NZ760009B2

NZ760009B2 - Means and methods for counteracting myeloproliferative or lymphoproliferative disorders

Info

Publication number: NZ760009B2
Application number: NZ760009A
Authority: NZ
Inventors: Adrianus Quirinus Bakker; Tim Beaumont; Marijn Aletta Gillissen; Mette Deborah Hazenberg; Martijn Kedde; Hergen Spits
Original assignee: Kling Biotherapeutics Bv
Priority date: 2013-12-17
Filing date: 2014-12-17
Publication date: 2021-06-29

Abstract

The invention provides a human AML-specific binding compound (AT14-013) that is able to bind a cell surface component of AML cells. The anti-AML antibody is able to bind AML primary blasts of at least three different French-American-British (FAB) classifications, namely M0, M4, and M5. The invention further relates to its method of use for diagnosing and treating acute myeloid leukaemia (AML). further relates to its method of use for diagnosing and treating acute myeloid leukaemia (AML).

Description

Title: Means and methods for counteracting myeloproliferative or lymphoproliferative disorders This application is a divisional of New Zealand patent application 722155, which is the national phase entry in New Zealand of PCT international application (published as ), filed 17 December 2014, all of which are incorporated herein by reference.

The invention relates to the fields of biology, immunology, medicine and cancer therapy, in particular therapy t myeloproliferative or lymphoproliferative disorders. More in ular, the invention relates to antibodies against acute myeloid leukemia cells.

Acute myeloid ia (AML) is a high risk malignancy with five year survival rates of 40 - 50% in patients younger than 60 years of age. For patients over 65 years of age outcomes are even worse, with only less than 20% of patients obtaining durable remissions. Allogeneic stem cell transplantation is frequently applied in the treatment of acute leukemia. It was initially ed to rescue patients from otherwise lethal myeloablative chemotherapy but was subsequently found to be complicated by alloreactive immune se related complications (graft versus host disease; GvHD). T cell depletion of grafts before reinfusion averted GvHD but the observation that T cell ed graft recipients, similar to monozygotic twin donor lant recipients, experienced much higher rates of relapse made it increasingly clear that the s of allogeneic SCT is dependent on the induction of an anti-leukemic immune response (graft versus leukemia (GvL)). This has led to the development of strategies to apply allogeneic stem cell transplantation without myeloablative conditioning (reduced intensity stem cell transplantation, RIST), to reduce cytotoxicity and to allow allogeneic SCT in a larger group of patients including older patients and heavily pretreated ts.

Preparative regimens in RIST are aimed at decimating the recipients adaptive immune system to prevent graft rejection, without complete ablation of the recipients bone marrow thereby ng early SCT toxicity. Following lantation, donor stem cells gradually replace stem cells of the recipient and full donor chimerism is usually achieved within three months after SCT. Although allogeneic SCT is curative in significant numbers of patients, and much progress has been made in the tive care of SCT recipients, still 15-30% of patients die as a result of transplantation related cations such as GvHD and ious complications (arising as a result of slow immune recovery following SCT or as a cation of immunosuppressive therapy of GvHD).

Hence, although SCT is potentially curative when potent graft versus leukemia (GvL) responses are induced, its therapeutic s is limited by antihost immune responses leading to GvHD which causes high morbidity and mortality.

About 70% of SCT patients develop GvHD at one point following SCT, with target organs including the skin, liver, intestine and lung. GvHD is treated with local or systemic immunosuppressive therapy including corticosteroids. A significant number of GvHD ts is not responsive to steroid therapy, and about half of these patients also respond poorly to alternative (and partly still experimental) measures such as mesenchymal stromal cell (MSC) transplantation or T cell modulating therapy such as anti-tumor necrosis factor α (anti-TNFα; imab). Extensive and long-term immunosuppressive y is rable, since it may hamper the development of therapeutic antileukemia responses.

Indeed, when an AML relapse occurs while the patient is still on suppressive therapy, the first step is to rapidly taper immunosuppressants. This may induce a curative GvL response, often at the expense of GvHD. In relapsed patients on immunosuppressive therapy who do not respond to ng of immunosuppressants or relapsed patients in whom immunosuppressants were already phased out before relapse occurred but who had not developed GvHD, tumor load reduction by herapy, followed by increasing doses of donor- lymphocyte infusions (DLI) may lead to durable ion of disease. While the absence of diagnostic tests to demonstrate the presence of a robust GvL makes it difficult to estimate exactly how often allogeneic SCT induce GvL responses in y or relapsed AML, some studies provided compelling evidence of the induction of such a response in a considerable number of patients. For example, Schmid and colleagues demonstrated potent GvL responses by DLI in 50% of a small group of AML patients with disease relapse who were in second remission following chemotherapy (Schmid et al., 2007). Schlenk and colleagues convincingly showed the additive value of allogeneic SCT in primary AML, with a doubling of the 5-year disease free survival in patients with high risk AML who received an allogeneic SCT from a sibling, compared with patients who did not have a suitable sibling donor (Schlenk et al., 2008). Thus, GvL responses often occur at the cost of GvHD, and the observation that T cell depletion from the graft reduced GvHD incidence but increased disease relapse rates suggested that both are primarily mediated by T cell dependent immune responses against recipient-antigens.

In view of the high GvHD incidence after allogeneic stem cell transplantation, resulting in death of 15-30% of the patients, as well as the fact that a suitable donor is not always available for a given patient, alternative treatment approaches are needed. It is an object of the present invention to provide alternative means and methods for counteracting and/or ting AML; and/or to at least provide with public with a useful choice.

SUMMARY OF THE INVENTION In a first aspect the t invention es an ed, synthetic or inant human antibody, or a functional part or a functional equivalent thereof, which is able to bind acute myeloid ia (AML) cells and which comprises: - a heavy chain CDR1 sequence comprising the sequence of SEQ ID NO: 209; - a heavy chain CDR2 sequence comprising the sequence of SEQ ID NO: 213; - a heavy chain CDR3 sequence comprising the sequence of SEQ ID NO: 217; - a light chain CDR1 sequence comprising the sequence of SEQ ID NO: 221; - a light chain CDR2 ce sing the sequence of SEQ ID NO: 225; and - a light chain CDR3 sequence comprising the sequence of SEQ ID NO: 229.

In a second aspect the present invention provides an isolated, synthetic or recombinant nucleic acid molecule with a length of at least 15 nucleotides, or a functional equivalent thereof, or a vector, encoding at least the six CDR sequences of an dy or functional part or functional equivalent according to the first aspect.

In a third aspect the present invention provides a nucleic acid molecule or functional equivalent thereof, or a vector, encoding an antibody or functional part or functional equivalent ing to the first aspect.

In a fourth aspect the present invention provides an ed or recombinant cell, or a non-human animal, comprising a nucleic acid molecule or functional equivalent or vector according to second or third aspect, with the proviso that said cell is not present in a human being.

In a fifth aspect the present invention provides a composition comprising an antibody or functional part or functional equivalent according to the first aspect, or a nucleic acid molecule or functional equivalent or vector according to the second or third aspect, or a cell according to the fourth aspect.

In a sixth aspect the present invention provides a use of an antibody or functional part or functional equivalent according to the first aspect, or a nucleic acid molecule or functional equivalent or a vector according to the second or third aspect, or a cell according to the fourth aspect, in the manufacture of a medicament or prophylactic agent.

In a seventh aspect the present ion provides a use of an antibody or functional part or functional equivalent according to the first aspect, or a nucleic acid molecule or functional lent or a vector ing to the second or third aspect, or a cell according to the fourth , in the manufacture of a medicament or prophylactic agent for treating or preventing acute myeloid ia (AML).

In an eighth aspect the t invention provides a use of an antibody or functional part or onal equivalent according to the first aspect, or a nucleic acid molecule or functional equivalent or a vector according to the second or third aspect, or a cell according to the fourth aspect, in the manufacture of a diagnostic agent for acute myeloid leukemia (AML).

In a ninth aspect the present invention provides a method for producing an antibody or onal part or functional equivalent according to the first aspect, the method comprising providing a cell with a nucleic acid molecule or functional equivalent or a vector ing to the second or third , and ng said cell to translate said nucleic acid molecule or functional equivalent or vector, thereby producing said antibody or functional part or onal equivalent according to the first aspect, with the proviso that said method is not d out in a human being.

In a tenth aspect the present invention provides a method for determining whether AML cells are present in a sample comprising: - contacting said sample with an antibody or functional part or functional lent according to the first aspect, and - allowing said antibody or functional part or functional lent to bind AML cells, if t, and - determining whether or not AML cells are bound to said antibody or functional part or functional equivalent, thereby determining whether or not AML cells are present in said sample.

In an eleventh aspect the present invention es a method for ining whether an AML patient has a Graft versus Leukemia response, comprising contacting a sample from said AML patient with an antibody or functional part or functional equivalent according to the first aspect, and allowing said antibody or functional part or functional equivalent to bind AML cells, if present, and determining whether or not AML cells are bound to said antibody or functional part or functional equivalent, thereby determining whether or nor said dual has a GvL response, whereby the absence of AML cells is indicative for a GvL response.

In a twelfth aspect the present invention provides a bispecific or multispecific binding compound, comprising an antibody or a functional part or a functional equivalent according to the first aspect and an immunomodulatory molecule.

In a thirteenth aspect the present invention provides a synthetic or recombinant antibody, or a onal part or a functional equivalent thereof, which comprises one Fab fragment of an antibody according to the first aspect, and one Fab fragment of another antibody.

In a fourteenth aspect the t invention provides a chimeric antigen receptor (CAR) T cell comprising an antibody or a functional part or a functional equivalent according to the first aspect.

DETAILED DESCRIPTION The present invention provides patient-derived, AML-specific, human antibodies that are able to bind intact AML cells. Importantly, the dies are derived from human AML patients that received an allogeneic SCT and are in complete remission indicating that the antibodies are effective t AML.

Indeed, in the es it has been trated that antibodies bed herein are able to bind intact AML cells. The AML-specific human antibodies described herein are, therefore, particularly suitable for use in anti AML therapy. For instance, an antibody described herein is provided with a toxic moiety. After administration, AML cells will be bound and/or internalised and the toxic moiety will exert its toxic effect on the AML cell. Alternatively, in some embodiments antibody-dependent cell-mediated cytotoxicity (ADCC) or ment-dependent cytotoxicity (CDC) is induced using an antibody described herein, optionally bound to an modulatory compound. The fact that human antibodies are described, or functional parts or functional equivalents of human antibodies, diminishes the chance of side effects in human beings, which is an important advantage. Hence, with the antibodies described herein, novel AML treatment options have become available which can be used in addition to existing AML therapy, or as an alternative.

An important embodiment of the present disclosure describes human AML- ic antibodies that are capable of diminishing proliferation of AML cells.

Administration of such antibodies to an AML t will counteract AML cells without the need to add additional (toxic) moieties to the antibody. A particularly preferred ment describes human AML-specific antibodies that are capable of diminishing proliferation of AML cells independently from antibody-dependent cell-mediated cytotoxicity (ADCC), ment-dependent cytotoxicity (CDC), apoptosis or phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells. Preferably, such antibodies are capable of diminishing proliferation of AML cells (essentially) independently from any other immune cells, or complement or apoptosis. As shown in the Examples, such antibodies are capable of directly diminishing or inhibiting AML cell growth, or are even capable of killing AML cells, in the absence of immune cells like NK cells or macrophages, and in the absence of ment. This embodiment is in contrast to prior art approaches such as for instance described in Majeti et al., 2009 and Willingham et al., 2012, wherein a CD47-specific antibody is used in order to enable macrophage phagocytosis of tumor cells. describes the use of C-type lectin-like molecule-1 (CLL-1)-specific antibodies, which are capable of inducing CDC against AML cells in vitro in the presence of rabbit complement. Bakker et al., 2004, however, does not envision that antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity via CLL-1 will be an effective targeting ism, and proposes toxin-conjugated CLL-1 antibodies for use against AML. discloses the use of antibodies specific for IL1RAP for inducing antibody-dependent ediated cytotoxicity against AML cells, by recruiting NK cells which induce AML cell death. Hence, the above bed prior art focuses on the use of antibodies in order to activate other immune cells, which may not provide the desired results in immune compromised individuals such as AML patients who have one chemotherapy with or t an allogeneic SCT. describes XCR4 antibodies that were raised in transgenic hromosomic mice expressing human antibody genes. The obtained antibodies bind a broad range of hematopoietic cells and are capable of inhibiting growth of an AML cell line in vitro. These anti-CXCR4 antibodies induce apoptosis of s AML cell lines.

Anti-CD33 monoclonal antibody therapy t AML has also been described (Walther et al., 2012). For instance, CD33-specific antibodies coupled to a drug conjugate are described. describes a humaneered phA3 antibody that is capable of inducing apoptosis of AML cells. Furthermore, Biernacki et al., 2010 and Wu et al., 2000 describe antibodies obtained from AML ts that are specific for intracellular ns such as RAB38, TBCE, DUSP12 and RAFTK.

In conclusion, several publications describe AML antibodies that bind intracellular antigens. Such antibodies are not a first choice for combating living, intact AML cells in vivo due to the unreachability of such intracellular targets when the AML cells are intact. Other publications describe antibodies that bind a broad range of poietic cells, for instance through CD33, CXCR4, CD47 or CLL-1. Antibodies which bind a broad range of (hematopoietic) cells involve the risk of severe side-effects.

Several antibodies described in the art act by inducing phagocytosis, ADCC or CDC, meaning that other immune cells or complement components are required for counteracting AML cells. The use of such antibodies is, therefore, limited in immune compromised individuals. Moreover, some of the described antibodies are not human, which involves a high risk of side effects. Other publications (such as WO 71068 and ) describe antibodies that induce apoptosis of AML cells.

In contrast to the mentioned publications, the present inventors have taken a different approach. Instead of artificially producing antibodies against a component that is present on, amongst other things, AML cells, the ors have ed antibodies from human AML patients who, after receiving an allogeneic SCT, mounted a potent graft versus leukemia response as they maintained in complete remission.These dies are capable of specifically binding intact AML cells. Hence, instead of using artificially ped antibodies, the present inventors have elegantly taken advantage of the natural immune es elicited in human AML patients after receiving an allogeneic SCT. The humoral se found in nature results in a very adequate selection and outgrowth of B-cells that produce ive antibodies in vivo. The antibodies described herein, or functional parts or functional derivatives thereof, are therefore particularly suitable for binding AML cells in AML patients. The fact that the antibodies are specific for intact AML cells, instead of intracellular antigens, makes them ularly suitable for AML therapy.

As described, an antibody or functional part or functional equivalent described herein can be d to a toxic moiety. Such toxic moiety will then be directed to AML cells in vivo through the binding of the antibody to AML cells. One embodiment of the present disclosure describes human dies, or onal parts or functional equivalents thereof, which are able to bind intact AML cells and which are able to diminish proliferation of AML cells. Such antibody obviates the need of coupling the dy to an additional, toxic component ugh the use of a toxic moiety can still be useful for providing additional anti-AML effects). In one particularly preferred embodiment, human antibodies, or functional parts or functional equivalents f, described herein are able to bind intact AML cells and which are able to diminish proliferation of AML cells independently from antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) or phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells. Preferably, such antibodies are capable of diminishing proliferation of AML cells independently from, or essentially independently from, other immune cells or ment components. The use of such antibodies, having a strong anti-AML activity, is preferred, especially in immune-compromised individuals. One preferred aspect of the present disclosure therefore describes an isolated, synthetic or recombinant human antibody, or a functional part or a functional lent thereof, which is able to bind a cell surface component of acute myeloid leukemia (AML) cells and which is able to diminish proliferation of AML cells independently from, or ially independently from, antibody-dependent cell-mediated cytotoxicity , complement-dependent cytotoxicity (CDC) or ytosis by tumor-associated myeloid cells such as macrophages or dendritic cells. Preferably, such antibodies are capable of diminishing proliferation of AML cells (essentially) independently from any other immune cells or complement. As shown in the Examples, at least antibodies AT12-023, AT12-025 and AT13-024 have these characteristics. These are, therefore, preferred antibodies according to the present disclosure.

In a further preferred embodiment, human antibodies, or functional parts or onal equivalents thereof, described herein are able to bind intact AML cells and which are able to diminish proliferation of AML cells independently from sis. As shown in the es, at least antibodies AT12-023, AT13-031 and AT13-037 have this characteristic. This is clear from the fact that these antibodies can induce death of AML cells in the presence of apoptosis inhibitors such as the pan caspase inhibitors Q-VD-OPh or Z-VAD-fmk, and from the fact that most of these antibodies (except antibody AT13-031) maintain their cytotoxic properties at 4ºC. According to the present disclosure, dies such as AT12-023, AT13-031 and AT13-037 kill their AML target cells via necrosis (such as oncosis or necroptosis). This provides the advantage over currently known apoptosis-inducing antibodies that the necrosis-inducing antibodies bed herein will enhance a t’s immune response more than sis-inducing dies. This is due to the fact that necrosis causes more exposure of the cell contents to an individual’s immune system. Further described is therefore an isolated, synthetic or recombinant human antibody, or a functional part or a onal equivalent thereof, which is able to bind a cell surface component of acute myeloid leukemia (AML) cells and which is able to diminish proliferation of AML cells independently from, or essentially independently from, apoptosis.

