inactive to ED-B) was determined to be 2.4 nmol. Table 1 also shows the CDR sequences (only L-CDR3 and H-CDR3) and framework combinations. Fab molecules from different batches were independently measured two or more times for protein expression and protein purification. The binding rate (K _on ) and dissociation rate (K _off ) of the Fab molecule are shown in separate columns.

Table 1

2.3 L- CDR3  And H- CDR2  Action by optimization of domain Blockability ED Affinity Maturation of -B- Antibodies

Affinity maturation of Fab molecules was carried out in two steps. First, the L-CDR3 sequence was diversified, and then the H-CDR2 sequence of the improved Fab molecule obtained in the first step was exchanged.

Two affinity maturation libraries were prepared for each step. Optimization was performed in two separate pools. L-CDR3 Library 1 with a diversity of 7 × 10 ⁸ elements shows four starting Fab molecules MOR02610. MOR02616, MOR02619 and MOR02622 were contained. L-CDR3 Library 2 with a diversity of 3.8 × 10 ⁸ elements contained only derivatives of MOR02715 and MOR02718. Thus, Fab molecules were combined in groups in each case according to their affinity and biological activity in the adhesion test.

The two libraries were kept separate during the selection process. In this case, two panning strategies were performed. As indicated above, panning I was performed using ED-B immobilized on the maxisorb plate for three rounds. For Panning II, the selection of biotinylated ED-B in solution was performed. In this case, the phage-antigen complex was recovered by streptavidin-coated particles in round 1 and on neutravidin in two consecutive rounds. Stringent conditions were used within the scope of the selection process.

K _off values were measured in Biacore systems to perform screening on optimized Fab molecules. In total, eleven derivatives of Library I were characterized. The five derivatives with the highest affinity are shown in Table 2. In this case, all of the improved clones were derivatives of MOR02619 and the affinity increased to 7 ×. The affinity in clone MOR03075 was found to be 2.4 nmol.

Two derivatives of MOR02715 from Library 2 were analyzed in detail. For clone MOR03062 it was found that the affinity was increased by 15-fold, thereby obtaining a monomer affinity of 2.4 nm. Changes in the amino acid sequence of the L-CDR3 region are shown in Tables 2a and 2b.

Table 2a

Table 2b

The specificity for ED-B (measured by ELISA, immunohistochemistry and cell adhesion test) of all derivatives from the first round of maturation remained unchanged.

The Fab molecules shown in Tables 2a and 2b were selected for the next H-CDR2 maturation from the two pools. Five Fab molecules in pool 1 had similar activity, but had different L-CDR3 regions in diversified H-CDR2 (library size 7 × 10 ⁷ elements). For pool 2 (library size 8.5 × 10 ⁷ elements) two Fabs were selected. Libraries were selected separately as described above. Under stringent conditions, binding molecules with increased affinity were concentrated by two rounds of panning in solution.

Three Fab molecules were selected from pool 1. For the derivatives MOR03243 and MOR03245, the affinity was found to be about 0.7 nmol. For the derivative MOR03246, the affinity was found to be about 0.6 nmol.

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

Table 3a

Derivatives with improved properties can also be selected from pool 2. Compared to the parent clone, the affinity of the derivative was improved 26 times to 250x. The affinity of clones MOR03255 and MOR03258 was determined to be 30 pM or 40 pM.

Table 3b shows the H-CDR2 amino acid sequence of the clones selected from pool 2, as well as the corresponding affinity data.

Table 3b

2.4 Highly Affinity Action-Blocking ED -B-antibody Characterization

Specificity tests (FIG. 6), immunohistochemical studies (FIG. 7) and adhesion tests (FIG. 8) were conducted in ELISA format to test whether antibodies obtained by affinity maturation are always specific for ED-B. . In all three tests the specificity of the affinity-matured Fab molecule for ED-B was found to be unchanged. In addition, both parent clones, such as, for example, MOR 02715, and clones produced by affinity maturation, such as, for example, MOR 03062, MOR 03255, MOR 03064, and MOR 03259, both are more significant than the known antibody L19. It was demonstrated from FIG. 8 that it has higher biological activity (adhesion inhibition).

In addition, the thermal stability of Fab molecules in human plasma was tested. For this, Fab molecules were incubated with human plasma for 4 hours at 37 ° C., as determined by ELISA, and found to be no significant loss in immunoreactivity (FIG. 9).

All of the selected Fab molecules can block the interaction of human microvascular endothelial cells with receptors on ED-B in a dose-dependent manner, which is a property without known ED-B-antibody L19. Since the attachment of HDMVEc to the extracellular matrix is one of the early stages of new angiogenesis, blocking the process by the binding molecule according to the present invention is to prepare a therapeutic agent that inhibits the formation of new blood vessels and inhibits tumor growth. .

2.5 In vivo  Action

F9-teratocarcinoma cells (10 ⁶ / mouse in Matrigel with or without 100 μg Fab MOR 03255) were sc implanted into the flanks of hairless mice. After 3 days, animals were treated with 100 μg MOR03255 / mouse in each case for 7 consecutive days. Both treatment groups were shown to inhibit tumor growth in the 42-64% range compared to the solvent control. A summary of the test results is shown in FIG. 10.

Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Therefore, the specific preferred embodiments above are merely exemplary and should not be construed as limiting the remainder of the disclosure in any way.

All temperatures in the above description and examples are given in degrees Celsius without correction, and unless stated otherwise all parts and percentages are parts by weight and percentages by weight.

All applications, patents, and publications cited herein and the corresponding German application number 102004050101.7 filed October 14, 2005 and US provisional serial number 60 / 697,565, filed July 11, 2005, are incorporated herein by reference.

This example can be similarly successfully repeated by substituting the reactants and / or operating conditions generally or specifically described in the present invention in place of those used in the above examples.