In a further red embodiment, human antibodies, or functional parts or functional equivalents thereof, are described which are able to diminish proliferation of AML cells independently from both apoptosis and the abovementioned immune cells and complement. Further bed is therefore an isolated, synthetic or recombinant human antibody, or a onal part or a functional equivalent thereof, which is able to bind a cell surface component of acute myeloid leukemia (AML) cells and which is able to diminish proliferation of AML cells essentially independently from antibody-dependent cell-mediated cytotoxicity , complement-dependent cytotoxicity (CDC), apoptosis, or phagocytosis by macrophages or dendritic cells.

An antibody or functional part or functional equivalent described herein is preferably capable of binding intact AML cells. Preferably, such antibody or functional part or functional equivalent is able to bind a cell surface ent that is specific for AML cells. This typically means that matopoietic cells or non-malignant hematopoietic cells, such as for instance hepatocytes, colon cells, fibroblasts, endothelial cells, healthy eral blood mononuclear cells (PBMC) and healthy bone marrow cells, are not, or to a icantly lesser extent, recognized as compared to the binding affinity of an antibody or functional part or functional equivalent described herein for AML cells. This means that the binding of an antibody or functional part or functional equivalent described herein to nonhematopoietic cells or non-malignant hematopoietic cells is typically in the same range as binding of an irrelevant control antibody to these cells (wherein the control antibody is not specific for said cells). Some vity towards other types of malignant hematopoietic cells is, r, embraced within the term “AML- specific”. For instance, it is shown in Table 4 and Figure 6 that antibodies AT13- 031 and AT12-023 are capable of binding patient-derived B- non-Hodgkin lymphoma cells. A use of antibody AT13-031 or antibody AT12-023, or a onal part or functional derivative of any of these antibodies, for the preparation of a medicament or prophylactic agent against B- dgkin lymphoma is therefore also described, as well as antibody AT13-031 or antibody AT12-023, or a functional part or onal derivative of any of these antibodies, for use in a method for at least in part treating or preventing B- non-Hodgkin lymphoma. Similarly, dies AT13-024, AT13-031 and AT12-019 are capable to bind lymphomaand /or multiple myeloma cell lines (Table 4). A use of antibody AT13-024 or antibody AT13-031 or antibody 19, or a functional part or functional derivative of any of these antibodies, for the preparation of a medicament or prophylactic agent against lymphoma and/or myeloma is therefore also described, as well as antibody AT13-024 or antibody AT13-031 or antibody AT12-019, or a functional part or functional derivative of any of these dies, for use in a method for at least in part treating or ting lymphoma and/or myeloma.

As used herein, the term “AML cells” embraces natural AML cells, such as primary AML blasts that are present in AML patients, as well as AML cell lines such as for instance THP-1, Mono-Mac 6 and Molm13.

The term “antibody” as used herein, refers to an immunoglobulin protein comprising at least a heavy chain variable region (VH), paired with a light chain variable region (VL), that is specific for a target epitope.

A “functional part of an antibody” is defined herein as a part that has at least one shared ty as said antibody in kind, not necessarily in amount. Said functional part is e of g the same antigen as said antibody, albeit not necessarily to the same extent. In one ment a functional part of an antibody comprises at least a heavy chain variable domain (VH). Non-limiting examples of a functional part of an antibody are a single domain antibody, a single chain antibody, a nanobody, an unibody, a single chain variable fragment (scFv), a Fab fragment and a F(ab')2 fragment.

A “functional lent of an antibody” is d herein as an artificial binding compound, comprising at least one CDR sequence of an antibody, preferably a heavy chain CDR3 sequence. Said functional equivalent preferably comprises the heavy chain CDR3 sequence of an dy, as well as the light chain CDR3 sequence of said antibody. More preferably, said functional equivalent comprises the heavy chain CDR1, CDR2 and CDR3 sequences of an antibody, as well as the light chain CDR1, CDR2 and CDR3 sequences of said antibody. A functional equivalent of an antibody is for instance produced by altering an antibody such that at least an antigen-binding property of the resulting compound is essentially the same in kind, not necessarily in amount. This is done in many ways, for instance h conservative amino acid substitution, whereby an amino acid residue is substituted by another residue with generally r properties (size, hydrophobicity, etc), such that the l functioning of the antibody is essentially not affected.

As is well known by the skilled person, a heavy chain of an antibody is the larger of the two types of chains making up an immunoglobulin molecule. A heavy chain comprises a constant domain and a variable domain, which le domain is involved in antigen binding. A light chain of an antibody is the smaller of the two types of chains making up an immunoglobulin molecule. A light chain comprises a constant domain and a variable domain. The variable domain is often, but not always, together with the le domain of the heavy chain involved in antigen binding.

Complementary-determining regions (CDRs) are the hypervariable regions present in heavy chain variable domains and light chain le domains. In case of whole dies, the CDRs 1-3 of a heavy chain and the CDRs 1-3 of the ted light chain together form the antigen-binding site.

As used , the term “an antibody or functional part or onal equivalent according to the invention” is also referred to as “a binding compound according to the invention”.

The term “cell surface component of AML cells” means any component that is at least in part present in or on the cell surface of AML cells, or a component that is attached to an AML cell surface. Non-limiting examples of cell surface components of AML cells are (trans)membrane proteins, glycoproteins, and any nd attached thereto.

The terms “specific for” and "capable of specifically binding" are used herein interchangeably and refer to the interaction between an antibody, or functional part or functional equivalent thereof, and its epitope. This means that said antibody, or functional part or functional equivalent thereof, preferentially binds to said epitope over other antigens or amino acid sequences. Thus, although the dy, functional part or equivalent may non-specifically bind to other antigens or amino acid sequences, the binding affinity of said antibody or functional part or functional equivalent for its epitope is significantly higher than the non-specific binding affinity of said antibody or onal part or functional equivalent for other antigens or amino acid sequences.

An antibody or functional part or functional equivalent described herein that is able to bind a particular epitope of AML cells can also be specific for other, non-AML cells if said e of AML cells is also present on other cells (for instance other leukemic cells, myeloma cells or lymphoma cells). In that case an antibody referred to herein as being specific for AML cells is also specific for said other cells sing the same epitope. Preferably, human AML antibodies and functional parts and functional equivalents thereof, as described herewith, do not significantly bind non-hematopoietic cells and non-malignant hematopoietic cells.

“Binding affinity” refers to the strength of the total sum of the noncovalent interactions between a single binding site of an antibody or functional part or functional equivalent and its binding r (e.g., an n). Unless indicated otherwise, as used herein, “binding ty” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity can generally be ented by the equilibrium dissociation constant (KD), which is calculated as the ka to kd ratio, see, e.g., Chen, Y., et al., (1999) J. Mol Biol 293:865-881. Affinity can be measured by common methods known in the art, such as for instance a surface plasmon resonance (SPR) assay such as BiaCore or IBIS-iSPR instrument at IBIS Technologies BV (Hengelo, the Netherlands) or solution phase assays, such as Kinexa. Preferably an antibody described herein has a binding affinity for an epitope at or on the cell surface of AML cells characterized by a dissociation constant (KD) of at most 100 nM, more preferably at most 50 nM, more preferably at most 25 nM, more preferably at most 10 nM, more preferably at most 5 nM, more preferably at most 2 nM, more preferably at most 1 nM, more preferably at most 0.5 nM, more preferably at most 0.3 nM, more ably at most 0.1 nM.

The percentage of identity of an amino acid or nucleic acid sequence, or the term “% sequence identity”, is defined herein as the percentage of residues in a candidate amino acid or nucleic acid sequence that is identical with the residues in a reference sequence after aligning the two sequences and introducing gaps, if necessary, to e the maximum percent ty. Methods and computer programs for the alignment are well known in the art, for example "Align 2".

In a particularly preferred embodiment, an antibody or functional part or functional equivalent according to the present disclosure is described which is able to induce death of primary AML blasts. Since primary AML blasts are directly derived from an AML patient, as opposed to commercially available cell lines, the activity of an antibody against such AML blasts is even more indicative for an in vivo situation. As shown in the es, at least antibodies AT13-024 and AT12- 025 have this characteristic. These antibodies are, therefore, preferred. In a particularly preferred ambodiment, an antibody or functional part or onal equivalent according to the present sure is described which is able to induce death of primary AML blasts independently from, or essentially independently from, antibody-dependent cell-mediated cytotoxicity , complementdependent xicity (CDC), apoptosis, and/or phagocytosis by macrophages or tic cells. ably, such binding compounds are capable of inducing death of AML blasts essentially ndently from other immune cells, or complement or apoptosis. Antibodies AT13-024 and AT12-025 also have this red teristic.

As used herein, the term “essentially independently from ADCC, CDC or phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells” means that ADCC, CDC or phagocytosis by tumor-associated myeloid cells such as hages or dendritic cells are not required for an anti-AML effect induced by a binding compound described , even though in an in vivo situation ADCC, CDC or phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells may also occur. Hence, in this ment, ADCC, CDC and phagocytosis by tumor-associated myeloid cells such as hages or dendritic cells is not excluded, but not essential either. Likewise, the term “essentially independently from other immune cells or complement” means that a binding compound described herein is, in principle, capable of exerting an anti- AML effect without the presence of other immune cells or complement, even though in an in vivo situation other immune cells or complement may also have an anti-AML activity. The term “essentially independently from apoptosis” means that the anti-AML effect is exerted by a binding compound described herein via a mechanism other than apoptosis. Preferably, said ML effect is exerted via necrosis.

In a further red embodiment, an antibody or functional part or functional equivalent according to the present disclosure is described which is able to diminish proliferation of AML cells in vitro within 7 days, preferably within 5 days, more preferably within 3 days and even more preferably within 1 day. This indicates a quick therapeutic effect.

The present disclosure bes isolated, synthetic and recombinant human antibodies, and functional parts or functional equivalents thereof, which are able to bind intact AML cells. Said AML cells preferably belong to a French-American- British (FAB) fication selected from the group consisting of M5, M0, M1, M2, M3 and M4. More preferably, said AML cells belong to the FAB classification M5 or M1 or M0 or M4, ably M5. These are the FAB classifications commonly found in AML patients.

In a further preferred embodiment, isolated, tic and recombinant human antibodies, or functional parts or functional equivalents thereof, are described which are able to bind different AML cells of at least two, preferably at least three, more preferably at least four different FAB classifications. Such antibodies are useful for different AML patients having different FAB classifications, so that these antibodies are broadly able. As shown in Table 3, antibody AT12-025 is capable of binding AML cells of at least two FAB classifications (M5 + M1). This is, therefore, a preferred antibody according to the present sure. Antibodies AT13-024, AT12-019, AT13-023, and AT13-022 are capable of binding AML cells of at least three FAB classifications ( M5 + M0 + M1). Antibody AT13-031 is also capable of binding AML cells of at least three FAB classifications ( M5 + M1 + M4).

These antibodies are, therefore, even more preferred. Furthermore, antibody AT12- 023 is capable of binding AML cells of at least four FAB classifications (M5 + M0 + M1 + M4). This dy is, ore, even more broadly applicable and is, therefore, particularly preferred.

In one particularly preferred embodiment, an antibody or functional part or functional equivalent according to the t disclosure is described wherein said antibody is of the IgG isotype, preferably IgG1 or IgG3. This is beneficial for medical applications in humans.

Tables 1A and 1B, and Figure 1, provide an overview of the variable heavy and light chain sequences, as well as the dual CDR sequences, of antibodies AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, AT12- 020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, 13, 14, AT14-015 and AT14-016. These are red antibodies according to the present disclosure, obtained from three human AML patients. The terms “AT12-023”, “AT12-025”, 024”, “AT12-019”, “AT13-022”, “AT13-023”, “AT13-031”, “AT12- 020”, “AT13-033”, “AT13-034”, “AT13-035”, “AT13-036”, “AT13-037”, “AT14-013”, “AT14-014”, “AT14-015” and “AT14-016” as used herein encompass all antibodies and functional parts and onal equivalents having at least the heavy and light chain CDR1-3 s, preferably the variable heavy chain and light chain sequences, of these antibodies as depicted in Tables 1A and 1B and Figure 1, such as for instance isolated and/or purified antibodies or recombinantly produced antibodies.

As used herein, any reference to “Table 1” includes a nce to Table 1A and/or Table 1B.

Based on the antibodies depicted in Table 1 and Figure 1, it is le to produce an antibody or functional part or functional equivalent thereof comprising at least one CDR ce of an antibody depicted in Table 1 or Figure 1, which is specific for AML cells. Described is therefore an isolated, recombinant and/or synthetic antibody or a functional part or functional equivalent thereof sing at least one CDR sequence of an antibody as depicted in Table 1. Said CDR ce is preferably a CDR3 sequence of an antibody according to the present sure. Preferably, binding compounds are described which comprise at least two CDRs, more ably at least three CDRs, of the heavy and light chains of the same antibody indicated in Table 1 or Figure 1. Hence, preferably at least two or three CDRs of the heavy and light chains of antibody AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, AT12-020, AT13-033, AT13- 034, AT13-035, AT13-036, AT13-037, 13, AT14-014, 15 or AT14-016 are jointly present in one binding compound according to the present disclosure. ably, a binding compound described herein comprises all three heavy chain CDRs and all three light chain CDRs of the same antibody ed in Table 1 or Figure 1. Optionally, at least one of said CDR sequences is optimized, thereby generating a variant binding compound, preferably in order to improve binding efficacy, selectivity, or stability. This is for instance done by mutagenesis procedures where after the stability and/or binding efficacy of the resulting nds are ably tested and an improved AML-specific binding compound is selected. A skilled person is well capable of generating variants comprising at least one altered CDR sequence according to the present disclosure. For instance, conservative amino acid substitution is applied. Examples of conservative amino acid substitution include the substitution of one hobic residue such as isoleucine, valine, leucine or methionine for another hydrophobic residue, and the substitution of one polar residue for another polar residue, such as the substitution of arginine for lysine, glutamic acid for aspartic acid, or glutamine for asparagine.

Preferably, an dy or functional part or functional equivalent is described comprising a CDR sequence which is at least 80% identical to a CDR sequence as depicted in Table 1 or Figure 1, so that the favourable nding and/or AML- killing characteristic of an AML-specific antibody as ed in Table 1 or Figure 1 is maintained or even improved. Variant binding compounds comprising an amino acid sequence which is at least 80% cal to a CDR sequence as depicted in Table 1 or Figure 1 are therefore also within the scope of the present invention.

Preferably, said binding nds comprise heavy chain and light chain CDR 1-3 ces which are at least 80% identical to the heavy and light chain CDR 1-3 sequences of the same antibody depicted in Table 1 or Figure 1. Preferably, the CDR ces differ in no more than three, preferably in no more than two, preferably in no more than one amino acid from the original CDR sequences of an antibody according to the present disclosure.

Besides optimizing CDR sequences in order to improve binding efficacy or stability, at least one sequence in at least one of the ork regions can be optimized. This is preferably done in order to improve binding efficacy or stability.

Framework sequences are for instance optimized by mutating a nucleic acid molecule encoding such framework sequence where after the characteristics of the resulting antibody – or functional part or functional equivalent – are preferably tested. This way, it is possible to obtain improved binding compounds. In a red embodiment, human germline sequences are used for ork regions in antibodies according to the t disclosure. The use of human germline sequences minimizes the risk of immunogenicity of said antibodies, because these sequences are less likely to contain somatic alterations which are unique to individuals from which the framework regions are d, and may cause an immunogenic response when applied to another human individual. Further described is therefore a synthetic or recombinant antibody or onal part or functional equivalent according to the present disclosure, comprising at least one non-natural mutation in a framework region. Additionally, or atively, a synthetic or recombinant antibody or onal part or functional equivalent according to the present disclosure is described that comprises at least one nonnatural mutation in a constant region. By a “non-natural mutation” is meant that the resulting amino acid sequence does not occur in nature. d, it has been artificially produced. In one embodiment, an IgG3 Fc region of antibody AT12-023, AT12-025, AT13-024, AT13-022, 20, AT14-014, AT14-015 or AT14-016 is at least partly replaced by an IgG1 Fc . This typically increases the stability and half life of the resulting immunoglobulin.