From the above detailed description, those skilled in the art can easily identify the essential features of the present invention, and various changes and modifications of the present invention can be made to suit various uses and conditions without departing from the spirit and scope thereof.

literature

<110> APPLICANT: Schering Aktiengesellschaft <120> TITLE OF A: Identification and Characterization of Function-Blocking       Anti-ED-B-Fibronectin Antibodies <130> FILE REFERENCE: 33042P DE (WWHC) <140> CURRENT APPLICATION NUMBER: US / 11 / 249,296 <141> CURRENT FILING DATE: 2005-10-14 <160> NUMBER OF SEQ ID NOS: 90 <170> SOFTWARE: Patent In Ver. 2.1 <210> SEQ ID NO 1 <211> LENGTH: 354 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (354) 223 OTHER INFORMATION: Antibody-VH-Region; MOR02610 <400> SEQUENCE: 1       cag gtg caa ttg gtt cag agc ggc gcg gaa gtg aaa aaa ccg ggc gcg 48       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       agc gtg aaa gtg agc tgc aaa gcc 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 cgc caa gcc cct ggg cag ggt ctc gag tgg atg 144       Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       ggc tgg atc aat ccg tat tct ggc aat acg cgt tac gcg cag aag ttt 192       Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gln Lys Phe            50 55 60       cag ggc cgg gtg acc atg acc cgt gat acc agc att agc acc gcg tat 240       Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr        65 70 75 80       atg gaa ctg agc agc ctg cgt agc gaa gat acg gcc 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 tct 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 Gln Gly Thr                   100 105 110       ctg gtg acg gtt agc tca 354       Leu Val Thr Val Ser Ser               115 <210> SEQ ID NO 2 <211> LENGTH: 118 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 2       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe                    20 25 30       Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gln Lys Phe            50 55 60       Gln Gly Arg Val 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 Gln Gly Thr                   100 105 110       Leu Val Thr Val Ser Ser               115 <210> SEQ ID NO 3 <211> LENGTH: 336 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (336) 223 OTHER INFORMATION: Antibody-VL Region; MOR02610 <400> SEQUENCE: 3       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc ggc aac att ggt att aat 96       Arg Val 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 144       Phe Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat aag aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Lys Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc cag tct tat gat aag act tct 288       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Lys Thr Ser                        85 90 95       tct act tat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 336       Ser Thr Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 4 <211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 4       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Gly Asn Ile Gly Ile Asn                    20 25 30       Phe Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Lys Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Lys Thr Ser                        85 90 95       Ser Thr Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 5 <211> LENGTH: 351 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (351) 223 OTHER INFORMATION: Antibody-VH Region; MOR02611 <400> SEQUENCE: 5       cag gtg caa ttg gtt cag agc ggc gcg gaa gtg aaa aaa ccg ggc gcg 48       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       agc gtg aaa gtg agc tgc aaa gcc tcc gga tat acc ttt tct ggt tct 96       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Gly Ser                    20 25 30       tat atg cat tgg gtc cgc caa gcc cct ggg cag ggt ctc gag tgg atg 144       Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       ggc att atc aat ccg gct tct ggc aag acg ctt tac gcg cag aag ttt 192       Gly Ile Ile Asn Pro Ala Ser Gly Lys Thr Leu Tyr Ala Gln Lys Phe            50 55 60       cag ggc cgg gtg acc atg acc cgt gat acc agc att agc acc gcg tat 240       Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr        65 70 75 80       atg gaa ctg agc agc ctg cgt agc gaa gat acg gcc 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 tct tgg ggc caa ggc acc ctg 336       Ala Arg Gly Leu Tyr Tyr Arg Phe Ala Ser Trp Gly Gln Gly Thr Leu                   100 105 110       gtg acg gtt agc tca 351       Val Thr Val Ser Ser               115 <210> SEQ ID NO 6 <211> LENGTH: 117 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 6       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Gly Ser                    20 25 30       Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       Gly Ile Ile Asn Pro Ala Ser Gly Lys Thr Leu Tyr Ala Gln Lys Phe            50 55 60       Gln Gly Arg Val 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 Gly Leu Tyr Tyr Arg Phe Ala Ser Trp Gly Gln Gly Thr Leu                   100 105 110       Val Thr Val Ser Ser               115 <210> SEQ ID NO 7 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (327) 223 OTHER INFORMATION: Antibody-VL Region; MOR02611 <400> SEQUENCE: 7       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc 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 tct gtg tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       His Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat cgt tct aat cgt ccc tca ggc gtg agc aac cgt ttt agc 192       Met Ile Tyr Arg Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser            50 55 60       gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc ggc ctg caa 240       Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln        65 70 75 80       gcg gaa gac gaa gcg 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                        85 90 95       gtg ttt ggc ggc ggc acg aat tta acc gtt ctt ggc cag 327       Val Phe Gly Gly Gly Thr Asn Leu Thr Val Leu Gly Gln                   100 105 <210> SEQ ID NO 8 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 8       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr                    20 25 30       His Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Arg Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln        65 70 75 80       Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Ala Thr Gly Gly Trp                        85 90 95       Val Phe Gly Gly Gly Thr Asn Leu Thr Val Leu Gly Gln                   100 105 <210> SEQ ID NO 9 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR02613 <400> SEQUENCE: 9       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct aat tat 96       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr                    20 25 30       act atg act tgg gtg cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc ttt atc att ggt tct ggt agc aat acc tct tat gcg gat agc gtg 192       Ser Phe Ile Ile Gly Ser Gly Ser Asn Thr Ser Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt tat gtt aat ggt ttt gat att tgg ggc caa ggc acc ctg gtg 336       Ala Arg Tyr Val Asn Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 10 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 10       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr                    20 25 30       Thr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Phe Ile Ile Gly Ser Gly Ser Asn Thr Ser Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Tyr Val Asn Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 11 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VL Region; MOR02613 <400> SEQUENCE: 11       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc gat gtt ggt gtt tat 96       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Val Tyr                    20 25 30       tat tat gtg tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       Tyr Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat tat gat tct aag cgt ccc tca ggc gtg agc aac cgt ttt 192       Met Ile Tyr Tyr Asp Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe            50 55 60       agc gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln 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 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       cag 339       Gln <210> SEQ ID NO 12 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 12       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Val Tyr                    20 25 30       Tyr Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Tyr Asp Ser Lys Arg Pro Ser Gly Val Ser 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr Ala Lys Lys                        85 90 95       Asp Tyr Ser Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       Gln <210> SEQ ID NO 13 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VH Region; MOR02614 <400> SEQUENCE: 13       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc ttt atc tct ggt tct ggt agc cat acc tat tat gcg gat agc gtg 192       Ser Phe Ile Ser Gly Ser Gly Ser His Thr Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt gct tat gat gtt tgg ggc caa ggc acc ctg gtg acg gtt agc 336       Ala Arg Ala Tyr Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser                   100 105 110       tca 339       Ser <210> SEQ ID NO 14 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 14       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Asn                    20 25 30       Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Phe Ile Ser Gly Ser Gly Ser His Thr Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Ala Tyr Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser                   100 105 110       Ser <210> SEQ ID NO 15 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (327) 223 OTHER INFORMATION: Antibody-VL Region; MOR02614 <400> SEQUENCE: 15       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt ttt aat 96       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Phe Asn                    20 25 30       tat gtg aat tgg tac cag cag ttg ccc ggg acg gcg ccg aaa ctt ctg 144       Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat ggt aat tct aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Gly Asn Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc gct atg ttt tct cct gag ggt 288       Ser 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 tta acc gtt ctt ggc cag 327       Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 <210> SEQ ID NO 16 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 16       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Phe Asn                    20 25 30       Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Gly Asn Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Met Phe Ser Pro Glu Gly                        85 90 95       Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 <210> SEQ ID NO 17 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR02616 <400> SEQUENCE: 17       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gct atc tct tct tct ggt agc ggt acc tat tat gcg gat agc gtg 192       Ser Ala Ile Ser Ser Ser Gly Ser Gly Thr Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln 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 Val Ile Val Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 18 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 18       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Asn                    20 25 30       Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Ala Ile Ser Ser Ser Gly Ser Gly Thr Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Val Ile Val Leu Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 19 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (327) 223 OTHER INFORMATION: Antibody-VL Region; MOR02616 <400> SEQUENCE: 19       gat atc gtg ctg acc cag agc ccg gcg acc ctg agc ctg tct ccg ggc 48       Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly         1 5 10 15       gaa cgt gcg acc ctg agc tgc aga gcg agc cag aat gtt cgt tct aat 96       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Val Arg Ser Asn                    20 25 30       ctg gct tgg tac cag cag aaa cca ggt caa gca ccg cgt cta tta att 144       Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile                35 40 45       tat ggt gct tct aat cgt gca act ggg gtc ccg gcg cgt ttt agc ggc 192       Tyr Gly 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 agc agc 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 Gln Lys Tyr Ser Ile Pro Phe                        85 90 95       acc ttt ggc cag ggt acg aaa gtt gaa att aaa cgt acg 327       Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr                   100 105 <210> SEQ ID NO 20 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 20       Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly         1 5 10 15       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Val Arg Ser Asn                    20 25 30       Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile                35 40 45       Tyr Gly Ala Ser Asn Arg Ala Thr Gly Val 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 Gln Lys Tyr Ser Ile Pro Phe                        85 90 95       Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr                   100 105 <210> SEQ ID NO 21 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR02618 <400> SEQUENCE: 21       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt aat 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc tct atc tat ggt tat ggt agc aat acc tat tat gcg gat agc gtg 192       Ser Ser Ile Tyr Gly Tyr Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat tat tgg gtt ttt gct tat tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Tyr Trp Val Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 22 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 22       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asn Tyr                    20 25 30       Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Ser Ile Tyr Gly Tyr Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Tyr Trp Val Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 23 <211> LENGTH: 330 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (330) 223 OTHER INFORMATION: Antibody-VL Region; MOR02618 <400> SEQUENCE: 23       gat atc gaa ctg acc cag ccg cct tca gtg agc gtt gca cca ggt cag 48       Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln         1 5 10 15       acc gcg cgt atc tcg tgt agc ggc gat aat att cct ggt aag tct gtt 96       Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Pro Gly Lys Ser Val                    20 25 30       cat tgg tac cag cag aaa ccc ggg cag gcg cca gtt ctt gtg att tat 144       His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr                35 40 45       ggt aag atg aat cgt ccc tca ggc atc ccg gaa cgc ttt agc gga tcc 192       Gly Lys Met Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser            50 55 60       aac agc ggc aac acc gcg acc ctg acc att agc ggc act cag gcg gaa 240       Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu        65 70 75 80       gac gaa gcg gat tat tat tgc cag tct tat gat aat ttt aat gat tct 288       Asp Glu Ala Asp Tyr Tyr Cys Gln 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 330       Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 24 <211> LENGTH: 110 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 24       Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ala Pro Gly Gln         1 5 10 15       Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Pro Gly Lys Ser Val                    20 25 30       His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr                35 40 45       Gly Lys Met Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser            50 55 60       Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu        65 70 75 80       Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Asn Phe Asn Asp Ser                        85 90 95       Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 25 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS <222> LOCATION: (1) .. (333) 223 OTHER INFORMATION: Antibody-VH Region; MOR02619 <400> SEQUENCE: 25       cag gtg caa ttg caa gaa agt ggt ccg ggc ctg gtg aaa ccg ggc gaa 48       Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu         1 5 10 15       acc ctg agc ctg acc tgc acc gtt tcc gga ggc agc att tct tct tat 96       Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr                    20 25 30       tat tgg tct tgg att cgc cag gcc cct ggg aag ggt ctc gag tgg att 144       Tyr Trp Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile                35 40 45       ggc atc ggt cat tgg ggc tct acc cag tat aat ccg agc ctg aaa ggc 192       Gly Ile Gly His Trp Gly Ser Thr Gln Tyr Asn Pro Ser Leu Lys Gly            50 55 60       cgg gtg acc att agc gtt gat act tcg aaa aac cag ttt agc ctg aaa 240       Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys        65 70 75 80       ctg agc agc gtg acg gcg gaa gat acg gcc gtg tat tat tgc gcg cgt 288       Leu Ser Ser Val Thr Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg                        85 90 95       ttt ttt gat gtt tgg ggc caa ggc acc ctg gtg acg gtt agc tca 333       Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                   100 105 110 <210> SEQ ID NO 26 <211> LENGTH: 111 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 26       Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu         1 5 10 15       Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr                    20 25 30       Tyr Trp Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile                35 40 45       Gly Ile Gly His Trp Gly Ser Thr Gln Tyr Asn Pro Ser Leu Lys Gly            50 55 60       Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys        65 70 75 80       Leu Ser Ser Val Thr Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg                        85 90 95       Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                   100 105 110 <210> SEQ ID NO 27 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS <222> LOCATION: (1) .. (333) 223 OTHER INFORMATION: Antibody-VL Region; MOR02619 <400> SEQUENCE: 27       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc cag tct tgg gat ggt gct tct 288       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Gly Ala Ser                        85 90 95       act ggt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 333       Thr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 28 <211> LENGTH: 111 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 28       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Gly Ala Ser                        85 90 95       Thr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 29 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR02622 <400> SEQUENCE: 29       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc ggt atc tct tac aag tct agc tct acc tat tat gcg gat agc gtg 192       Ser Gly Ile Ser Tyr Lys Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt ggt ctt gtt act ttt gat aat tgg ggc caa ggc acc ctg gtg 336       Ala Arg Gly Leu Val Thr Phe Asp Asn Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 30 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 30       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr                    20 25 30       Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Gly Ile Ser Tyr Lys Ser Ser Ser Thr Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Gly Leu Val Thr Phe Asp Asn Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 31 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VL Region; MOR02622 <400> SEQUENCE: 31       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc gat ggt ggt act tat 96       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Thr Tyr                    20 25 30       aat ttt gtg tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat cgt gtt tct aat cgt ccc tca ggc gtg agc aac cgt ttt 192       Met Ile Tyr Arg Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe            50 55 60       agc gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc 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 tct tct tgg act cat tct 288       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Trp Thr His Ser                        85 90 95       ttt act gat tat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336       Phe Thr Asp Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       cag 339       Gln <210> SEQ ID NO 32 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 32       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Thr Tyr                    20 25 30       Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Arg Val Ser Asn Arg Pro Ser Gly Val Ser 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Trp Thr His Ser                        85 90 95       Phe Thr Asp Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       Gln <210> SEQ ID NO 33 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR02715 <400> SEQUENCE: 33       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt atc tct tct tct ggt agc tat atc tat tat gcg gat agc gtg 192       Ser Val Ile Ser Ser Ser Gly Ser Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 34 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 34       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val Ile Ser Ser Ser Gly Ser Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 35 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VL Region; MOR02715 <400> SEQUENCE: 35       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc gat 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 tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat tat gtt cat aag cgt ccc tca ggc gtg agc aac cgt ttt 192       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser Asn Arg Phe            50 55 60       agc gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Asn Gln                        85 90 95       ggt atg aag tat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336       Gly Met Lys Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       cag 339       Gln <210> SEQ ID NO 36 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 36       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr                    20 25 30       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Asn Gln                        85 90 95       Gly Met Lys Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       Gln <210> SEQ ID NO 37 <211> LENGTH: 345 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (345) 223 OTHER INFORMATION: Antibody-VH Region; MOR02718 <400> SEQUENCE: 37       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt aat tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc ttt atc tct ggt tct ggt agc tct acc tat tat gcg gat agc gtg 192       Ser Phe Ile Ser Gly Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt ggt tgg ttt ttt gct cat tgg ggc caa ggc acc ctg gtg acg 336       Ala Arg Gly Trp Phe Phe Ala His Trp Gly Gln Gly Thr Leu Val Thr                   100 105 110       gtt agc tca 345       Val Ser Ser               115 <210> SEQ ID NO 38 <211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 38       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Ser Asn                    20 25 30       Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Phe Ile Ser Gly Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Gly Trp Phe Phe Ala His Trp Gly Gln Gly Thr Leu Val Thr                   100 105 110       Val Ser Ser               115 <210> SEQ ID NO 39 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (327) 223 OTHER INFORMATION: Antibody-VL Region; MOR02718 <400> SEQUENCE: 39       gat atc gtg ctg acc cag agc ccg gcg acc ctg agc ctg tct ccg ggc 48       Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly         1 5 10 15       gaa cgt gcg acc ctg agc tgc aga gcg agc cag tct ggt cgt ggt aat 96       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Gly Arg Gly Asn                    20 25 30       ctg gct tgg tac cag cag aaa cca ggt caa gca ccg cgt cta tta att 144       Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile                35 40 45       tat gat gct tct aat cgt gca act ggg gtc ccg gcg cgt ttt agc 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 agc agc 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 Gln Tyr Ser Ser Val Pro Leu                        85 90 95       acc ttt ggc cag ggt acg aaa gtt gaa att aaa cgt acg 327       Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr                   100 105 <210> SEQ ID NO 40 <211> LENGTH: 109 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 40       Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly         1 5 10 15       Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Gly Arg Gly Asn                    20 25 30       Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile                35 40 45       Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val 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 Phe Gln Tyr Ser Ser Val Pro Leu                        85 90 95       Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr                   100 105 <210> SEQ ID NO 41 <211> LENGTH: 342 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (342) 223 OTHER INFORMATION: Antibody-VH Region; MOR02721 <400> SEQUENCE: 41       cag gtg caa ttg gtt cag agc ggc gcg gaa gtg aaa aaa ccg ggc gaa 48       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu         1 5 10 15       agc ctg aaa att agc tgc aaa ggt tcc gga tat tcc ttt act tct 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 cgc cag atg cct ggg aag ggt ctc gag tgg atg 144       Tyr Ile Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met                35 40 45       ggc att atc tat ccg tct act agc cgt acc att tat tct ccg agc ttt 192       Gly Ile Ile Tyr Pro Ser Thr Ser Arg Thr Ile Tyr Ser Pro Ser Phe            50 55 60       cag ggc cag gtg acc att agc gcg gat aaa agc att agc acc gcg tat 240       Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr        65 70 75 80       ctt caa tgg agc agc ctg aaa gcg agc gat acg gcc atg tat tat tgc 288       Leu Gln 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 Gln Gly Thr Leu Val Thr Val                   100 105 110       agc tca 342       Ser Ser <210> SEQ ID NO 42 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 42       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu         1 5 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 Val Arg Gln 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       Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr        65 70 75 80       Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys                        85 90 95       Ala Arg Tyr His Gly Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val                   100 105 110       Ser Ser <210> SEQ ID NO 43 <211> LENGTH: 342 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (342) 223 OTHER INFORMATION: Antibody-VL Region; MOR02721 <400> SEQUENCE: 43       cag gtg caa ttg gtt cag agc ggc gcg gaa gtg aaa aaa ccg ggc gaa 48       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu         1 5 10 15       agc