A binding nd described herein preferably comprises a human variable region. More preferably, said binding compound comprises a human constant region and a human variable region. Most preferably, said binding compound is a human antibody. The use of human AML-specific antibodies is advantageous over the use of man antibodies. The in vivo use of non-human antibodies for diagnosis and/or treatment of human diseases is hampered by a number of factors. In particular, the human body may recognize non-human antibodies as foreign, which will result in an immunogenic response against the non-human antibodies, resulting in adverse side effects and/or rapid clearance of the antibodies from the circulation. A human antibody shes the chance of side-effects when stered to a human dual and often results in a longer half-life in the circulation because of reduced clearance when compared to nonhuman antibodies. In another embodiment a binding compound described herein is a humanized antibody. In another embodiment a binding compound described herein is a chimeric antibody. In a chimeric antibody, sequences of interest, such as for instance an additional binding site of interest, are included into a binding nd according to the present disclosure.

Further, binding compounds described herein are preferably monoclonal antibodies. A monoclonal antibody is an antibody consisting of a single molecular s. Monoclonal antibodies can be ed in large quantities by onal antibody-producing cells or recombinant DNA technology.

Hence, variant binding nds based on the preferred antibodies depicted in Table 1 and Figure 1 can also be generated, using techniques known in the art such as for instance nesis. Typically, sequence variations between 80 and 99% are tolerated while maintaining a certain antigen specificity. Binding nds described herein comprising a sequence that has at least 80% sequence ty to at least a CDR sequence of any of the antibodies of Table 1 or Figure 1 are therefore also described herein. Since the antigen specificity of an antibody is typically dominated by the CDR3 sequences, a variant dy described herein preferably comprises at least a heavy chain CDR3 sequence having at least 80% sequence ty with a heavy chain CDR3 sequence as depicted in Table 1 or Figure 1. Said variant antibody preferably comprises a heavy chain CDR3 sequence and a light chain CDR3 sequence having at least 80% sequence identity with the heavy and light chain CDR3 sequences of the same antibody, selected from the group consisting of AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13- 023, AT13-031, AT12-020, 33, AT13-034, AT13-035, 36, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016. r described is, ore, an ed, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises at least a heavy chain CDR3 sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 27-39 and 217-220, and a light chain CDR3 sequence having at least 80% sequence ty with a ce selected from the group consisting of SEQ ID NOs: 66-78 and 229-232.

These are the CDR3 sequences of antibodies AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, AT12-020, AT13-033, AT13-034, AT13- 035, AT13-036, 37, AT14-013, AT14-014, AT14-015 and AT14-016 depicted in Table 1 and Figure 1. Preferably, said sequence identity is at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more ably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As said before, a binding compound described herein preferably comprises a heavy and light chain CDR3 sequence having at least 80% sequence identity with the heavy and light chain CDR3 sequences of the same antibody, selected from Table 1 or Figure 1. lly, at least 1, 2 or 3 amino acid residues of a given CDR sequence may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, a binding compound described herein preferably contains a heavy chain and light chain CDR3 sequence wherein at most 3, preferably at most 2, more preferably at most 1 amino acid deviates from a heavy and light chain CDR 3 sequence from the same antibody selected from the group consisting of AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, 20, AT13- 033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with a ce selected from the group consisting of SEQ ID NOs: 1-13 and 209-212; and/or - a heavy chain CDR2 sequence comprising a ce which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 14-26 and 213-216; and/or - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 27-39 and 217-220; and/or - a light chain CDR1 ce comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 40-52 and 221-224; and/or - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with a sequence selected from the group ting of SEQ ID NOs: 53-65 and 225-228; and/or - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 66-78 and 229-232.

These are the heavy and light chain CDR sequences of antibodies 23, AT12- 025, AT13-024, AT12-019, AT13-022, 23, AT13-031, AT12-020, AT13-033, AT13-034, AT13-035, AT13-036, 37, AT14-013, 14, AT14-015 and AT14-016, depicted in Table 1A and 1B and in Figure 1.

The above mentioned heavy and light chain CDR 1 to 3 sequences are preferably from the same antibody selected from Table 1 or Figure 1. Preferably, said antibody or functional part or equivalent comprises heavy chain CDR1, CDR2 and CDR3 sequences and light chain CDR1, CDR2 and CDR3 sequences that are at least 85%, more ably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more ably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100% identical to the above recited CDR sequences (SEQ ID NOs 1-78 and 209-232).

In a preferred embodiment, the heavy chain CDR1 and CDR2 and CDR3 ces, as well as the light chain CDR1 and CDR2 and CDR3 sequences, of the same antibody, selected from the group consisting of antibodies AT12-023, AT12- 025, AT13-024, AT12-019, AT13-022, 23, AT13-031, AT12-020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016 are present in a given binding compound according to the present sure.

A preferred antibody bed herein is antibody 23. This antibody is preferred because it is capable of efficiently binding and killing cells of the AML cell line THP-1, as shown in the Examples and Figures 7 and 8. This antibody is, therefore, ularly suitable for AML therapy and/or diagnosis. Interestingly, AT12-023 is of the IgG3 isotype and belongs to the VH4-34 family, which is a family of VH sequences known for their potential killing properties (Bhat et al, 1997). Antibody AT12-023 is also capable of ently binding y AML blasts of at least four different FAB classifications (Table 3). The heavy chain CDR1, CDR2 and CDR3 sequences, and the light chain CDR1, CDR2 and CDR3 sequences of antibody AT12-023 are SEQ ID NOs 1, 14, 27, 40, 53 and 66, respectively, as ed in Table 1. Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 85% sequence ty with SEQ ID NO: 1; and - a heavy chain CDR2 sequence comprising a sequence which has at least 85% sequence identity with SEQ ID NO: 14; and - a heavy chain CDR3 sequence comprising a sequence which has at least 85% sequence identity with SEQ ID NO: 27; and - a light chain CDR1 sequence comprising a sequence which has at least 85% sequence identity with SEQ ID NO: 40; and - a light chain CDR2 sequence comprising a sequence which has at least 85% sequence identity with SEQ ID NO: 53; and - a light chain CDR3 sequence comprising a sequence which has at least 85% sequence identity with SEQ ID NO: 66. Preferably, said sequence identities are at least 86%, more preferably at least 87%, more ably at least 88%, more preferably at least 89%, more preferably at least 90%, more ably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more ably 100%. As described herein before, at least 1, 2 or 3 amino acid residues in the recited CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, said heavy and light chain CDR 1, 2 and 3 sequences preferably n antibody AT12 derived CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT12-023 CDR sequences.

Another preferred antibody described herein is antibody AT12-025. This dy is preferred because it is capable of efficiently binding and killing cells of the AML cell line THP-1, as well as patient-derived primary AML blasts, as shown in the Examples and Figures 8 and 10. This antibody is, therefore, particularly suitable for AML y and/or diagnosis. Interestingly, AT12-025 is of the IgG3 isotype and belongs to the VH4-34 family, which is a family of VH sequences known for their potential killing properties (Bhat et al, 1997). The heavy chain CDR1, CDR2 and CDR3 sequences and the light chain CDR1, CDR2 and CDR3 ces of antibody 25 are SEQ ID NOs 2, 15, 28, 41, 54 and 67, respectively, as depicted in Table 1. Also described is an ed, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 2; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 15; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 28; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 41; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 54; and - a light chain CDR3 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 67. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more ably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT12-025 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences ably n CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT12-025 CDR sequences.

Another preferred dy described herein is antibody AT13-024. This antibody is preferred because it is capable of g and g patient-derived primary AML blasts, as shown in the Examples and Figure 10. This antibody is, therefore, particularly suitable for AML therapy and/or diagnosis. Interestingly, AT13-024 is of the IgG3 isotype and belongs to the VH3-30 family. The heavy chain CDR 1, CDR2 and CDR3 ces and the light chain CDR1, CDR2 and CDR3 sequences of antibody AT13-024 are SEQ ID NOs 3, 16 29, 42, 55 and 68, respectively, as depicted in Table 1. Also described is an isolated, synthetic or recombinant antibody, or a functional part or a onal equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 3; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 16; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 29; and - a light chain CDR1 ce comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 42; and - a light chain CDR2 sequence comprising a ce which has at least 80% ce identity with SEQ ID NO: 55; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 68. Again, said sequence identities are preferably at least 85%, more ably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more ably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-024 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT13-024 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a onal equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 4; and - a heavy chain CDR2 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 17; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 30; and - a light chain CDR1 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 43; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 56; and - a light chain CDR3 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 69. These are the CDR sequences of antibody AT12-019. Antibody AT12-019, derived from a human AML patient in complete remission, is capable of efficiently binding intact AML cells, which makes a binding compound containing AT12derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic compound will be ed to AML cells, or it is used by ng CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune se.

Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more ably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more ably at least 91%, more ably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As bed above, at least 1, 2 or 3 amino acid residues in the recited AT12-019 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited 19 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional lent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 5; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 18; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 31; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 44; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 57; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 70. These are the CDR sequences of antibody AT13-022. Interestingly, antibody 22 is of the IgG3 isotype. dy AT13- 022, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a binding compound containing AT13derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic compound will be ed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or onally, such binding nd can be used to mark AML cells for specific ytosis by tumorassociated myeloid cells such as hages or dendritic cells, which cells can subsequently induce an AML specific immune response. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more ably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-022CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more ably no more than one amino acid from the recited AT13-022 CDR sequences.

Also decribed is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent f, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 6; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 19; and - a heavy chain CDR3 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 32; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 45; and - a light chain CDR2 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 58; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 71. These are the CDR sequences of antibody AT13-023. stingly, AT13-023 belongs to the VH4-34 family, which is a family of VH sequences known for their potential killing properties (Bhat et al, 1997).

Antibody AT13-023, d from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a binding compound containing AT13derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune se.

Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more ably at least 87%, more preferably at least 88%, more preferably at least 89%, more ably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more ably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-023 CDR sequences may vary while retaining the same kind of binding activity (in kind, not arily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more ably no more than one amino acid from the recited AT13-023 CDR ces.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 7; and - a heavy chain CDR2 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 20; and - a heavy chain CDR3 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 33; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 46; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 59; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 72. These are the CDR sequences of antibody AT13-031. Interestingly, AT13-031 belongs to the VH4-34 family, which is a family of VH sequences known for their potential killing properties (Bhat et al, 1997).

Antibody AT13-031, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells. Moreover, this antibody is preferred because it is capable of efficiently binding and killing cells of the AML cell line THP-1. Hence, a g compound containing AT13derived CDR sequences is particularly suitable for AML y and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding nd can be used to mark AML cells for specific ytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can uently induce an AML ic immune response. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-031 CDR sequences may vary while ing the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences ably contain CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT13-031 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 8; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 21; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 34; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 47; and - a light chain CDR2 ce comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 60; and - a light chain CDR3 ce sing a sequence which has at least 80% sequence identity with SEQ ID NO: 73. These are the CDR sequences of dy AT12-020. Interestingly, antibody AT12-020 is of the IgG3 isotype. Antibody AT12- 020, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a binding compound containing -derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an dy-drug conjugate (ADC), such that a toxic nd will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or onally, such binding compound can be used to mark AML cells for specific phagocytosis by tumorassociated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune response. Again, said sequence identities are ably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more ably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more ably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT12-020 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably n CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT12-020 CDR sequences.

Also described is an isolated, synthetic or recombinant dy, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 9; and - a heavy chain CDR2 ce comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 22; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 35; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 48; and - a light chain CDR2 sequence comprising a sequence which has at least 80% ce identity with SEQ ID NO: 61; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 74. These are the CDR sequences of antibody AT13-033. Antibody AT13-033, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells. er, this antibody is preferred because it is capable of efficiently binding and killing cells of the AML cell line THP-1. Hence, a g compound containing AT13derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an antibody-drug ate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or tic cells, which cells can subsequently induce an AML specific immune response. Again, said ce identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more ably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-033 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences ably n CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT13-033 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent f, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 10; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% ce identity with SEQ ID NO: 23; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 36; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 49; and - a light chain CDR2 sequence comprising a sequence which has at least 80% ce identity with SEQ ID NO: 62; and - a light chain CDR3 sequence comprising a sequence which has at least 80% ce identity with SEQ ID NO: 75. These are the CDR sequences of antibody AT13-034. Antibody 34, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a binding compound containing AT13derived CDR sequences particularly suitable for AML y and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic nd will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or onally, such g compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML ic immune response.

Again, said sequence identities are preferably at least 85%, more ably at least 86%, more preferably at least 87%, more preferably at least 88%, more ably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-034 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount). Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that e in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT13-034 CDR sequences.

Also described is an isolated, synthetic or inant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 11; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 24; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 37; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 50; and - a light chain CDR2 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 63; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 76. These are the CDR ces of antibody AT13-035. Antibody AT13-035, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells. Moreover, this antibody is preferred because it is capable of efficiently binding and killing cells of the AML cell line THP-1. Hence, a binding compound containing AT13derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic nd will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such g compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML ic immune response. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more ably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-035 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT13-035 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 12; and - a heavy chain CDR2 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 25; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 38; and - a light chain CDR1 ce sing a ce which has at least 80% sequence identity with SEQ ID NO: 51; and - a light chain CDR2 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 64; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 77. These are the CDR sequences of antibody AT13-036. Antibody AT13-036, derived from a human AML patient in complete remission, is capable of ically binding intact AML cells. Moreover, this antibody is preferred because it is capable of efficiently binding and killing cells of the AML cell line THP-1. Hence, a binding compound containing AT13derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific ytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune response. Again, said ce identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more ably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT13-036 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in ).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more preferably no more than one amino acid from the d AT13-036 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a onal equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 13; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 26; and - a heavy chain CDR3 sequence sing a sequence which has at least 80% ce identity with SEQ ID NO: 39; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 52; and - a light chain CDR2 sequence comprising a ce which has at least 80% sequence identity with SEQ ID NO: 65; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 78. These are the CDR sequences of antibody AT13-037. Antibody AT13-037, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells. Moreover, this antibody is preferred because it is capable of ently binding and killing cells of the AML cell line THP-1, as well as patient-derived primary AML blasts, as shown in the Examples. Hence, a binding compound containing 37-derived CDR sequences particularly suitable for AML therapy and/or sis. Such g compound is for instance used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune response. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more ably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid es in the recited AT13-037 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences preferably n CDR sequences that e in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT13-037 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence sing a sequence which has at least 80% sequence ty with SEQ ID NO: 209; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 213; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 217; and - a light chain CDR1 sequence comprising a sequence which has at least 80% ce identity with SEQ ID NO: 221; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 225; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 229. These are the CDR sequences of dy AT14-013. Antibody AT14-013, d from a human AML patient in complete remission, is capable of specifically binding primary AML blasts of at least three different FAB classifications, which makes a binding compound containing AT14- 013-derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used for diminishing proliferation of AML cells, preferably ndently from apoptosis and/or independently from ADCC, CDC or ytosis by macrophages or dendritic cells. Preferably, said binding compound is used for inducing death of AML cells. In some embodiments, such g compound is used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as hages or dendritic cells, which cells can subsequently induce an AML specific immune se. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more ably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT14-013 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above ned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, preferably no more than two, more ably no more than one amino acid from the recited AT14-013 CDR sequences.

Also described is an ed, synthetic or recombinant antibody, or a functional part or a onal equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 210; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 214; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 218; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 222; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 226; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 230. These are the CDR sequences of antibody AT14-014. Interestingly, antibody AT14-014 is of the IgG3 isotype. Antibody AT14-014, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a binding compound containing AT14derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for ce used for diminishing proliferation of AML cells, preferably independently from apoptosis and/or independently from ADCC, CDC or phagocytosis by macrophages or tic cells. Preferably, said binding compound is used for inducing death of AML cells. In some embodiments, such binding compound is used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such g compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can uently induce an AML specific immune response. Again, said sequence identities are ably at least 85%, more ably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT14-014 CDR sequences may vary while retaining the same kind of g activity (in kind, not necessarily in ).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences ably contain CDR sequences that e in no more than three, preferably no more than two, more preferably no more than one amino acid from the recited AT14-014 CDR sequences.

Also described is an isolated, synthetic or inant antibody, or a functional part or a functional equivalent thereof, which ses: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 211; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 215; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 219; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 223; and - a light chain CDR2 ce comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 227; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 231. These are the CDR sequences of antibody AT14-015. Interestingly, antibody AT14-015 is of the IgG3 isotype. Antibody AT14-015, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a binding compound containing AT14derived CDR ces particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used for diminishing proliferation of AML cells, preferably independently from apoptosis and/or independently from ADCC, CDC or phagocytosis by hages or dendritic cells. Preferably, said binding compound is used for inducing death of AML cells. In some embodiments, such binding compound is used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune response. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more ably at least 91%, more ably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT14-015 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above mentioned heavy and light chain CDR 1, 2 and 3 sequences ably contain CDR sequences that deviate in no more than three, preferably no more than two, more ably no more than one amino acid from the recited AT14-015 CDR sequences.