ctg aaa att agc tgc aaa ggt tcc gga tat tcc ttt act tct 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 cgc cag atg cct ggg aag ggt ctc gag tgg atg 144       Tyr Ile Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met                35 40 45       ggc att atc tat ccg tct act agc cgt acc att tat tct ccg agc ttt 192       Gly Ile Ile Tyr Pro Ser Thr Ser Arg Thr Ile Tyr Ser Pro Ser Phe            50 55 60       cag ggc cag gtg acc att agc gcg gat aaa agc att agc acc gcg tat 240       Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr        65 70 75 80       ctt caa tgg agc agc ctg aaa gcg agc gat acg gcc atg tat tat tgc 288       Leu Gln 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 Gln Gly Thr Leu Val Thr Val                   100 105 110       agc tca 342       Ser Ser <210> SEQ ID NO 44 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 44       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu         1 5 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 Val Arg Gln 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       Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr        65 70 75 80       Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys                        85 90 95       Ala Arg Tyr His Gly Ala Phe Trp Gly Gln Gly Thr Leu Val Thr Val                   100 105 110       Ser Ser <210> SEQ ID NO 45 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VH Region; MOR02722 <400> SEQUENCE: 45       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 gtg cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Ala Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc tct atc tct ggt tct ggt agc aat acc tat tat gcg gat agc gtg 192       Ser Ser Ile Ser Gly Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val            50 55 60       aaa ggc cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt ttt att gct tct tgg ggc caa ggc acc ctg gtg acg gtt agc 336       Ala Arg Phe Ile Ala Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser                   100 105 110       tca 339       Ser <210> SEQ ID NO 46 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 46       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Asn                    20 25 30       Ala Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Ser Ile Ser Gly Ser Gly Ser Asn Thr Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Phe Ile Ala Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser                   100 105 110       Ser <210> SEQ ID NO 47 <211> LENGTH: 342 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (342) 223 OTHER INFORMATION: Antibody-VL Region; MOR02722 <400> SEQUENCE: 47       gat atc gtg atg acc cag agc cca ctg agc ctg cca gtg act ccg ggc 48       Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly         1 5 10 15       gag cct gcg agc att agc tgc aga agc agc caa agc ctg gtt cat tct 96       Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser                    20 25 30       aat ggc tat act gat ctg aat tgg tac ctt caa aaa cca ggt caa agc 144       Asn Gly Tyr Thr Asp Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser                35 40 45       ccg cag cta tta att tat ctt ggt tct tat cgt gcc agt ggg gtc ccg 192       Pro Gln Leu Leu Ile Tyr Leu Gly Ser Tyr Arg Ala Ser Gly Val Pro            50 55 60       gat cgt ttt agc ggc tct 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       agc cgt gtg gaa gct gaa gac gtg ggc gtg tat tat tgc cag cag tat 288       Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Tyr                        85 90 95       tct aat ttt cct ttt acc ttt ggc cag ggt acg aaa gtt gaa att aaa 336       Ser Asn Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys                   100 105 110       cgt acg 342       Arg Thr <210> SEQ ID NO 48 <211> LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 48       Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly         1 5 10 15       Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser                    20 25 30       Asn Gly Tyr Thr Asp Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser                35 40 45       Pro Gln Leu Leu Ile Tyr Leu Gly Ser Tyr Arg Ala Ser Gly Val Pro            50 55 60       Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile        65 70 75 80       Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln Tyr                        85 90 95       Ser Asn Phe Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys                   100 105 110       Arg Thr <210> SEQ ID NO 49 <211> LENGTH: 336 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (336) 223 OTHER INFORMATION: Antibody-VL Region; MOR03055 <400> SEQUENCE: 49       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc 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 Gln 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 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 50 <211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 50       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Thr Arg Ala His                        85 90 95       Arg Tyr Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 51 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS <222> LOCATION: (1) .. (333) 223 OTHER INFORMATION: Antibody-VL Region; MOR03066 <400> SEQUENCE: 51       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc tct tct tat gat act cag gtt 288       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Asp Thr Gln Val                        85 90 95       act cgt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 333       Thr Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 52 <211> LENGTH: 111 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 52       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Asp Thr Gln Val                        85 90 95       Thr Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 53 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS <222> LOCATION: (1) .. (333) 223 OTHER INFORMATION: Antibody-VL Region; MOR03075 <400> SEQUENCE: 53       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc cag tct tgg gat cct cgt tct 288       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Pro Arg Ser                        85 90 95       ttt act gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 333       Phe Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 54 <211> LENGTH: 111 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 54       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Pro Arg Ser                        85 90 95       Phe Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 55 <211> LENGTH: 330 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (330) 223 OTHER INFORMATION: Antibody-VL Region; MOR03069 <400> SEQUENCE: 55       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc tgg act ggt atg tct tat 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 tta acc gtt ctt ggc cag 330       Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 56 <211> LENGTH: 110 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 56       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Trp Thr Gly Met Ser Tyr His                        85 90 95       Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 57 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS <222> LOCATION: (1) .. (333) 223 OTHER INFORMATION: Antibody-VL Region; MOR03071 <400> SEQUENCE: 57       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc ctt gct tat att cag tct aag 288       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Ala Tyr Ile Gln Ser Lys                        85 90 95       ggt cat gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 333       Gly His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 58 <211> LENGTH: 111 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 58       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Ala Tyr Ile Gln Ser Lys                        85 90 95       Gly His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 59 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VL Region; MOR03064 <400> SEQUENCE: 59       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc gat 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 tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat tat gtt cat aag cgt ccc tca ggc gtg agc aac cgt ttt 192       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser Asn Arg Phe            50 55 60       agc gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc 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 tct tgg gat ctt ctt 288       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Leu Leu                        85 90 95       gct cct tct gtt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336       Ala Pro Ser Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       cag 339       Gln <210> SEQ ID NO 60 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 60       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr                    20 25 30       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Leu Leu                        85 90 95       Ala Pro Ser Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       Gln <210> SEQ ID NO 61 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Antibody-VL Region; MOR03062 <400> SEQUENCE: 61       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc gat 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 tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat tat gtt cat aag cgt ccc tca ggc gtg agc aac cgt ttt 192       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser Asn Arg Phe            50 55 60       agc gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc 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 tct tgg gat ctt tct 288       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Leu Ser                        85 90 95       gtt cat cag gtt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336       Val His Gln Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       cag 339       Gln <210> SEQ ID NO 62 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 62       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr                    20 25 30       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Leu Ser                        85 90 95       Val His Gln Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       Gln <210> SEQ ID NO 63 <211> LENGTH: 336 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (336) 223 OTHER INFORMATION: Derivative of MOR03055: Antibody-VH Region;       MOR03243 <400> SEQUENCE: 63       cag gtg caa ttg caa gaa agt ggt ccg ggc ctg gtg aaa ccg ggc gaa 48       Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu         1 5 10 15       acc ctg agc ctg acc tgc acc gtt tcc gga ggc agc att tct tct tat 96       Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr                    20 25 30       tat tgg tct tgg att cgc cag gcc cct ggg aag ggt ctc gag tgg att 144       Tyr Trp Ser Trp Ile Arg Gln 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 Gln Tyr Asn Pro Ser Leu Lys            50 55 60       tct cgg gtc acc att agc gtt gat act tcg aaa aac cag ttt agc ctg 240       Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu        65 70 75 80       aaa ctg agc agc gtg acg gcg gcg gat acg gcc gtg tat tat tgc gcg 288       Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala                        85 90 95       cgt ttt ttt gat gtt tgg ggc caa ggc acc ctg gtg acg gtt agc tca 336       Arg Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                   100 105 110 <210> SEQ ID NO 64 <211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 64       Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu         1 5 10 15       Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr                    20 25 30       Tyr Trp Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile                35 40 45       Gly Glu Ile His Arg Gly Gly Tyr Thr Gln Tyr Asn Pro Ser Leu Lys            50 55 60       Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu        65 70 75 80       Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala                        85 90 95       Arg Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                   100 105 110 <210> SEQ ID NO 65 <211> LENGTH: 336 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (336) 223 OTHER INFORMATION: Derivative of MOR03055: Antibody-VL Region;       MOR03243 <400> SEQUENCE: 65       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc 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 Gln 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 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 66 <211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 66       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Thr Arg Ala His                        85 90 95       Arg Tyr Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 67 <211> LENGTH: 336 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (336) 223 OTHER INFORMATION: Derivative of MOR03069; Antibody-VH Region;       MOR03245 <400> SEQUENCE: 67       cag gtg caa ttg caa gaa agt ggt ccg ggc ctg gtg aaa ccg ggc gaa 48       Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu         1 5 10 15       acc ctg agc ctg acc tgc acc gtt tcc gga ggc agc att tct tct tat 96       Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr                    20 25 30       tat tgg tct tgg att cgc cag gcc cct ggg aag ggt ctc gag tgg att 144       Tyr Trp Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile                35 40 45       ggc gtt att cat aag tgg ggt ttt act aat tat aat cct tct ctt aag 192       Gly Val Ile His Lys Trp Gly Phe Thr Asn Tyr Asn Pro Ser Leu Lys            50 55 60       tct cgg gtc acc att agc gtt gat act tcg aaa aac cag ttt agc ctg 240       Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu        65 70 75 80       aaa ctg agc agc gtg acg gcg gcg gat acg gcc gtg tat tat tgc gcg 288       Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala                        85 90 95       cgt ttt ttt gat gtt tgg ggc caa ggc acc ctg gtg acg gtt agc tca 336       Arg Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                   100 105 110 <210> SEQ ID NO 68 <211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 68       Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Glu         1 5 10 15       Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr                    20 25 30       Tyr Trp Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile                35 40 45       Gly Val Ile His Lys Trp Gly Phe Thr Asn Tyr Asn Pro Ser Leu Lys            50 55 60       Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu        65 70 75 80       Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala                        85 90 95       Arg Phe Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser                   100 105 110 <210> SEQ ID NO 69 <211> LENGTH: 330 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (330) 223 OTHER INFORMATION: Derivative of MOR03069; Antibody-VL Region;       MOR03245 <400> SEQUENCE: 69       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc tgg act ggt atg tct tat 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 tta acc gtt ctt ggc cag 330       Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 70 <211> LENGTH: 110 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 70       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Trp Thr Gly Met Ser Tyr His                        85 90 95       Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 71 <211> LENGTH: 354 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (354) 223 OTHER INFORMATION: Derivative of MOR03075; Antibody-VH Region;       MOR03246 <400> SEQUENCE: 71       cag gtg caa ttg gtt cag agc ggc gcg gaa gtg aaa aaa ccg ggc gcg 48       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       agc gtg aaa gtg agc tgc aaa gcc 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 cgc caa gcc cct ggg cag ggt ctc gag tgg atg 144       Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       ggc tgg atc aat ccg tat tct ggc aat acg cgt tac gcg cag aag ttt 192       Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gln Lys Phe            50 55 60       cag ggc cgg gtg acc atg acc cgt gat acc agc att agc acc gcg tat 240       Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr        65 70 75 80       atg gaa ctg agc agc ctg cgt agc gaa gat acg gcc 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 tct 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 Gln Gly Thr                   100 105 110       ctg gtg acg gtt agc tca 354       Leu Val Thr Val Ser Ser               115 <210> SEQ ID NO 72 <211> LENGTH: 118 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 72       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe                    20 25 30       Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gln Lys Phe            50 55 60       Gln Gly Arg Val 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 Gln Gly Thr                   100 105 110       Leu Val Thr Val Ser Ser               115 <210> SEQ ID NO 73 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS <222> LOCATION: (1) .. (333) 223 OTHER INFORMATION: Derivative of MOR03075; Antibody-VL Region;       MOR03246 <400> SEQUENCE: 73       gat atc gtg ctg acc cag ccg cct tca gtg agt ggc gca cca ggt cag 48       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       cgt gtg acc atc tcg tgt agc ggc agc agc agc aac att ggt tct aat 96       Arg Val 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 Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       att tat tct aat aat aag cgt ccc tca ggc gtg ccg gat cgt ttt agc 192       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       gga tcc aaa agc ggc acc agc gcg agc ctt gcg att acg ggc ctg caa 240       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       agc gaa gac gaa gcg gat tat tat tgc cag tct tgg gat cct cgt tct 288       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Pro Arg Ser                        85 90 95       ttt act gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc cag 333       Phe Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 74 <211> LENGTH: 111 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 74       Asp Ile Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln         1 5 10 15       Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn                    20 25 30       Thr Val Arg Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu                35 40 45       Ile Tyr Ser Asn Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser            50 55 60       Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln        65 70 75 80       Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Pro Arg Ser                        85 90 95       Phe Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln                   100 105 110 <210> SEQ ID NO 75 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Derivative of MOR03062; Antibody-VH Region;       MOR03251 <400> SEQUENCE: 75       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt att tct aat atg tct tat act att tat tat gct gat tct gtt 192       Ser Val Ile Ser Asn Met Ser Tyr Thr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       aag ggt cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 76 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 76       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val 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 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 77 <211> LENGTH: 339 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (339) 223 OTHER INFORMATION: Derivative of MOR03062; Antibody-VL Region;       MOR03251 <400> SEQUENCE: 77       gat atc gca ctg acc cag cca gct tca gtg agc ggc tca cca ggt cag 48       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       agc att acc atc tcg tgt acg ggt act agc agc gat 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 tct tgg tac cag cag cat ccc ggg aag gcg ccg aaa ctt 144       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       atg att tat tat gtt cat aag cgt ccc tca ggc gtg agc aac cgt ttt 192       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser Asn Arg Phe            50 55 60       agc gga tcc aaa agc ggc aac acc gcg agc ctg acc att agc 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 tct tgg gat ctt tct 288       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Leu Ser                        85 90 95       gtt cat cag gtt gtg ttt ggc ggc ggc acg aag tta acc gtt ctt ggc 336       Val His Gln Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       cag 339       Gln <210> SEQ ID NO 78 <211> LENGTH: 113 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 78       Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln         1 5 10 15       Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Gly Gly Gly Tyr                    20 25 30       Asn Thr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu                35 40 45       Met Ile Tyr Tyr Val His Lys Arg Pro Ser Gly Val Ser 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       Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Trp Asp Leu Ser                        85 90 95       Val His Gln Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly                   100 105 110       Gln <210> SEQ ID NO 79 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR03252 <400> SEQUENCE: 79       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt att tct aat tat tct tgg cat att tat tat gct gat tct gtt 192       Ser Val Ile Ser Asn Tyr Ser Trp His Ile Tyr Tyr Ala Asp Ser Val            50 55 60       aag ggt cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 80 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 80       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val Ile Ser Asn Tyr Ser Trp His Ile Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 81 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR03253 <400> SEQUENCE: 81       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt att tct aat atg ggt ttt gag att tat tat gct gat tct gtt 192       Ser Val Ile Ser Asn Met Gly Phe Glu Ile Tyr Tyr Ala Asp Ser Val            50 55 60       aag ggt cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 82 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 82       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val Ile Ser Asn Met Gly Phe Glu Ile Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 83 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR03255 <400> SEQUENCE: 83       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt att tct aat cgt tct tct tat att tat tat gct gat tct 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 tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 84 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 84       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val Ile Ser Asn Arg Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 85 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Antibody-VH Region; MOR03257 <400> SEQUENCE: 85       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt att tct aat cgt ggt aat tat att tat tat gct gat tct gtt 192       Ser Val Ile Ser Asn Arg Gly Asn Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       aag ggt cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 86 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 86       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val Ile Ser Asn Arg Gly Asn Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 87 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (348) 223 OTHER INFORMATION: Derivative of MOR03075; Antibody-VH Region;       MOR03258 <400> SEQUENCE: 87       cag gtg caa ttg gtg gaa agc ggc ggc ggc ctg gtg caa ccg ggc ggc 48       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       agc ctg cgt ctg agc tgc gcg gcc tcc gga ttt acc ttt tct tct 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 cgc caa gcc cct ggg aag ggt ctc gag tgg gtg 144       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       agc gtt att tct aat cag tct aat tat att tat tat gct gat tct gtt 192       Ser Val Ile Ser Asn Gln Ser Asn Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       aag ggt cgt ttt acc att tca cgt gat aat tcg 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 agc ctg cgt gcg gaa gat acg gcc gtg tat tat tgc 288       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       gcg cgt aat aag gtt ggt ttt gat gtt tgg ggc caa ggc acc ctg gtg 336       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       acg gtt agc tca 348       Thr Val Ser Ser               115 <210> SEQ ID NO 88 <211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 88       Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly         1 5 10 15       Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr                    20 25 30       Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val                35 40 45       Ser Val Ile Ser Asn Gln Ser Asn Tyr Ile Tyr Tyr Ala Asp Ser Val            50 55 60       Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr        65 70 75 80       Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys                        85 90 95       Ala Arg Asn Lys Val Gly Phe Asp Val Trp Gly Gln Gly Thr Leu Val                   100 105 110       Thr Val Ser Ser               115 <210> SEQ ID NO 89 <211> LENGTH: 354 <212> TYPE: DNA <213> ORGANISM: human <220> FEATURE: <221> NAME / KEY: CDS LOCATION: (1) .. (354) 223 OTHER INFORMATION: Derivative of MOR03075; Antibody-VL Region;       MOR03258 <400> SEQUENCE: 89       cag gtg caa ttg gtt cag agc ggc gcg gaa gtg aaa aaa ccg ggc gcg 48       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       agc gtg aaa gtg agc tgc aaa gcc 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 cgc caa gcc cct ggg cag ggt ctc gag tgg atg 144       Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       ggc tgg atc aat ccg tat tct ggc aat acg cgt tac gcg cag aag ttt 192       Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gln Lys Phe            50 55 60       cag ggc cgg gtg acc atg acc cgt gat acc agc att agc acc gcg tat 240       Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr        65 70 75 80       atg gaa ctg agc agc ctg cgt agc gaa gat acg gcc 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 tct 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 Gln Gly Thr                   100 105 110       ctg gtg acg gtt agc tca 354       Leu Val Thr Val Ser Ser               115 <210> SEQ ID NO 90 <211> LENGTH: 118 <212> TYPE: PRT <213> ORGANISM: human <400> SEQUENCE: 90       Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala         1 5 10 15       Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Phe                    20 25 30       Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met                35 40 45       Gly Trp Ile Asn Pro Tyr Ser Gly Asn Thr Arg Tyr Ala Gln Lys Phe            50 55 60       Gln Gly Arg Val 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 Gln Gly Thr                   100 105 110       Leu Val Thr Val Ser Ser               115  