Also described is an isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent f, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 212; and - a heavy chain CDR2 sequence sing a sequence which has at least 80% sequence ty with SEQ ID NO: 216; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence ty with SEQ ID NO: 220; and - a light chain CDR1 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 224; and - a light chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with SEQ ID NO: 228; and - a light chain CDR3 sequence sing a sequence which has at least 80% sequence identity with SEQ ID NO: 232. These are the CDR sequences of antibody AT14-016. Interestingly, antibody AT14-016 is of the IgG3 isotype. Antibody AT14-016, derived from a human AML patient in complete remission, is capable of specifically binding intact AML cells, which makes a g compound containing AT14derived CDR sequences particularly suitable for AML therapy and/or diagnosis. Such binding compound is for instance used for diminishing proliferation of AML cells, preferably independently from apoptosis and/or independently from ADCC, CDC or phagocytosis by macrophages or dendritic cells. Preferably, said binding nd is used for inducing death of AML cells. In some embodiments, such binding compound is used as an antibody-drug conjugate (ADC), such that a toxic compound will be directed to AML cells, or it is used by inducing CDC and/or ADCC. Alternatively, or additionally, such binding compound can be used to mark AML cells for specific phagocytosis by tumor-associated myeloid cells such as macrophages or dendritic cells, which cells can subsequently induce an AML specific immune response. Again, said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more ably at least 96%, more ably at least 97%, more preferably at least 98%, more ably at least 99%, more preferably 100%. As described above, at least 1, 2 or 3 amino acid residues in the recited AT14-016 CDR sequences may vary while retaining the same kind of binding activity (in kind, not necessarily in amount).

Hence, the above ned heavy and light chain CDR 1, 2 and 3 sequences preferably contain CDR sequences that deviate in no more than three, ably no more than two, more preferably no more than one amino acid from the recited AT14-016 CDR ces.

Preferably, an dy described hereincomprises a variable heavy chain sequence and/or a variable light chain sequence as depicted in Table 1 or Figure 1, or a sequence which has at least 80% sequence identity thereto. As shown in Table 1, the variable heavy chain sequences of antibodies AT12-023, 25, AT13- 024, AT12-019, AT13-022, AT13-023, AT13-031, AT12-020, 33, AT13-034, AT13-035, AT13-036, AT13-037, 13, AT14-014, AT14-015 and AT14-016 are SEQ ID NOs 79-91 and 233-236, respectively. The variable light chain sequences of antibodies AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13- 031, AT12-020, AT13-033, 34, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016 are SEQ ID NOs 92-104 and 237-240, respectively. Also described is, therefore, an antibody or functional part or equivalent thereof according to the present disclosure, comprising a variable heavy chain sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 79-91 and 233-236, and/or comprising a le light chain sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 92-104 and 237-240, or sequences that are at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, or even 100% identical to any one of these heavy chain or light chain sequences. The higher the identity, the more closely an antibody resembles an antibody depicted in Figure 1. Preferably, a binding compound described hereincomprises the variable heavy chain sequence of any one of the dies depicted in Figure 1, together with the variable light chain sequence of the same antibody, or heavy and light chain ces that are at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, thereto.

For instance, antibody AT12-023 has the variable heavy chain ce of SEQ ID NO: 79 and the variable light chain sequence of SEQ ID NO: 92 as depicted in Table 1. A binding compound ing to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence ty with SEQ ID NO: 79 is therefore preferably described. ably, said binding compound also ses a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 92.

Antibody AT12-025 has the variable heavy chain sequence of SEQ ID NO: 80 and the variable light chain sequence of SEQ ID NO: 93 as ed in Table 1.

Further described is therefore a binding compound according to the present disclosure, having a variable heavy chain sequence having at least 80%, ably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 80. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, ably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 93.

Antibody AT13-024 has the variable heavy chain sequence of SEQ ID NO: 81 and the variable light chain sequence of SEQ ID NO: 94 as depicted in Table 1. r described is therefore a binding compound ing to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 81. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 94.

Antibody AT12-019 has the variable heavy chain sequence of SEQ ID NO: 82 and the variable light chain sequence of SEQ ID NO: 95 as depicted in Table 1. r described is therefore a binding compound according to the present disclosure, having a variable heavy chain sequence having at least 80%, ably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 82. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, ably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 95.

Antibody AT13-022 has the variable heavy chain sequence of SEQ ID NO: 83 and the variable light chain sequence of SEQ ID NO: 96 as depicted in Table 1.

Further described is therefore a binding compound according to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence ty with SEQ ID NO: 83. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 96. dy AT13-023 has the variable heavy chain sequence of SEQ ID NO: 84 and the variable light chain sequence of SEQ ID NO: 97 as depicted in Table 1.

Further described is therefore a g compound ing to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 84. Preferably, said binding compound also comprises a le light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, ce identity with SEQ ID NO: 97.

Antibody AT13-031 has the le heavy chain sequence of SEQ ID NO: 85 and the variable light chain sequence of SEQ ID NO: 98 as depicted in Table 1.

Further described is therefore a binding nd according to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 85. Preferably, said binding compound also ses a variable light chain sequence having at least 80%, ably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 98.

Antibody AT12-020 has the variable heavy chain sequence of SEQ ID NO: 86 and the variable light chain sequence of SEQ ID NO: 99 as depicted in Table 1.

Further described is therefore a binding compound according to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 86. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 99.

Antibody AT13-033 has the le heavy chain sequence of SEQ ID NO: 87 and the variable light chain sequence of SEQ ID NO: 100 as depicted in Table 1.

Further provided is therefore a binding compound ing to the t disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 87. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 100.

Antibody AT13-034 has the le heavy chain sequence of SEQ ID NO: 88 and the variable light chain sequence of SEQ ID NO: 101 as depicted in Table 1.

Further described is therefore a binding compound according to the present disclosure, having a variable heavy chain ce having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 88. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 101.

Antibody AT13-035 has the variable heavy chain sequence of SEQ ID NO: 89 and the variable light chain sequence of SEQ ID NO: 102 as depicted in Table 1.

Further described is therefore a binding compound according to the present sure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 89. Preferably, said g compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 102.

Antibody 36 has the variable heavy chain sequence of SEQ ID NO: 90 and the variable light chain sequence of SEQ ID NO: 103 as depicted in Table 1.

Further described is therefore a binding compound according to the t disclosure, having a le heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 90. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 103.

Antibody AT13-037 has the variable heavy chain sequence of SEQ ID NO: 91 and the variable light chain sequence of SEQ ID NO: 104 as ed in Table 1.

Further bed is therefore a binding compound according to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 91. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 104.

Antibody AT14-013 has the le heavy chain sequence of SEQ ID NO: 233 and the le light chain sequence of SEQ ID NO: 237 as depicted in Table 1. r described is therefore a binding compound ing to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 233. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 237.

Antibody AT14-014 has the variable heavy chain ce of SEQ ID NO: 234 and the variable light chain sequence of SEQ ID NO: 238 as depicted in Table 1. Further described is therefore a binding compound according to the present disclosure, having a variable heavy chain ce having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 234. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 238.

Antibody AT14-015 has the variable heavy chain sequence of SEQ ID NO: 235 and the variable light chain sequence of SEQ ID NO: 239 as depicted in Table 1. Further desribed is therefore a binding compound according to the present disclosure, having a variable heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 235. Preferably, said binding compound also comprises a variable light chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 239.

Antibody AT14-016 has the variable heavy chain sequence of SEQ ID NO: 236 and the le light chain sequence of SEQ ID NO: 240 as depicted in Table 1. Further described is therefore a binding nd according to the present disclosure, having a le heavy chain sequence having at least 80%, preferably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity with SEQ ID NO: 236. ably, said g compound also comprises a variable light chain sequence having at least 80%, ably at least 85%, or at least 86%, or at least 87%, or at least 88%, or at least 89%, or at least 90%, or at least 91%, or at least 92%, or at least 93%, or at least 94%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, sequence identity with SEQ ID NO: 240.

In one ularly preferred embodiment, an antibody or functional part or functional equivalent according to the present disclosure is described, which is able to bind snRNP200. snRNP200, also known as U5-snRNP, is a protein complex that is part of the spliceosome in all eukaryotic cells. Normally, snRNP200 is located in the nucleus. r, the present disclosure describes the surprising insight that snRNP200 is also present on the surface of AML cells. This antigen is bound by at least antibodies AT12-023, AT13-031 and AT13-037, and functional parts and functional equivalents thereof. Hence, snRNP200 is an important target for anti- AML therapy and snRNP200-specific antibodies described are therefore particularly suitable for counteracting these cells.

Also described is an isolated, synthetic or recombinant nucleic acid le with a length of at least 15 nucleotides, or a functional equivalent thereof, encoding at least one CDR ce of an antibody or functional part or functional equivalent according to the disclosure. Preferably a nucleic acid molecule bed hereinhas a length of at least 30 tides, more preferably at least 50 nucleotides, more preferably at least 75 nucleotides. A c acid molecule described hereinis for instance isolated from a B-cell which is capable of producing an antibody according to the disclosure. Said B-cell preferably produces antibody 23, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, AT12- 020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037 AT14-013, AT14-014, AT14-015, or AT14-016. In a preferred embodiment a nucleic acid molecule encoding at least the heavy chain CDR3 sequence and the light chain CDR3 sequence of an antibody according to the t disclosure is described.

As used herein the term “an isolated, synthetic or recombinant nucleic acid molecule with a length of at least 15 nucleotides, or a functional equivalent thereof, ng at least one CDR sequence of an antibody or functional part or functional equivalent according to the invention” is herein also referred to as “a c acid molecule or functional equivalent ing to the invention”.

As used herein, a c acid molecule or nucleic acid sequence of the invention preferably comprises a chain of nucleotides, more preferably DNA, cDNA or RNA. In other embodiments a nucleic acid molecule or nucleic acid ce of the invention comprises other kinds of nucleic acid structures such as for instance a DNA/RNA helix, peptide nucleic acid (PNA), locked c acid (LNA) and/or a ribozyme. Such other nucleic acid structures are referred to as functional equivalents of a nucleic acid sequence. The term “functional equivalent of a nucleic acid molecule” thus encompasses a chain comprising non-natural nucleotides, modified nucleotides and/or non-nucleotide building blocks which exhibit the same function as l nucleotides.

Nucleic acid sequences encoding heavy chain and light chain CDRs of antibodies AT12-023, AT12-025, AT13-024, AT12-019, 22, AT13-023, AT13- 031, 20, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016 are depicted in Table 1. Nucleic acid molecules encoding a heavy or light chain CDR of an antibody described hereinwhich differ from the CDR nucleic acid sequences depicted in Table 1 but have nucleic acid codons which encode the same amino acids of said heavy or light chain CDR are also encompassed by the disclosure. Such nucleic acid molecules for instance se nucleic acid sequences that have been codon optimized for a er cell, such as for instance E.coli or Chinese hamster ovary (CHO) cells, NSO cells (a mouse myeloma) or 293(T) cells, enabling high scale production of binding compounds ing to the present disclosure. It should be noted that antibody production can be done by any recombinant antibody production system; the four producer cell systems mentioned here are only a few examples of the many systems that are ble to date. As used herein, the term “codon” means a triplet of tides (or functional equivalents thereof) that encode a specific amino acid residue. The term “codon optimized” means that one or more codons from the original, human nucleic acid sequence are replaced by one or more codons that are red by a certain antibody production system. These replacement codons preferably encode the same amino acid residue as the original human codon that has been replaced. Alternatively, one or more replacement codons encode a different amino acid residue. This preferably results in vative amino acid substitution, although this is not necessary. Typically, in constant regions and framework regions one or more amino acid substitutions are generally allowed. In CDR regions, ably codons are used that encode the same amino acid residue as the original human codon that has been replaced. rmore, c acid molecules encoding a heavy or light chain CDR which is not identical to, but based on, a CDR sequence of an antibody depicted in Table 1 are also encompassed by the present disclosure, as long as the resulting CDR has at least 80% sequence identity with a CDR sequence depicted in Table 1.

Further described is, ore, a nucleic acid le or functional equivalent thereof or a vector, comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs:105-182 and 241-264. Preferably, the resulting CDR differs in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequence of an antibody ing to the present disclosure.

Preferred nucleic acid molecules or functional equivalents or vectors described hereincomprise: - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence ty to a sequence which is selected from the group consisting of SEQ ID NO's:105-117 and 241-244, and/or - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to a sequence which is selected from the group consisting of SEQ ID 18-130 and 245-248, and/or - a heavy chain CDR3 ng sequence which has at least 80% sequence identity to a sequence which is selected from the group consisting of SEQ ID NO's:131-143 and 249-252, and/or - a light chain CDR1 encoding sequence which has at least 80% sequence identity to a sequence which is selected from the group consisting of SEQ ID NO's:144-156 and 6, and/or - a light chain CDR2 encoding sequence which has at least 80% sequence identity to a sequence which is selected from the group consisting of SEQ ID NO's:157-169 and 257-260, and/or - a light chain CDR3 encoding sequence which has at least 80% sequence ty to a sequence which is selected from the group consisting of SEQ ID NO's:170-182 and 261-264.

Said ce identities are preferably at least 85%, more preferably at least 90%, most preferably at least 95% sequence, most preferably 100%. A nucleic acid molecule described preferably comprises heavy chain CDR 1-3 -encoding sequences and light chain CDR 1-3 -encoding sequences from the same dy, wherein said antibody is selected from the group consisting of AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, 31, AT12-020, AT13-033, AT13- 034, AT13-035, AT13-036, AT13-037, 13, AT14-014, AT14-015 and AT14-016, and heavy chain CDR 1-3 -encoding sequences and light chain CDR 1-3 - encoding sequences that have at least 80% sequence identity thereto.

Further described is a nucleic acid le or functional equivalent or one or more s that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence ty to SEQ ID NO: 105, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 118, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 131, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 144, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 157, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 170. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT12-023. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT12-023.

Further described is a c acid molecule or functional equivalent or one or more s that comprise(s): - a heavy chain CDR1 encoding nucleic acid ce which has at least 80% sequence identity to SEQ ID NO: 106, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 119, and - a heavy chain CDR3 ng ce which has at least 80% sequence identity to SEQ ID NO: 132, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 145, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 158, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 171. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT12-025. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. ably, the resulting CDR ces differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of dy AT12-025. r described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 107, and - a heavy chain CDR2 ng sequence which has at least 80% sequence identity to SEQ ID NO: 120, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 133, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 146, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 159, and - a light chain CDR3 encoding sequence which has at least 80% ce ty to SEQ ID NO: 172. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT13-024. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 108, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 121, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 134, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 147, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 160, and - a light chain CDR3 encoding sequence which has at least 80% sequence ty to SEQ ID NO: 173. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody 19. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the ing CDR sequences differ in no more than three, preferably in no more than two, ably in only one amino acid from the original CDR sequences of antibody AT12-019. r described is a nucleic acid molecule or onal equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 109, and - a heavy chain CDR2 encoding sequence which has at least 80% ce identity to SEQ ID NO: 122, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 135, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 148, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 161, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 174. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT13-022. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR ces of antibody AT13-022.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 110, and - a heavy chain CDR2 encoding sequence which has at least 80% ce identity to SEQ ID NO: 123, and - a heavy chain CDR3 encoding ce which has at least 80% ce identity to SEQ ID NO: 136, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 149, and - a light chain CDR2 encoding ce which has at least 80% sequence identity to SEQ ID NO: 162, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 175. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT13-023. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT13-023.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 ng nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 111, and - a heavy chain CDR2 encoding ce which has at least 80% sequence identity to SEQ ID NO: 124, and - a heavy chain CDR3 encoding ce which has at least 80% sequence identity to SEQ ID NO: 137, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 150, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 163, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 176. The recited SEQ ID NOs are the heavy and light chain CDR1-3 ces of antibody 31. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the ing CDR sequences differ in no more than three, ably in no more than two, preferably in only one amino acid from the al CDR sequences of antibody AT13-031.

Further described is a nucleic acid molecule or functional lent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 112, and - a heavy chain CDR2 encoding ce which has at least 80% sequence ty to SEQ ID NO: 125, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 138, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 151, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 164, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 177. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT12-020. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT12-020.

Further bed is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 113, and - a heavy chain CDR2 encoding sequence which has at least 80% ce identity to SEQ ID NO: 126, and - a heavy chain CDR3 encoding ce which has at least 80% sequence identity to SEQ ID NO: 139, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 152, and - a light chain CDR2 encoding sequence which has at least 80% sequence ty to SEQ ID NO: 165, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 178. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody 33. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most ably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT13-033.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 ng nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 114, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 127, and - a heavy chain CDR3 encoding sequence which has at least 80% ce identity to SEQ ID NO: 140, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 153, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 166, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 179. The d SEQ ID NOs are the heavy and light chain CDR1-3 sequences of dy AT13-034. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. ably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT13-034.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 115, and - a heavy chain CDR2 ng sequence which has at least 80% sequence identity to SEQ ID NO: 128, and - a heavy chain CDR3 encoding sequence which has at least 80% ce identity to SEQ ID NO: 141, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 154, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 167, and - a light chain CDR3 ng sequence which has at least 80% sequence identity to SEQ ID NO: 180. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT13-035. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more ably at least 90%, most preferably at least 95%, most preferably 100%. ably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT13-035.

Further described is a c acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 116, and - a heavy chain CDR2 encoding sequence which has at least 80% ce identity to SEQ ID NO: 129, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 142, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 155, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 168, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 181. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT13-036. Again, said sequence identities are ably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the ing CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT13-036.

Further bed is a nucleic acid molecule or functional equivalent or one or more s that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 117, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 130, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 143, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 156, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 169, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 182. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT13-037. Again, said ce identities are preferably at least 80%, more ably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. ably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of antibody AT13-037.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% ce identity to SEQ ID NO: 241, and - a heavy chain CDR2 encoding sequence which has at least 80% ce identity to SEQ ID NO: 245, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 249, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 253, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 257, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 261. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT14-013. Again, said sequence identities are preferably at least 80%, more ably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the al CDR sequences of antibody AT14-013.

Further described is a nucleic acid molecule or onal lent or one or more vectors that se(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 242, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 246, and - a heavy chain CDR3 ng sequence which has at least 80% sequence identity to SEQ ID NO: 250, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 254, and - a light chain CDR2 encoding sequence which has at least 80% sequence ty to SEQ ID NO: 258, and - a light chain CDR3 encoding ce which has at least 80% sequence identity to SEQ ID NO: 262. The recited SEQ ID NOs are the heavy and light chain CDR1-3 ces of antibody AT14-014. Again, said sequence identities are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR ces of antibody AT14-014.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that comprise(s): - a heavy chain CDR1 encoding nucleic acid ce which has at least 80% sequence identity to SEQ ID NO: 243, and - a heavy chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 247, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 251, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 255, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 259, and - a light chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 263. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody 15. Again, said sequence identities are ably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR sequences differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR ces of antibody AT14-015.

Further described is a nucleic acid molecule or functional equivalent or one or more vectors that se(s): - a heavy chain CDR1 encoding nucleic acid sequence which has at least 80% sequence identity to SEQ ID NO: 244, and - a heavy chain CDR2 encoding sequence which has at least 80% ce identity to SEQ ID NO: 248, and - a heavy chain CDR3 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 252, and - a light chain CDR1 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 256, and - a light chain CDR2 encoding sequence which has at least 80% sequence identity to SEQ ID NO: 260, and - a light chain CDR3 encoding ce which has at least 80% sequence identity to SEQ ID NO: 264. The recited SEQ ID NOs are the heavy and light chain CDR1-3 sequences of antibody AT14-016. Again, said sequence ties are preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95%, most preferably 100%. Preferably, the resulting CDR ces differ in no more than three, preferably in no more than two, preferably in only one amino acid from the original CDR sequences of dy 16.

A preferred nucleic acid molecule or vector(s) described encode(s) at least the variable heavy chain sequence and/or the variable light chain sequence of an antibody or functional part or functional lent according to the present disclosure. Preferably, said nucleic acid molecule(s) or vector(s) encode(s) at least the variable heavy chain sequence and the le light chain sequence of an antibody or functional part or functional equivalent according to the present disclosure. In one embodiment, a nucleic acid molecule or functional equivalent or one or more vectors described herein which comprise(s) a ce which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs 183-195 and 265-268 and/or a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs 196-208 and 269-272. Said sequence identities are preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more ably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%.

More preferably, a nucleic acid molecule or a functional equivalent or one or more vectors according to the present disclosure comprise(s) a variable heavy chain encoding sequence as well as a variable light chain encoding sequence which resemble the variable heavy and light chain encoding ces of the same antibody depicted in Table 1. Thus, in a preferred embodiment a c acid le or functional equivalent or vector(s) described hereincomprise(s) the variable heavy chain encoding ce of antibody AT12-023, AT12-025, AT13- 024, AT12-019, AT13-022, 23, AT13-031, AT12-020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 or AT14-016, and the variable light chain encoding sequence of the same antibody, or sequences that are at least 80%, more preferably at least 85%, more preferably at least 86%, more preferably at least 87%, more preferably at least 88%, more preferably at least 89%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, cal thereto.

In some embodiments, nucleic acid molecules and functional equivalents thereof and vectors are described that encode an antibody or functional part or functional equivalent according to the present disclosure. Further described is therefore a nucleic acid molecule, or functional equivalent thereof, or one or more vectors, that encode(s) antibody AT12-023, AT12-025, AT13-024, 19, AT13- 022, AT13-023, 31, AT12-020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 or AT14-016, or functional part or functional equivalent thereof. In some ments, said nucleic acid molecule or functional lent or vector(s) is/are codon optimized for a man recombinant expression system.

Further described is a vector comprising a nucleic acid molecule or functional equivalent according to the present disclosure. As used herein “a vector comprising a nucleic acid molecule or functional equivalent according to the invention” is also referred to as “a vector according to the invention”. These terms encompass one or more (s) according to the invention, comprising one or more nucleic acid molecule(s) or functional equivalent(s) according to the invention. As used herein, the singular term “a” encompasses the term “one or more”.

Methods for constructing s comprising one or more nucleic acid molecule(s) or onal equivalent(s) described herein are well known in the art.

Non-limiting es of vectors suitable for ting a vector bed herein are retroviral and iral vectors. Such vectors are suitable for a variety of applications. For instance, one or more vectors described herein comprising a therapeutically beneficial nucleic acid sequence described hereinis/are suitable for prophylactic or therapeutic ations against AML. Administration of such vector(s) to an individual, preferably a human, in need thereof s in expression of said prophylactic or therapeutic nucleic acid sequence in vivo resulting in at least partial treatment or prophylaxis against AML. Said vector(s) can also be used in ations ing in vitro expression of a nucleic acid molecule of interest, for instance for (commercial) tion of antibodies or functional equivalents according to the present disclosure. Also described is therefore an ed or recombinant cell, or a non-human animal, comprising at least one nucleic acid molecule or functional lent, or at least one vector, according to the present disclosure.

A nucleic acid molecule or a vector described hereinis particularly useful for generating antibodies or functional parts or functional equivalents ing to the present disclosure, which are specific for AML. This is for instance done by introducing such nucleic acid le or vector(s) into a cell so that the cell’s nucleic acid translation machinery will produce the encoded antibodies or functional parts or functional equivalents. In one embodiment, a nucleic acid molecule or vector encoding a heavy and/or light chain described herein is expressed in so called producer cells, such as for instance E.coli, CHO, NSO or 293(T) cells, some of which are adapted to commercial antibody production. Of note, any recombinant antibody production system is suitable; these four producer cell systems mentioned are only a few examples of the many s that are available to date. As described herein before, in such cases it is preferred to use nucleic acid molecules wherein the original human sequences as bed herein are codon optimized for the producer cell. Proliferation of said producer cells results in a producer cell line capable of producing binding compounds according to the present disclosure. Preferably, said producer cell line is suitable for producing antibodies for use in humans. Hence, said producer cell line is preferably free of pathogenic agents such as enic micro-organisms. Most preferably, antibodies ting of human sequences are generated using at least one nucleic acid molecule or vector according to the present disclosure.

An isolated or recombinant antibody producing cell capable of producing a binding compound described herein is therefore also described. Such cell typically comprises at least one c acid le or vector according to the present sure, which preferably contains a nucleic acid sequence that is codon optimized for said cell. An antibody producing cell is defined herein as a cell which is capable of producing and/or secreting antibodies or functional parts or functional equivalents thereof, and/or which is capable of developing into a cell which is capable of producing and/or secreting antibodies or functional parts or functional equivalents thereof. An antibody producing cell bed herein is preferably a producer cell which is adapted to cial antibody production. As explained above, said er cell is ably suitable for producing antibodies for use in humans. A method for producing an antibody or functional part or onal equivalent according to the present sure is therefore also described, said method comprising providing a cell, preferably an antibody producing cell, with a nucleic acid molecule or functional equivalent or a vector according to the present disclosure, and allowing said cell to translate said nucleic acid molecule or functional equivalent or vector, thereby producing said antibody or functional part or functional equivalent according to the present disclosure. A method described herein preferably further ses a step of harvesting, purifying and/or isolating said antibody or functional part or onal equivalent according to the present disclosure. Obtained binding compounds described herein are preferably used in human therapy, optionally after onal purifying, isolation or processing steps.

Another aspect of the present sure describes an antibody or functional part or functional equivalent described herein, which is coupled to another compound. In one embodiment, a binding compound described herein is coupled to another therapeutic moiety, such as a chemotherapeutic drug or other toxic compound or ctive compound, to form a so called “antibody-drug conjugate”.

In another embodiment, a moiety that is coupled to a binding compound described herein is an immunomodulatory molecule such as for instance a CD3-specific antibody. Such CD3-specific antibody is capable of binding T cells and, if coupled to a binding compound described herein, it will target T cells to AML cells, thereby enhancing an anti-leukemic T-cell response. This provides an even stronger anti- AML effect. One preferred embodiment of the present disclosure therefore describes a bispecific or multispecific binding compound, comprising an AML- specific binding compound described herein and an modulatory le, preferably a CD3-specific binding compound. Another preferred embodiment describes an anti-AML nd, said compound comprising a binding compound according to the present sure, which is specific for AML cells, and a toxic moiety. In some other embodiments, a binding compound described herein is coupled to a label. This allows detection of myeloproliferative cells, such as AML cells, using such labeled binding compound. Other embodiments describe a binding compound bed herein that is coupled to another AML-binding compound. In some embodiments, such other AML-binding nd is also a binding compound according to the present disclosure. Described is therefore a compound comprising two g compounds described herein that are coupled to each other. This is, however, not necessary since a binding compound described herein can also be coupled to other nding compounds, such as currently known antibodies that bind AML cells. Bispecific compounds described herein allow, for instance, for increased binding of AML cells, especially when the two coupled binding compounds are specific for ent epitopes on AML cells. Such bispecific compound is thus very le for therapeutic or diagnostic applications. It is also possible to use bispecific compounds described herein in assays wherein ent AML cells are bound to the same bispecific g compound.

In one embodiment, a synthetic or inant antibody is bed, or a functional part or a functional lent thereof, which comprises one Fab fragment of an antibody according to the present disclosure, and one Fab fragment of another dy according to the present disclosure. The resulting binding compound is specific for AML cells, but each Fab arm will typically bind its own e. In some embodiments, the epitopes recognized by the Fab fragments are ent from each other. In another embodiment, the epitopes are the same. The Fab arms may bind the epitopes with different affinity. Alternatively, the Fab arms bind their epitopes with essentially the same affinity, g that the KD of the Fab arms differ no more than 30%, preferably no more than 20% or no more than % from each other.

Said other moiety, for example a chemotherapeutic agent or a CD3-specific antibody, is preferably d to a binding compound described herein via a linker such as for ce an acid-labile hydrazone linker, or via a peptide linker like citruline-valine, or through a thioether linkage, or by e catalized transamidation, which is described in detail in WO 87994.

Sortase catalized transamidation involves engineering of a sortase recognition site (LPETGG) on the heavy chain of an antibody, preferably on the C- terminal part of the heavy chain, and on the moiety to be coupled to said antibody.

The antibody and the moiety further typically contain a GGGGS sequence and a tag for purification purposes, such as a HIS tag. Subsequently e mediated transamidation is performed followed by click chemistry linkage. In a sortase catalized transaminidation, "click chemistry linkage" typically involves chemical coupling of, for instance, an alkyne-containing reagent and, for instance, an azidecontaining reagent which are added by e through addition of glycines to the e motif on the heavy chain of the antibody and to a e motif on the moiety (such as a protein, peptide or antibody) to be coupled to the antibody. In one embodiment, the present disclosure therefore describes an antibody described herein wherein a sortase recognition site (LPETGG) is engineered on the heavy chain of the antibody, preferably on the inal part of the heavy chain, the antibody preferably further containing a GGGGS sequence and a purification tag, such as a HIS tag.

In another embodiment a g compound described herein is coupled to another moiety via a thioether linkage. In such case, one or more cysteines are preferably incorporated into a binding compound according to the invention.

Cysteines contain a thiol group and, therefore, incorporation of one or more cysteines into a binding compound according to the present disclosure, or replacement of one or more amino acids by one or more cysteines of a binding compound according to the present disclosure, enable coupling of said binding compound to another moiety. Said one or more nes are preferably introduced into a binding compound described herein at a position where it does not significantly influence folding of said binding compound, and does not significantly alter antigen g or effector function. The present disclosure therefore also describes a binding compound described herein wherein at least one amino acid other than cysteine has been replaced by a ne.

In one embodiment, an AML-specific binding compound described herein is coupled to at least one other ecific binding compound according to the present disclosure. Such bispecific or multispecific binding compound provides a stronger anti-AML effect.

Binding nds described herein are suitable for use t roliferative disorders such as AML, or acute leukemia’s that developed from myelodysplastic syndrome, chronic myeloid leukemia, myelofibrosis or other, nonmalignant myeloproliferative syndromes. As some of the antibodies also bind to non-myeloid, lymphoproliferative malignancies such as multiple myeloma and B- non n ma (B-NHL), they are suitable for use against these disorders as well. Binding compounds described herein are therefore particularly suitable for use as a medicine or prophylactic agent. Preferably, binding nds bed herein are used which t of human sequences, in order to reduce the chance of adverse side effects when human individuals are d. Such human sequences can be isolated from a human or tically or recombinantly produced based on the sequence of human antibodies, optionally using codon optimized nucleic acid sequences that encode the same amino acids as the original human nucleic acid sequence. Described is therefore an antibody or functional part or functional equivalent described herein for use as a ment and/or prophylactic agent.

Said antibody preferably comprises an dy selected from the group consisting of AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, AT12-020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016. Also described is a nucleic acid molecule or functional equivalent thereof described herein or a vector described herein comprising such nucleic acid or functional equivalent, or a cell according to the present disclosure, for use as a medicament and/or prophylactic agent. When (a vector comprising) one or more c acid molecule(s) or functional equivalent(s) bed herein is/are administered, the c acid molecule(s) or functional equivalent(s) will be translated in situ by the host’s machinery into a binding compound according to the present disclosure. Produced binding compounds described herein are capable of preventing and/or counteracting myeloproliferative disorders such as AML and lymphoproliferative disorders such as for instance lymphoma, B-NHL and multiple a. Further described is therefore an antibody or functional part or functional equivalent according to the present disclosure, or a nucleic acid molecule or functional equivalent according to the present disclosure, or a vector or a cell according to the present disclosure, for use in a method for at least in part treating or ting a roliferative or lymphoproliferative er. As described herein before, such er can be treated or prevented by using cytotoxic binding compounds according to the present disclosure. As demonstrated in the Examples, at least antibodies AT13-033, AT13- 035, AT13-036, AT13-037, 23, AT12-025 and AT13-031 have cytotoxic activity. Further described is therefore an antibody selected from the group consisting of antibodies AT13-033, AT13-035, AT13-036, AT13-037, AT12-023, 25 and AT13-031, and functional parts and functional equivalents thereof, or a nucleic acid molecule or functional equivalent or one or more vectors encoding therefore, for use in a method for at least in part treating or preventing a myeloproliferative or lymphoproliferative disorder. Preferably, said disorder is AML.

In some embodiments, a binding compound described herein is coupled to a therapeutic moiety, such as a chemotherapeutic drug or other toxic compound or a radioactive compound or an modulatory molecule such as for instance a CD3-specific antibody, to form a so called “antibody-drug conjugate” or a “chimeric antigen receptor (CAR) T cell”, respectively, which is able to counteract a myeloproliferative or lymphoproliferative disorder.

In some embodiments, said proliferative disorder is d with one or more antibodies selected from the group consisting of antibodies AT12-019, AT12-023, AT12-025, AT13-024 and AT13-031, and functional parts and functional equivalents thereof. Further described is therefore an antibody selected from the group consisting of antibodies AT12-019, AT12-023, AT12-025, AT13-024 and AT13-031, and onal parts and functional equivalents thereof, or a nucleic acid molecule or functional equivalent or one or more vectors encoding therefore, for use in a method for at least in part treating or ting a lymphoproliferative disorder. Preferably, said lymphoproliferative disorder is lymphoma, B-NHL or multiple a.