Claims (66)

(i) specifically binds to the ED-B domain of fibronectin, (ii) inhibits the interaction between the ED-B domain and its receptor. The polypeptide of claim 1 which is an antibody or antibody fragment. The method according to claim 1 or 2, wherein K _D for the ED-B domain. A polypeptide exhibiting an affinity corresponding to a value ≦ 100 nmol. The method of claim 3, wherein K _D for the ED-B domain. A polypeptide exhibiting an affinity corresponding to a value ≦ 10 nmol. The method of claim 3, wherein K _D for the ED-B domain. Polypeptides exhibiting affinity corresponding to values ≤ 1 nmol. The polypeptide of claim 1, which exhibits at least five times higher specificity for the fibronectin ED-B domain than for fibronectin domain 6 and / or fibronectin domain 7-8-9. The polypeptide of any one of claims 1 to 6 which inhibits the adhesion of ED-B to HDMVEc cells, tumor cells and / or stromal cells in vitro. The polypeptide of any one of claims 1 to 6 which inhibits tumor growth produced by transplantation of F9- teratocarcinoma cells in test animals in vivo. The method according to any one of claims 1 to 8, (a) (i) Nucleic acid sequence SEQ ID NO: 1 (MOR 02610), SEQ ID NO: 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: : At least one of the H-CDR1, H-CDR2 and / or H-CDR3 regions of the VH region, or one of the above-mentioned VH regions, encoded by 41 (MOR 02721), SEQ ID NO: 45 (MOR 02722), or (ii) a VH region derived from the VH region according to (i) by a change in at least one H-CDR region, and / or (b) (i) 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: : VL region encoded by 43 (MOR 02721), SEQ ID NO: 47 (MOR 02722), or at least one of the L-CDR1, L-CDR2 and / or L-CDR3 regions of one of the above-mentioned VL regions, or (ii) a polypeptide selected from antibodies and antibody fragments comprising a VL region derived from the VL region according to (i) by a change in at least one L-CDR region. The polypeptide of claim 9, wherein the polypeptide exhibits a VL region derived from the VL region according to (b) (i) by a change in the L-CDR3 region. The polypeptide of claim 10 exhibiting a VL region derived from a VL region encoded by nucleic acid sequence SEQ ID NO: 27 (MOR 02619) or SEQ ID NO: 35 (MOR 02715). The method according to any one of claims 9 to 11, (a) (i) H-CDR1, H-CDR2 of the VH region, or one of the above-mentioned VH regions, encoded by nucleic acid sequence SEQ ID NO: 25 (MOR 02619), or SEQ ID NO: 33 (MOR 02715) And / or at least one of the H-CDR3 regions, or (ii) a VH region derived from the VH region according to (i) by a change in at least one H-CDR region, and / or (b) (i) nucleic acid sequence SEQ ID NO: 49 (MOR 03055), SEQ ID NO: 51 (MOR 03066), SEQ ID NO: 53 (MOR 03075), SEQ ID NO: 55 (MOR 03069), SEQ ID NO: 57 (MOR 03071), SEQ ID NO: 59 (MOR 03064), SEQ ID NO: 61 (MOR 03062), or at least L-CDR3 region of one of the above-mentioned VL regions, or (ii) a polypeptide comprising a VL region derived from the VL region according to (i) by a change in at least one L-CDR region. The polypeptide of claim 9, wherein the polypeptide exhibits a VH region derived from the VH region according to (a) (i) by a change in the H-CDR2 region. The polypeptide of claim 13 exhibiting a VH region derived from a VH region encoded by nucleic acid sequence SEQ ID NO: 25 (MOR 02619) or SEQ ID NO: 33 (MOR 02715). The method according to any one of claims 9 to 14, (a) (i) 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 H- CDR2 region, or (ii) a VH region derived from the VH region according to (i) by a change in at least one H-CDR region, and / or (b) (i) 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), SEQ ID NO: 89 (MOR 03258), or at least the L-CDR1, L-CDR2 or L-CDR3 region of one of the above-mentioned VL regions, or (ii) a polypeptide comprising a VL region derived from the VL region according to (i) by a change in at least one L-CDR region. The VH region encoded by SEQ ID NO: 1 and the VL region encoded by SEQ ID NO: 3 (MOR 02610), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region according to any one of claims 9 to 14, wherein the VH region is encoded by SEQ ID NO: 5 and the VL region is encoded by SEQ ID NO: 7 (MOR 02611), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 9 and the VL region encoded by SEQ ID NO: 11 (MOR 02613), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 13 and the VL region encoded by SEQ ID NO: 15 (MOR 02614), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 17 and the VL region encoded by SEQ ID NO: 19 (MOR 02616), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 21 and the VL region encoded by SEQ ID NO: 23 (MOR 02618), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 25 and the VL region encoded by SEQ ID NO: 27 (MOR 02619), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 29 and the VL region encoded by SEQ ID NO: 31 (MOR 02622), or at least one H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 33 and the VL region encoded by SEQ ID NO: 35 (MOR 02715), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region according to any one of claims 9 to 14, wherein the VH region is encoded by SEQ ID NO: 37 and the VL region is encoded by SEQ ID NO: 39 (MOR 02718), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region according to any one of claims 9 to 14, wherein the VH region is encoded by SEQ ID NO: 41 and the VL region is encoded by SEQ ID NO: 43 (MOR 02721), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 45 and the VL region encoded by SEQ ID NO: 47 (MOR 02722), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 25 and the VL region encoded by SEQ ID NO: 49 (MOR 03055), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 25 and the VL region encoded by SEQ ID NO: 51 (MOR 03066), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 25 and the VL region encoded by SEQ ID NO: 53 (MOR 03075), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 25 and the VL region encoded by SEQ ID NO: 55 (MOR 03069), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 25 and the VL region encoded by SEQ ID NO: 57 (MOR 03071), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 33 and the VL region encoded by SEQ ID NO: 59 (MOR 03064), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 33 and the VL region encoded by SEQ ID NO: 61 (MOR 03062), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 63 and the VL region encoded by SEQ ID NO: 65 (MOR 03243), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 67 and the VL region encoded by SEQ ID NO: 69 (MOR 03245), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 71 and the VL region encoded by SEQ ID NO: 73 (MOR 03246), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 75 and the VL region encoded by SEQ ID NO: 77 (MOR 03251), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 79 and the VL region encoded by SEQ ID NO: 77 (MOR 03252), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 81 and the VL region encoded by SEQ ID NO: 77 (MOR 03253), or at least one of H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 83 and the VL region encoded by SEQ ID NO: 77 (MOR 03255), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 85 and the VL region encoded by SEQ ID NO: 77 (MOR 03257), or at least one of H-CDR1, H- according to claim 9. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The VH region encoded by SEQ ID NO: 87 and the VL region encoded by SEQ ID NO: 89 (MOR 03258), or at least one H-CDR1, H-. A polypeptide comprising a CDR2, H-CDR3, L-CDR1, L-CDR2 or L-CDR3 region. The polypeptide of claim 1 in the form of a conjugate with a therapeutically active ingredient. The polypeptide of claim 44, wherein the therapeutically active ingredient is selected from radiation- or chemotherapy. The polypeptide of claim 1, which is in the form of a fusion protein. 47. The polypeptide of claim 46 as a fusion protein with cytokines or as a bispecific antibody. The polypeptide of any one of claims 1-43 in the form of a conjugate with a diagnostically detectable labeling group. The polypeptide of claim 46, wherein the diagnostically detectable labeling group is selected from radio-, NMR-, dye-, enzyme, and fluorescent labeling groups. A pharmaceutical composition comprising the polypeptide according to any one of claims 1 to 47 as an active ingredient and a pharmaceutically acceptable vehicle, adjuvant, and / or diluent. 51. The composition of claim 50 for preventing or treating hyperproliferative disease. 62. The composition of claim 50 or 61 for preventing or treating cancer. 50. A diagnostic composition comprising a polypeptide according to any one of claims 1 to 43, 48 or 49 as a diagnostic reagent. The composition of claim 53 for diagnosing hyperproliferative disease or predisposition thereof. 55. The composition of claim 53 or 54 for diagnosing cancer or predisposition thereof. The composition of any one of claims 50-55 for use as a medicament for humans. 48. A nucleic acid encoding a polypeptide according to any one of claims 1-43 or 46-47. The nucleic acid of claim 57 operably linked to an expression control sequence. 59. A vector containing a nucleic acid according to claim 57 or 58. 60. A cell transformed with a nucleic acid according to claim 57 or 58, or a vector according to claim 59. 60. An organism, except humans, transformed with a nucleic acid according to claim 57 or 58, or a vector according to claim 59. 44. A polypeptide according to any one of claims 1 to 43, wherein the polypeptide according to any one of claims 1 to 43 is obtained by culturing an organism other than the cell according to claim 60 or the human according to claim 61 under conditions such that the polypeptide is expressed. How to manufacture. 48. Use of a polypeptide according to any one of claims 1 to 47 for the production of a medicament for the prevention or treatment of ED-B-related diseases. 63. The use of claim 62 for the production of a medicament for the prevention or treatment of cancer. Use of a polypeptide according to any one of claims 1 to 43, 48 or 49 for the production of diagnostic reagents for diagnosing ED-B-related diseases or predisposition thereof. 66. The use of claim 65 for the production of diagnostic reagents for diagnosing cancer or predisposition thereof.

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