A binding compound according to the present disclosure, or a nucleic acid molecule or functional equivalent thereof according to the present disclosure, or at least one vector or cell according to the present disclosure, is preferably used for at least in part treating and/or preventing AML. As used herein the term “at least in part treating and/or preventing AML” includes counteracting AML tumor growth and/or alleviating symptoms resulting from the presence of AML cells in a patient.

Also described is therefore a use of an antibody or functional part or functional lent according to the present sure, or of a nucleic acid molecule or functional equivalent according to the t disclosure, or of at least one vector or cell according to the present disclosure, for the ation of a medicament and/or prophylactic agent for at least in part treating and/or preventing AML.

Further described is an antibody or onal part or functional equivalent according to the present disclosure, or a nucleic acid molecule or functional equivalent according to the present disclosure, or at least one vector or cell according to the t disclosure, for use in a method for at least in part treating and/or preventing AML.

Preferred antibodies for use in any of the recited methods are antibodies AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, 23, AT13-031, AT12- 020, AT13-033, AT13-034, AT13-035, AT13-036, AT13-037, AT14-013, AT14-014, AT14-015 and 16.

The present disclosure further describes a composition comprising an antibody or onal part or onal lent according to the present disclosure. A composition comprising a nucleic acid molecule or functional equivalent described herein is also described, as well as a composition comprising a vector or a cell according to the present disclosure. In some embodiments a composition described herein comprises at least two antibodies, functional parts or functional equivalents according to the present disclosure.

A composition described herein preferably comprises a pharmaceutical composition. Said pharmaceutical composition preferably also comprises a pharmaceutical acceptable carrier, diluent and/or excipient. Non-limiting examples of suitable carriers for instance comprise keyhole limpet haemocyanin (KLH), serum albumin (e.g. BSA or RSA) and ovalbumin. In one red embodiment said suitable carrier comprises a solution, like for example saline. A pharmaceutical composition described herein is ably suitable for human use.

The present disclosure further describes a method for at least in part treating and/or preventing a myeloproliferative or lymphoproliferative disorder, comprising administering to an individual in need thereof a therapeutically ive amount of an antibody or functional part or functional equivalent according to the present disclosure, and/or a nucleic acid molecule or functional equivalent thereof according to the present sure, and/or a vector or cell according to the present disclosure, and/or a composition according to the present disclosure. As used herein, an “individual” or “subject” is a human or an animal, preferably a human AML patient. Said composition is preferably a ceutical composition according to the present sure.

A binding compound and/or ition described herein is particularly suitable for administering to immune compromised individuals with an sed risk of complications, such as individuals that have one chemotherapy, ularly s and elderly people. A binding compound, or a nucleic acid molecule or functional equivalent thereof, or a , and/or a pharmaceutical composition described herein is ably stered via one or more injections.

Typical doses of administration of a binding compound bed herein are between 0.1 and 10 mg per kg body weight.

A binding compound described herein is also ularly suitable for diagnostic use. For instance, if an individual, preferably a human, is suspected of suffering from a myeloproliferative disorder such as AML or a lymphoproliferative disorder such as B-NHL or le myeloma, a sample, such as a blood or tissue sample, from said individual can be tested for the presence of roliferative cells or lymphoproliferative cells, using a binding compound according to the present disclosure. Preferably, said sample is mixed with a binding compound according to the present disclosure, which will specifically bind to roliferative cells. Myeloproliferative cells or lymphoproliferative cells bound to a binding compound described herein can be isolated from the sample and/or detected using any method known in the art, for example, but not limited to, isolation using magnetic beads, streptavidin-coated beads, or ion h the use of secondary antibodies immobilized on a column. Alternatively, or additionally, a binding compound described herein is labeled in order to be able to detect said antibody, for instance, but not limited to, fluorescently labeled, enzymatically labeled, or ctively d. Alternatively, a binding compound described herein is detected using a labeled secondary antibody which is directed against said binding compound. If binding of said antibody is ed, it is indicative for the presence of myeloproliferative or lymphoproliferative cells.

Therefore also described is an antibody or functional part or onal equivalent according to the present disclosure, or a nucleic acid molecule or functional equivalent according to the present sure, or a vector or a cell according to the present disclosure, for use in ing myeloproliferative cells or lymphoproliferative cells. Also bed is an antibody or functional part or functional equivalent according to the present disclosure, or a nucleic acid molecule or functional equivalent according to the present disclosure, or a vector or a cell according to the present disclosure, for use in diagnosis of a myeloproliferative disorder or lymphoproliferative disorder. Said myeloproliferative disorder is preferably AML. In some embodiments, said lymphoproliferative disorder is lymphoma, B-NHL or multiple myeloma. proliferative cells are preferably detected with one or more antibodies selected from the group consisting of AT12- 019, AT12-023, AT12-025, 24 and AT13-031, and functional parts and functional equivalents thereof.

A use of an antibody or functional part or functional equivalent according to the present disclosure, or use of a nucleic acid molecule or functional equivalent according to the present sure, or use of a vector or a cell according to the present disclosure, for determining whether a sample comprises myeloproliferative cells or lymphoproliferative cells is also described, as well as a method for detecting myeloproliferative cells or lymphoproliferative cells using an antibody or functional part or functional equivalent according to the t disclosure. Also described is a method for determining whether myeloproliferative cells or lymphoproliferative cells are present in a sample comprising: - contacting said sample with an dy or functional part or functional equivalent according to the present disclosure, and - ng said antibody or functional part or functional equivalent to bind myeloproliferative cells or proliferative cells, if present, and - determining whether or not myeloproliferative cells or lymphoproliferative cells are bound to said antibody or functional part or functional equivalent, y determining whether or not roliferative cells or proliferative cells are present in said sample.

In a preferred embodiment, said myeloproliferative cells are AML cells. In another preferred embodiment, said lymphoproliferative cells are lymphoma, B-NHL or le myeloma cells. Lymphoproliferative cells are preferably detected with one or more antibodies selected from the group consisting of AT12- 019, AT12-023, AT12-025, AT13-024 and AT13-031, and functional parts and onal lents thereof.

In a further ment it is determined whether an individual is suffering from a myeloproliferative or lymphoproliferative disorder. Also described is therefore a method for determining whether an individual is suffering from a myeloproliferative disorder or a proliferative disorder, comprising: - contacting a sample from said individual with an antibody or functional part or functional equivalent according to the present disclosure, and - allowing said antibody or functional part or functional equivalent to bind myeloproliferative cells or lymphoproliferative cells, if present, and - determining whether or not myeloproliferative cells or lymphoproliferative cells are bound to said antibody or functional part or functional equivalent, thereby determining whether or nor said individual is suffering from a myeloproliferative disorder or a proliferative disorder. Preferably said individual is a human.

In some embodiments, said myeloproliferative disorder is AML. In other embodiments, said lymphoproliferative disorder is lymphoma, B-NHL or multiple myeloma.

As described herein before, the present disclosure desribes the surprising insight that snRNP200 is present on the e of AML cells, whereas snRNP200 is normally located in the nucleus only. Hence, snRNP200 is an important target for anti-AML therapy. er, antibodies AT12-023 and AT13-031, which are specific for snRNP200, also bind B-NHL cells and multiple myeloma cells. This indicates that surface expression of 00 also occurs on B-NHL cells and multiple myeloma cells. Now that this insight has been provided, many applications have become possible. For instance, snRNP200-specific binding compounds can now be used for treating or preventing myeloproliferative or lymphoproliferative disorders. Further described is therefore a use of an snRNP200-specific binding compound for the preparation of a medicament for the treatment or prophylaxis of a myeloproliferative or lymphoproliferative disorder, such as AML, B-NHL or le myeloma. An snRNP200-specific binding compound for use in a method for at least in part treating or preventing a myeloproliferative or lymphoproliferative disorder is also described, as well as a method for at least in part treating and/or ting a myeloproliferative or lymphoproliferative er, comprising administering to an dual in need thereof a therapeutically ive amount of an snRNP200-specific g compound.

Novel detection s have also become available. Since snRNP200 is normally only present in the nucleus, but appears to be also present at the surface of myeloproliferative and lymphoproliferative cells, these cells can now be detected and distinguished from healthy cells by determining whether snRNP200 is present at their surface. Further described is therefore a method for ining whether a d cell or lymphoid cell is a myeloproliferative cell or lymphoproliferative cell, the method sing determining whether snRNP200 is present on the surface of said cell, wherein the presence of snRNP200 on the surface of said cell indicates that said cell is myeloproliferative or lymphoproliferative. Also described is a method for identifying myeloproliferative or lymphoproliferative cells, comprising detecting the presence of 00 on the surface of said cells. As used herein, the expression “present at the surface of a cell” or “present on the surface of a cell” means that at least part of snRNP200 is present on, or within, the cell surface, or associated therewith.

In some embodiments, a cell-containing sample of an individual is typed.

Such sample, which typically contains lymphoid cells and/or myeloid cells, is in some ments tested for the presence of snRNP200 on the surface of these cells. If snRNP200 appears to be present on the surface of cells, the sample is typed as containing roliferative or lymphoproliferative cells. Further described is therefore a method for typing a myeloid cell-containing sample or a lymphoid cellcontaining sample of an individual, the method comprising determining whether snRNP200 is present on the surface of cells of said sample. If this is the case, it indicates that myeloproliferative cells or lymphoproliferative cells are present in said .

In some embodiments, the individual is suffering from, or suspected of ing from, a myeloproliferative or lymphoproliferative disorder. This is however not necessary, since such typing method can also be part of a general screening test, for instance for health checks.

Said sample can be any sample that contains d and/or lymphoid cells, such as for instance a bone marrow , a tissue sample or a lymph fluid sample. Preferably, said sample ses peripheral blood mononuclear cells, since a blood sample is easily obtainable with little discomfort for the individual.

The present disclosure provides the insight that at least a subpopulation of patients who suffer from a myeloproliferative or lymphoproliferative disorder e antibodies that are specific for snRNP200. The presence of such antibodies in a sample from an individual is thus indicative for a myeloproliferative or lymphoproliferative disorder. r described is therefore a method for determining whether an individual is suffering from a myeloproliferative or proliferative disorder, comprising determining whether a sample from said dual comprises antibodies that are specific for snRNP200. In some embodiments such method comprises the steps of: - contacting a sample from said individual with snRNP200 or an epitope thereof; - ng said snRNP200 or epitope to bind snRNP200-specific antibodies from said sample, if present, and - determining whether or not said snRNP200 or epitope is bound to snRNP200- ic antibodies, wherein binding of said 00 or epitope to snRNP200- ic antibodies tes that said individual is suffering from a myeloproliferative or proliferative disorder.

Screening assays as bed herein can be performed using methods such as for instance enzyme-linked immunosorbent assays (ELISA), radio-immuno assays (RIA), Western Blot assays and immunohistochemical ng assays.

These assays are well known in the art and therefore need no further explanation. ions or tions of ELISA, RIA, Western blot assay and immunohistochemical staining assay are also known in the art.

Also described is a method for determining whether a patient suffering from a myeloproliferative or lymphoproliferative disorder has an improved chance of a positive outcome of treatment with an antibody, functional part or functional equivalent according to the present sure, as compared to the mean population of patients suffering from a myeloproliferative or lymphoproliferative disorder, the method comprising determining whether snRNP200 is present on the surface of myeloproliferative cells or lymphoproliferative cells of said patient. If this is the case, snRNP200-specific antibodies such as AT12-023, AT13-031 and AT13-037 are particularly suitable for counteracting such myeloproliferative or lymphoproliferative disorder. Therefore, if it is known that myeloproliferative or lymphoproliferative cells of an individual express snRNP200 at their surface, the chance of succesfull ent is increased. Such method described herein preferably comprises the steps of: - contacting a myeloproliferative cell- or lymphoproliferative cell-containing sample from said individual with an antibody or functional part or functional equivalent that is specific for snRNP200; - allowing said antibody or functional part or onal equivalent to bind myeloproliferative cells or lymphoproliferative cells of said sample, and - determining whether or not said a snRNP200-specific antibody or functional part or functional equivalent is bound to myeloproliferative cells or lymphoproliferative cells of said sample, wherein binding of said snRNP200-specific antibody or functional part or onal lent to myeloproliferative cells or lymphoproliferative cells of said sample indicates that said patient has an improved chance of a positive outcome of treatment with an antibody, functional part or functional equivalent according to the present disclosure, as compared to the mean population of patients suffering from a myeloproliferative or lymphoproliferative disorder. Said treatment preferably comprises the use of antibodies AT12-023, AT13-031 or AT13-037, or functional parts or functional equivalents thereof, since at least these antibodies are able to bind snRNP200.

Further described is therefore an antibody according to the present disclosure, or an antibody for use as described herein, or a use or a method according to the present disclosure, n said antibody is AT12-023, AT13-031, AT13-037, or a functional part or a functional equivalent thereof.

If the use of dy AT12-023, 31 and/or AT13-037 is contemplated, it is preferably determined beforehand if a certain patient contains malignant cells that express snRNP200 at their surface. Some ments therefore describe a method for determining whether a patient ing from a myeloproliferative disorder or lymphoproliferative disorder is a candidate for treatment with antibody AT12-023, 31 or AT13-037, or a functional part or a onal equivalent f, the method comprising determining whether snRNP200 is present on the surface of myeloproliferative cells or lymphoproliferative cells of said patient.

In a method according to the present disclosure, said myeloproliferative disorder is preferably AML and said myeloproliferative cells are preferably AML cells. Moreover, said lymphoproliferative disorder is preferably lymphoma, B- non- Hodgkin lymphoma or multiple myeloma and said lymphoproliferative cells are preferably lymphoma, B- non-Hodgkin lymphoma or multiple a cells.

The above-mentioned procedures for detecting roliferative or proliferative cells using binding compounds described herein are for instance particularly suitable for determining whether a patient suffering from a myeloproliferative er or lymphoproliferative disorder who has received medical treatment, such as for instance an AML patient who has been d against AML, for instance an AML patient who has received immunotherapy such as a stem cell transplantation or donor-lymphocyte infusion, has a GvL se.

Until to date, there are no diagnostic tools to test for the presence of a potent GvL response in a treated patient. Such diagnostic tool is much needed, for instance because: 1) It will allow early identification of allogeneic SCT recipients at high risk for relapse, at a time-point before relapse has occurred y ng earlier interventions such as tapering of immunosuppressants or donor-lymphocyte infusions; 2) It will allow titrating such donor lymphocyte infusions until anti- leukemia antibodies do appear; and 3) It will offer hope for allogeneic SCT recipients at a time they often suffer from one of many SCT-related complications when the ce of a potent GvL response can be demonstrated. Nowadays patients have to wait and see whether or not a relapse occurs, and there is no way to predict relapse of e. The availability of a test for determing whether a t has a GvL se will therefore greatly improve the al care of SCT patients, affecting prognosis and quality of life. r described is, therefore, a use of a g compound described herein for determining whether a sample is indicative for a GvL response. Also described is a use of a binding compound described herein for determining whether or not an AML patient has a GvL response, and a use of a binding compound described herein for determining whether a treatment against a myeloproliferative or lymphoproliferative disease, such as for instance anti-AML therapy, anti-B-NHL therapy or anti-multiple myeloma therapy, is efficaceous. This is for instance done by ining whether a sample (for instance a blood or tissue sample) from a patient (that has for instance received a SCT or DLI or any other form of immunotherapy) contains myeloproliferative or proliferative cells, for instance AML cells, B-NHL cells or multiple myeloma cells. The absence of myeloproliferative or lymphoproliferative cells indicates that said patient has a GvL response. Further described is, therefore, a method for determining r a patient suffering from a myeloproliferative disorder or a lymphoproliferative disorder who has received immunotherapy against said disorder has a GvL response, the method comprising ting a sample from said t with an antibody or functional part or functional equivalent according to the present disclosure, and allowing said antibody or functional part or functional equivalent to bind myeloproliferative or lymphoproliferative cells, if present, and determining whether or not myeloproliferative cells or lymphoproliferative cells are bound to said antibody or functional part or functional equivalent, thereby determining r or not said individual has a GvL response, whereby the absence of roliferative or lymphoproliferative cells is indicative for a GvL se and the presence of myeloproliferative or proliferative cells is indicative for a lack of, or icient (ineffective), GvL response. In some embodiments, said lymphoproliferative disorder is lymphoma, B-NHL, or multiple myeloma. In some embodiments, said myeloproliferative disorder is AML. Also described is, therefore, a method for determining r an AML patient that has received anti-AML immunotherapy has a GvL response, the method comprising contacting a sample from said AML patient with an antibody or functional part or functional equivalent according to the present disclosure, and allowing said antibody or functional part or functional lent to bind AML cells, if present, and determining whether or not AML cells are bound to said dy or functional part or functional equivalent, thereby ining whether or nor said individual has a GvL response, whereby the absence of AML cells is indicative for a GvL response and the presence of AML response is indicative for a lack of, or insufficient (ineffective), GvL response. Preferably said individual is a human. Alternatively, binding nds described herein that are labeled with a detectable moiety, such as for ce with a copper compound, are administered to an AML patient that has received anti-AML immunotherapy such as a SCT or DLI, and it is subsequently determined whether said labeled antibody is bound to AML cells of said patient in vivo, for instance using a PET scan. The absence of bound g compounds is indicative for a GvL response and the presence of bound binding compounds is tive for a lack of, or insufficient (ineffective), GvL response.

It is also possible to determine the amount of antibody belonging to the VH4-34 family before and after anti-AML immunotherapy. If the amount of antibody belonging to the VH4-34 family, which is a family of VH sequences known for their potential killing properties (Bhat et al, 1997), is significantly raised after immunotherapy, it indicates that a GvL response is present. Further described is, therefore, a method for determining whether an AML patient that has received anti-AML immunotherapy has a GvL response, the method comprising determining the amount of antibody belonging to the VH4-34 family before and after anti-AML immunotherapy, and ining whether the amount of antibody belonging to the VH4-34 family is significantly raised after immunotherapy. If this is the case, it is concluded that a GvL response is present in said patient. If this is not the case, it is concluded that a GvL response is lacking, or not sufficient.

The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification, and claims which include the term “comprising”, it is to be understood that other features that are additional to the features prefaced by this term in each statement or claim may also be t. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

In this specification where reference has been made to patent specifications, other external nts, or other sources of information, this is generally for the purpose of providing a context for sing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such s of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current ation. That subject matter should be readily identifiable by a person skilled in the art and may assist in g into practice the invention as defined in the claims of this ation.

The invention is further explained in the following examples. These examples do not limit the scope of the invention, but merely serve to clarify the invention.

Brief description of the drawings Figure 1. Sequences of dies AT12-023, AT12-025, AT13-024, AT12-019, AT13-022, AT13-023, AT13-031, AT12-020, AT13-033, 34, AT13-035, AT13- 036, AT13-037, AT14-013, AT14-014, AT14-015 and AT14-016.

Figure 2. 36 year old patient with AML, who obtained complete remission after the first cycle of induction herapy and received a myeloablative (MA) allogeneic stem cell transplantation (SCT) from her HLA-matched brother (sib) as consolidation y. AML relapse ed however 5 months posttransplantation. uction chemotherapy resulted again in complete remission and in severe, grade IV graft versus host disease (GvHD) of the liver and grade I GvHD of the skin. The observation that she has remained in complete remission for more than three years now implies that she has developed a potent graft versus leukemia response. B lymphocytes were isolated from a phlebotomy product obtained about 1,5 years after the one cycle of uction chemotherapy.

Figure 3. a) Supernatant of one of the minicultures (20 or 40 cells per well) binding to the AML cell line THP-1. b) B cells from this lture were plated into 1 cell/well solutions and supernatants again ed for binding to THP-1. THP-1 express HLA-DR, that was used in this screening experiment as a positive control.

As a negative control an influenza-specific monoclonal antibody was used.

Figure 4. Two examples of the AML specific antibodies identified. AT12-023 (a) and AT13-031 (b) bind to AML cell lines THP-1 and MonoMac6, but not to healthy peripheral blood mononuclear cells (PBMC), endothelial cells (human umbilical vein endothelial cells: HUVEC), the T cell line Jurkat, primary fibroblasts, hepatocytes (liver hepatocellular oma cell line: HepG2) or the colon adenocarcinoma cell line HT-29. The MRSA-mAb F1 is an in-house generated human IgG3 mAb that is used as control antibody.

Figure 5. dies derived from donor 59 bind to the AML cell lines THP-1 and c6, and to primary leukemic blasts isolated from newly diagnosed AML patients (ranging from FAB classification M0-M4). See also table 3 for a more detailed overview.

Figure 6. Some of the dies also bind to other hematological malignancies.

Here, binding of AT12-023 (antibodies isolated from supernatant of B cell clone) and AT13-031 (recombinant antibody) to B-non Hodgkin lymphoma (B-NHL) cells that were freshly isolated from a lymphoma patient is shown. The antibodies did not bind to non-malignant B cells (not shown in this experiment). The RSV antibody Palivizumab was used as a negative control, and Rituximab, a CD20- antibody specifically g B-cell lymphoma, as a positive control. See for more details of antibody binding to other hematologic malignancies table 4.

Figure 7. THP-1 cells were cultered in medium alone or with antibodies added at a concentration of 5 μg/ml at day 0. In the presence of AT12-023, THP-1 cells showed significant growth inhibition. Depicted are total cell numbers in e.

Figure 8. When added at day 0 of the culture, antibodies 23 and AT12-025 strongly reduced the ity of THP-1 cells. Viability is depicted as the proportion of cells -negative for cell-death markers Annexin V and 7AAD.

Figure 9. To quantify the amount of THP-1 cells specifically killed by AT12-023 we used a calcein AM release assay. Briefly, before THP-1 cells were ted with 23, the THP-1 cells were loaded with calcein AM, that is released when cells are dying and the cell membranbe becomes instable. Lysis was read out after 4 hours of incubation and was related to the background death of calcein-loaded cells as measured with an vant antibody.

Figure 10. a) s killing of THP-1 cells, AT12-025 does also induce death of primary tumor cells, similar to AT13-024. Leukemic blasts, isolated from a patient with AML-M5 at diagnosis, were incubated with AT12-025 or AT13-024 (5 ug/ml) for 24 hours at 37°C, after which cells were stained with 7AAD and AnnexinV to determine the amount of dead cells (7AAD and Annexin V double-positive). b) In addition, Lactate dehydrogenase (LDH) can be used as a marker to determine dying cells. Leukemic blasts, isolated from a patient with AML-M0, were incubated with AT13-024 or the RSV antibody palivizumab for 18 hrs, after which LDH release was ed. These two experiments show that AT13-024, but not palivizumab, d death of leukemic blasts and that this property was not restricted to one type of AML but includes different FAB classifications (M0 to M5).

Figure 11. Donor 58 was diagnosed with AML-M5, for which she received three cycles of chemotherapy. She remained in complete ion for about a year, after which the AML relapsed. She ed one cycle of re-induction chemotherapy, followed by an allogeneic reduced intensity stem cell transplantation (RIST) from a matched unrelated donor (MUD). She developed GvHD grade I of the liver and has remained in complete remission for almost 4 years now, implicating that she has developed a potent graft versus leukemia response. B cells were isolated from a phlebotomy product obtained from this patient about 3 years post-SCT.

Figure 12. Antibodies derived from donor 58 bind to the AML cell lines THP-1 and MonoMac6. Palivizumab, the cially available RSV specific dy, was used as a negative control.

Figure 13. al history of a third patient with a potent GvL response. Donor 101 was diagnosed with an ediate-risk AML (no cytogenetic or molecular abnormalities; FAB fication AML-M5) at the age of 49 years. He received two courses of chemotherapy and one course of consolidation chemotherapy followed by an autologous HSCT, as there was no HLA-matched g stem cell donor available. en months after the first sis his disease relapsed. He obtained complete remission after one cycle of high-dose cytarabine, after which he received a rediced-intensity allogeneic HSCT with a matched unrelated donor (RIST-MUD). Six weeks later he developed acute GvHD of skin, liver and intestine (stage 1; grade II) that responded well to corticosteroid therapy. B cells were isolated from a phlebotomy product obtained from this patient 38 months after the neic HSCT. He has maintained durable remission until today.

Figure 14. Antibodies derived from donor 101 bind to the AML cell lines THP-1 and Molm13, but not to fibroblasts, monocytes, B cells and T cells. An in-house produced human antibody against CD30 was used as a negative control. AT14-013 showed minor reactivity with fibroblasts, compared to its high binding to the AML cell lines. See tables 7 and 8 for an overview of the binding capacities of the antibodies derived from donor 101.

Figure 15. AML-specific antibody AT14-013 (donor 101) binds y leukemic blasts isolated from newly diagnosed AML patients (FAB classifications M0-M5).

Negative l: in-house generated CD30 antibody. See table 7 for an overview of the primary AML blast binding capacities of the antibodies d from donor 101.

Figure 16. Antibody AT13-037 induces death of primary blasts. Leukemic blasts, isolated from an AML patient at sis (BL-038; AML-M5), were incubated with antibodies purified from the supernatants of the parental B cell clone (sAT13-037) or with the recombinant antibody (rAT13-037) at a concentration of 5 ug/ml for 4 hours at 37°C, after which cells were stained with the death cell marker Dapi. To quantify death of cells a standard amount of beads was added. Recombinant influenza specific rAT10-002 was used as a negative control.

Figure 17. Cytotoxic antibodies induced a non-apoptotic death pathway. a) Phase contrast imaging of THP-1 cells. THP-1 cells were incubated with the otoxic ecific antibody AT13-023 (left panel) or the cytotoxic antibody AML-specific AT13-037 (right panel). Interaction was visualized using time-lapse imaging and demonstrated swelling of target cells after which cells died. Stills were taken after 4 hours of incubation, with blue arrows ting large cells that are dead. b) Double staining with DiOC6 and PI showed that xic antibodies do not induce apoptosis. THP-1 cells were incubated with the cytotoxic AML-specific antibody AT12-023, with diclofenac (that induces apoptosis in THP-1 cells) or with medium only. Cells undergoing apoptosis first loose their mitochondrial membrane ial (loss of DiOC6 stain) after which they become ble (PI positive), as can be seen after incubation of THP-1 cells with diclofenac. THP-1 cells incubated with 23 showed increased membrane permeability (PI+) but maintained mitochondrial membrane potential (DioC6+), indicating the induction of a nonapoptotic cell death pathway. c) To m the non-apoptotic nature of the death pathway induced we tested the involvement of caspases in cell death induction.

Cell death of THP-1 cells by AML-specific antibodies could not be prevented with the pan caspase inhibitors Q-VD-OPh (left panel) or Z-VAD-fmk (right panel).

Figure 18. Cell death induced by AML-specific dies also occured at 4°C, suggesting the involvement of a passive process. This was true for all antibodies except AT13-031, which is cytotoxic at 37°C only (not shown). Negative controls included the AML-specific totoxic antibodies AT13-034, AT12-019, AT13- 022, AT13-023 and AT13-024.

Figure 19. (a) Incubation of target cells with alasin D did not inhibit binding of the antibodies. THP-1 cells were incubated with cytochalasin D, after which AML-specific antibodies AT12-023, 31 and AT13-037 were added. (b) Preincubation of the target cells with the membrane stabilizing agent cytocholasin D did protect the THP-1 cells against cell death by the AML-specific cytotoxic antibodies.

Figure 20. Target verification of AT12-023, AT13-031 and AT13-037. a) THP-1 membrane lysate was incubated with AT12-023 and AT13-031, with the influenzaspecific dy AT10-002 or with marker alone. Western blot analysis including mouse-anti-human snRNP200 (and HMGB1 as a negative control) revealed specific binding of AT12-023 and AT13-031 to snRNP200. b) AML specific antibodies AT12- 019, AT12-023, AT13-031 and 37 or commercially available snRNP200- specific antibodies snRNP200 453 and snRNP200 454 were coated on an ELISA plate, incubated with a snRNP200-flag construct for capturing and with anti-flag HRP for detection. AT12-023, AT13-031 and AT13-037 ically bound snRNP200, whereas negative controls and for example AT12-019 did not.

Figure 21. THP-1 cells express snRNP200 on their membrane. THP-1 cells and Jurkat cells were stained with a commercially available human-anti-mouse 00 antibody. Intracellular staining of Jurkat cells and THP-1 cells showed nuclear staining, as expected (left panels). However, membrane staining of snRNP200 was cted to THP-1 cells (right panels).

Examples Example 1 MATERIALS & METHODS Patient and healthy human materials Study protocols were approved by the Medical Ethical Committee of the Academic Medical Centre. All participants signed informed consent. We selected two patients who had received an allogeneic stem cell transplantation (myeloablative g transplant for donor 59 and a matched unrelated donor- reduced intensity stem cell transplantation for donor 58) for AML and who, based on their al histories, can be assumed to have generated strong graft versus leukemia responses. These two SCT recipients donated 500 ml peripheral blood each, the products of one of many phlebotomies they underwent for post-transfusion erritinemia. In addition, patients admitted to our clinic with newly diagnosed AML consented to donate 2-5 ml bone marrow or blood ning AML blasts to be used for antibody binding assays. Healthy bone marrow was donated by patients oing thoracotomy for cardiac surgery in our institute. B-non Hodgkin’s lymphoma cells were obtained as rest material from biopsies of patients with newly diagnosed B- non Hodgkin’s ma. These B-non Hodgkin’s lymphoma cells were used to test for binding of our antibodies as described below. Rest material of human umbilical vein elial cells (HUVECS), that were freshly isolated at the Department of Ophthalmology (AMC, Amsterdam, The Netherlands) were directly used for binding assays as described below. For purity, cells were co stained with and selected for anti human CD14+.

Mononuclear cells were isolated from peripheral blood and bone marrow of healthy individuals and AML patients by Ficoll separation. Extra s like CD45, CD33, CD34, CD14, CD3 and CD19 were used to isolate specific cell populations (AML blasts, monocytes, T and B lymphocytes, respectively, obtained from blood bank donors).

Isolation of B cells We obtained B cells from peripheral blood by Ficoll tion and CD22 MACS microbeads (Miltenyi Biotech). uently we sorted these cells for CD27- or CD27+ CD19+CD3−IgM−IgA− (naïve or memory IgG cells, respectively) and CD19+CD3−CD27+IgG−IgA− (memory IgM cells) on a FACSAria (Becton Dickinson).

Cell culture We maintained B cells (2×105 cells/ml) in IMDM ) e medium containing 8% FBS (HyClone) and penicillin/streptomycin (Roche), supplemented with recombinant mouse IL-21 (50 ng/ml, in house produced) and co-cultured them on γ-irradiated (50Gy) mouse L cell fibroblasts stably expressing CD40L (CD40L-L cells, 105 cells/ml). The cultures were tested routinely for the presence of mycoplasma by PCR (data not shown).

Retroviral transduction Retroviral transduction was performed as described in Kwakkenbos ea, Nat Med 2010. Briefly, naïve and memory IgG and memory IgM B cells were ed and activated during 36 hours on CD40L-L cells in the presence of mIL-21. Then, BCL6 and Bcl-xL retroviral constructs that include the marker gene for GFP were used to transduce the B cells as described before (Diehl ea, J Immunol 2008), with the addition that we centrifuged cells and virus at room ature for 60 min at 360 × g (1800 RPM). Transduction efficiency ranged from 69-90%.

Culture of target cell lines Target AML cell lines THP-1 (ATCC; density of 2×105 cells/ml to 1×106 cells/ml) and Mono-Mac6 (a kind gift from Dr. Hamann of the Experimental Immunology ment, density of 2×105 cells/ml to 2×106 ml) were maintained in RPMI 1640 (Gibco) culture medium, containing 10% FBS ne) and penicillin/streptomycin (Roche). Culture medium of Mono-Mac6 was enriched with non-essential amino acids (Invitrogen), 1 mM sodium pyruvate (Invitrogen) and 10 µg/ml human insulin (Sigma). The AML cell line Molm13 was maintained at a density of 5×105 cells/ml to 1,5×106 ml in RPMI 1640 (Gibco) culture medium, containing 20% FBS (HyClone) and penicillin/streptomycin (Roche). The liver cell lines HepG2 and Huh7 and the colon cell line HT29 (a kind gift from the Tytgat Institute, AMC, Amsterdam, The Netherlands) were cultured in DMEM ) culture medium, containing 8% FBS (HyClone) and penicillin/streptomycin (Roche). The acute T-cell leukemia cell line Jurkat (ATCC) was ined in RPMI 1640 (Gibco) culture medium, containing 10% FBS (HyClone) and penicillin/streptomycin (Roche) at a density of 1×105 ml to 2×106 cells/ml. Skin primary fibroblasts (a kind gift of the University of Leiden, The Netherlands) were cultured twice a week in DMEM (Gibco) culture medium, containing 10% FBS (HyClone) and penicillin/streptomycin (Roche). Cells were passaged no more then 10 times. The diffuse large cell B cell lymphoma (DLBCL) cell lines OCI-Ly1 and OCI-Ly7 (DSMZ and ATCC, respectively) were maintained in IMDM (Gibco) culture medium containing 8% FBS (HyClone) and penicillin/streptomycin (Roche).

The cultures were ined at 0,5-2×106 ml. Finally, the multiple myeloma (MM) cell lines U266 and NCI-H929 were ined and cultured as described for THP-1 cells. tion of AML-specific clones Transduced naïve and memory IgG and IgM B cells of each t were seeded at concentrations of 20 or 40 cells per well (hereafter named microcultures) and ed with IL-21 and CD40L. Supernatants of expanded B cell micro cultures were then screened for antibody binding to leukemia cell lines (THP-1, MonoMac6 and the cell lines depicted in Table 4), to liver- and colon cell lines, and some supernatants also to the primary blasts isolated from patients with AML- M0, M1, M4 and M5, by FACS, using IgG-PE (Southern Biotech) or human IgG H+L AF647 (Life Technologies) as a secondary antibody. Several in-house generated antibodies were used as negative control antibodies, such as anti-CD30 ssed on activated B and T lymphocytes), anti-CD33 (expressed on monocytes, myeloid progenitor cells and myeloid leukaemias), D25 (against RSV; bed in ), AT10-002, 04 (against influenza; described in ), and F1 (against MRSA; described in ). In addition, some commercially available antibodies were used, such as Rituximab (anti-CD20), Palivizumab (anti-RSV), Panitumumab (anti-EGFR) and HLA-DR.

Microcultures binding to AML cell lines but not to liver- and colon cell lines were selected and seeded at a concentration of 1 cell/well and their supernatants tested again for specificity for AML cell lines. Clones with supernatants specifically binding AML cell lines and not liver- or colon cell lines, or healthy PBMC and bone marrow were selected for sequencing. Clones were expanded under normal culture conditions in the presence of FBS IgG low serum (Hyclone) and antibodies ed from the supernatants of these cultures as described below for the recombinant antibodies.

Cloning of AML-specific antibodies To produce recombinant antibodies we isolated total RNA with the RNeasy® mini kit (Qiagen), generated cDNA, performed PCR and cloned the heavy and light chain variable regions into the pCR2.1 TA cloning vector rogen). To rule out e transcriptase or DNA polymerase induced mutations, we performed several ndent cloning experiments. To produce recombinant mAb we cloned heavy and light variable regions of each dy in frame with human IgG1 or IgG3 and Kappa constant regions into a pcDNA3.1 (Invitrogen) based vector and transiently ected 293T cells. We purified recombinant dies from the culture supernatant with Protein A or G, depending on the Ig subtype of the clone.

In vitro activity of AML-specific antibodies To measure the in vitro effect of AML-specific antibodies on AML cells we used several approaches. First, THP-1 cells (2x104) were seeded in flat bottom 96 well plates r). AML or control -antibodies were added on day 1, in a concentration of 5-10 μg/ml. Numbers of cells per well were counted daily. Induction of cell death on both THP-1 cells and primary leukemic cells by AML-specific antibodies was ed in parallel by costaining an t of cells for Annexin V (BD Pharmingen) and 7- Aminoactinomycin D (7-AAD; Beckman Coulter), doublenegative cells being the viable cells. In addition, we used a specific lysis assay.

Target cells ) were labeled with Calcein AM (Becton Dickinson), a green scent dye that is released from the cytoplasm when cells die. Briefly, 2 million THP-1 cells were incubated with 2 ml of 2 μM Calcein AM for 30 minutes at 37°C. AML or control antibodies were added for 4 hours, after which green fluorescence was measured using a fluoresence plate reader. The proportion of specific lysis was calculated as (experimental value-low control) / (high control-low control) x 100, where low control means the spontaneous release of Calcein AM by unaffected cells and high control means the maximum amount of released Calcein AM when all cells are lysed. In addition to the Calcein AM release assay we applied the lactate dehydrogenase (LDH) release assay to measure the killing activity of AML specific antibodies. LDH is ed by d cells, from the cytosol.

Leukemic blasts, isolated at diagnosis from a t with , were incubated with AT13-024 at a maximum concentration of 10 μg/ml per 10.000 blasts. LDH release is measured after adding Reaction mixture and Stop Solution (Roche Diagnostics/Applied Science) according to the manufacturer’s protocol on an ELISA reader. The percent cytotoxicity is calculated as the (experimental value- low control) / (high control-low control) x 100, where low control means the spontaneous release of LDH by unaffected cells and high control means the maximum amount of LDH when all cells are lysed. To quantify death of target cells d by AML-specific antibodies we used a FACS-based leukemia cell lysis assay as previously described edel et al, 2013). In brief, FACS calibration beads (Accudrop scent Beads, BD Biosciences) were added to the cells in a 50/50 ratio after which a standard amount of beads was acquired with FACS. As an equal assay volume was ascertained by the calibration beads, the amount of dead or vanished cells can then be calculated as followes: 100 - ((Dapi negative cells in respective ent/Dapi negative cells in control) × 100).

Finally, to discern between apoptotic and optotic pathways of cell death induced by our antibodies we co-stained target cells with DiOC6 and ium iodide (PI). DiOC6 (3,3-dihexyloxacabocyanine iodide) is a cell-permeant, greenfluorescent , ilic dye that is selective for the mitochondria of live cells, when used at low concentrations. Apoptotic cells will lose their mitochondrial membrane potential (loss of DiOC6 stain) before the cell membrane becomes permeable (PI positive); necrotic cells become PI positive before they loose their mitochondrial membrane potential (and become DiOC6-negative). The methods used for staining were adapted from Hugh J. M et al., 2004. In brief, THP-1 cells were stained with 40nM of DiOC6 (Invitrogen) for 20 minutes at 37°C. PI was added after which the samples were analyzed immediately by flow cytometry.

Flow cytometry Stained cells were analyzed on FACSAria (BD), FACSCanto (BD), FACS LSRFortessa X-20 (BD) and Guava (Millipore) flowcytometers and flow cytometry data were processed with FlowJo software (Tree Star).

Phase contrast imaging THP-1 cells were added to a two chambered Cover glass system (LabTek). Using a phase contrast-imaging microscope (in-house manufactured), four fields of interest per r were . The software was set to take a picture of every field of interest every other minute. Just prior to the run, the THP-1 binding, non-cytotoxic antibody AT13-023 and the THP-1 binding, cytotoxic antibody AT13-037 were added to their respective wells at a concentration of 10 ug/ml.

Target verification: Immunoprecipitation and flow cytometry THP-1 cells were lysed and ared with an irrelevant antibody (in-house ted RSV antibody D25) and beads to remove non specific binding ns.

Precleared lysate was then incubated with bead-labeled AML-specific dies or with the influenza specific dy AT10-002 as a ve control (3 hrs at 4°C).

Antibody-incubated lysates were washed five times, bound proteins were eluted from the THP-1 lysate and then run on an SDS-PAGE gel. Proteins were blotted and d with Ponseau S to reveal total n. The blot was d with BSA and incubated with mouse-anti-snRNP200 (Millipore, clone 3B6.1) or Rabbit-anti- HMGB1 (Abcam) for Western blot is. Intracelllar staining for snRNP200 was performed after fixing and permeabilizing THP-1 cells with methanol (Sigma) and permeabilization buffer containing triton X-100 (Sigma), EDTA (Gibco) and BSA (Roche), followed by incubation with rabbit-anti-human snRNP200 antibody (Sigma) overnight at 4°C.

Target conformation: snRNP200 ELISA HEK 293T cells were transfected with an expression vector containing the fulllength open reading frame of snRNP200 with an N-terminal FLAG tag. At 2 days after transfection cells were harvested and lysed in lysis buffer containing protease inhibitors. This lysate was cleared and protein concentration was measured. AML specific antibodies AT12-019, AT12-023, AT13-031 and AT13-037 or commercially available snRNP200 specific antibodies (Bethyl labs) were then coated on an ELISA plate. The lysate was added at a concentration of 3 μg/ml for ing.

After extensive washing, captured snRNP200-flag was detected with a monoclonal mouse anti-flag HRP antibody (Sigma-Aldrich, clone M2).

RESULTS Generation of AML-specific antibodies In our project we use a unique technology that was recently developed in our laboratory (; incorporated herein by reference) that allows for selection of naturally occurring leukemia-specific B cells and the antibodies produced by these cells. We employed this technology to generate leukemia-specific B cell lines from two AML patients who developed potent GvL responses in parallel with severe GvHD of the liver and skin. With our B cell immortalization technique, it became possible to identify B cell responses of leukemia ts and to create leukemia-specific B cell lines that allow functional studies of the antibodies these cell lines produce and allow tion of larger numbers of antibodies, as compared to other methods known in the art, with stic and therapeutic potential.

First, we applied our technique as described in to perform a set of pilot ments, where we isolated and immortalized B cytes from a lly selected patient (donor 59) who developed a potent GvL response following extensive GvHD of liver and skin. This t was diagnosed with AML at the age of 36 years. She obtained complete ion after the first of two courses induction chemotherapy after which she ed a myeloablative, HLA- matched sibling donor SCT as consolidation therapy. Only 5 months after SCT, shortly after immunosuppressive therapy had been tapered, her AML relapsed.

With one cycle of high-dose cytarabine she obtained complete remission again, after which she spontaneously, before the led donor-lymphocyte infusion, developed stage III GvHD of the liver and stage II GvHD of the skin. She was successfully treated with high-dose corticosteroid therapy but during tapering of therapy hepatic GvHD relapsed twice. In the end, corticosteroid therapy was successfully phased out about 6 months before the current experiments were started (1,5 yrs after AML relapse) and she has remained in complete remission from her leukemia for more than three years now (Figure 2).

From this patient, we generated B cell clones using our technique to immortalize B cells. Briefly, PBMC were isolated from the peripheral blood by ficoll centrifugation, and B lymphocytes sorted by FACS. Isolated B lymphocytes were then cultured with IL21 and CD40L and transduced with BCL6 and BCL-xL, with a transduction efficiency of around 70%. Using this technique, unique B cell clones that concurrently express the B cell receptor and secrete monoclonal dies were generated. alized CD27- naïve and CD27+ memory IgG+ B cells were seeded at concentrations of 20 or 40 cells per well and expanded with IL21 and CD40L. Supernatants of expanded B cell micro es were then screened for antibody binding to leukemia-, liver- and colon cell lines by FACS, using human- IgG-PE as a secondairy detection antibody.

As the patient had been sed with AML-M5 according to the - American-British (FAB) classification (Bennett et al., 1976), we selected the THP-1 cell line that logically and ypically is roughly similar to AML-M5 for these screening essays (Tsuchiya et al., 1988). In addition, because the patient suffered from extensive GvHD of the liver we screened for the identification of liver-binding B cell clones using the liver cell line HepG2. As a negative control, and to select out cross-binding B cell clones we used the colon cell lines HT-29 and LSTR. Micro cultures with the highest binding to either of these cell lines were then sorted and single cells were deposited in 96 well formats, expanded and the supernatants of these ed clones were again screened for binding against leukemia cell lines (Figure 3).

Properties of AML-specific antibodies With this approach we generated eight B cell lines from this one patient, producing antibodies that bind to THP-1 (Figure 3) but not liver or colon cell lines, fibroblasts, elial cells (human umbilical vein endothelial cells or HUVEC), healthy PBMC or bone marrow (Table 2 and Figure 4). These are antibodies AT12-019, AT12-023, AT12-025, AT13-022, AT13-023, AT13-024, AT13-031 and AT12-020.

The heavy and light chain le regions of these antibodies are depicted in Table 1 and Figure 1.

Interestingly, the antibodies are of the IgG1 and IgG3 isotypes, and several of the DNA sequences showed somatic hypermutations. Antibodies AT12-023, AT12-025, AT13-023 and AT13-031 belong to the VH4-34 family, which is a family of VH sequences known for their potential g ties (Bhat et al, 1997). The antibodies are of donor-origin, as confirmed by microchimerism analyses.

We then determined the breadth of binding within the spectrum of AML subtypes, and tested the generated AML-specific B cell clones for binding to other AML FAB classification types. Selected leukemia-specific clones also bound to the AML-M5 cell line MonoMac6 (Table 3) (see for review of AML cell lines (Drexler and Minowada, 1998)).

Our AML-specific antibodies also bound to freshly isolated AML blasts of newly diagnosed patients (Table 3 and Figure 5).

Furthermore, some antibodies also bound other poietic malignancy -cell lines, such as the e large cell B cell lymphoma cell lines OCI-Ly1 and OCILy7 and the le myeloma cell lines U266 and 29, and/or patientderived hematologic tumor cells (Table 4 and Figure 6).

In vitro activity of AML specific antibodies While testing the specificity of the AML-binding antibodies, we made a striking observation. Three of the eight antibodies spontaneously induced death of the leukemic cells they were binding to. THP-1 cells were killed by AT12-023 and , and primary AML blasts isolated from patients diagnosed with AML were killed by AT12-025 and AT12-024 (Table 5 and Figures 7-10).

Figure 7 shows rapid killing of THP-1 cells by AT12-023. Dying blasts expressed 7- AAD and n V. Strikingly, while co-culture of THP-1 with AT12-025 at first did not affect total cell numbers in the cultures (Figure 7), this antibody appeared to also induce death of THP-1 cells, albeit with a little delay compared to AT12-023 (Figure 8). The observation that some of the antibodies show direct killing activity against leukemic cells is highly exciting and has to the best of our knowledge not been ed before.

Confirmation of our findings by generating AML-specific B cell lines from a second patient About 0.05 to 0.1% of the B cells that we screened from the first patient were found to be AML-specific. To confirm our findings, we selected a second patient with relapsed AML who obtained durable remission after an allogeneic SCT (donor 58; Figure 11). Also this patient developed GvHD of the skin and liver for which she was treated with oral steroids. After steroids were phased out, about one year after the SCT, PBMC were isolated, B cells immortalized, and B cell lines screened for binding to AML cell lines as described above. Five B cell clones have been generated from this patient that bind to the AML cell lines THP-1 and MonoMac6 (Figure 12), but not to liver or gut cell lines, fibroblasts or y PBMC (Table 6).

These clones produce antibodies AT13-033, AT13-034, AT13-035, AT13-036 and AT13-037. Interestingly, all these antibodies are of the IgG3 isotype. The sequences of the heavy and light chain variable regions of these antibodies are also depicted in Table 1 and Figure 1. These data confirm the achievability of our t; despite the low frequencies of the B cells we are aiming at, we were able to isolate them and to generate robust antibody-producing B cell lines that were specific for AML.

Discussion These preliminary date are highly exciting, as - to the best of our knowledge - we are the first to generate several human, imeric, leukemia-specific B lymphocyte clones from ts that developed a , lasting GvL response against AML. The observation that some of these antibodies spontaneously show killing activity against leukemic blasts in vitro is highly exciting and very ing. In addition, the observation that some of the antibodies have a germline sequence and are of the IgG3 subclass, a type of dy that can be induced t T cell help, warrants further attention as these findings demonstrate that ‘natural’ antibodies generated in a T-cell-independent way affect GvL ses in SCT patients. antly, these data offer proof of concept that using this technique, we can select leukemia-specific B cell clones.

Example 2 AML-specific dies from a third patient To further confirm our approach and to show this anti-AML response is not only reserved for female patients, we selected a male patient as well. This patient (Figure 13), donor 101, was diagnosed with an intermediate-risk AML (no cytogenetic or molecular abnormalities; FAB classification ) at the age of 49 years. He received two courses of chemotherapy abine, idarubicine, amsacrine) and one course of consolidation chemotherapy (busulphan, cyclophosphamide) ed by an autologous HSCT, as there was no HLA-matched sibling stem cell donor available. Fourteen months after the first diagnosis his e relapsed. He obtained complete ion after one cycle of high-dose cytarabine, after which he ed a reduced intensity allogeneic HSCT of a matched, unrelated donor (RIST-MUD). Six weeks later he developed acute GvHD of skin, liver and intestine (stage 1; grade II) that responded well to corticosteroid therapy. B cells were ed from a phlebotomy product obtained from this patient 38 months post-SCT.

Using the same methods as described in Example 1, four B cell clones have been generated from this patient that bind to the AML cell lines THP-1 and/or Molm13 (Figure 14 and Table 7) but not to (fetal) liver or gut cell lines, fibroblasts or healthy PBMC (Table 8). These clones produce antibodies AT14-013 , AT14- 014 (IgG3), 15 (IgG3) and AT14-016 (IgG3). Interestingly, again the majority of the antibodies is of the IgG3 isotype. The sequences of the heavy and light chain variable regions of these antibodies show high amounts of somatic utations and are depicted in Table 1B and Figure 1. Clone AT14-013 shows very minor reactivity with the hepatocellular carcinoma cell line Huh7, but not to the hepatocellular carcinoma cell line HepG2 or healthy fetal liver cells. Also minor reactivity to fibroblasts is observed, however, the binding of this antibody to these tissue specific cells, compaired to the binding to primary leukemic blasts is negligible (Figure 14).

It was also tested whether the four antibodies of donor 101 could bind primary AML blasts ials & Methods: see Example 1). Figure 15 and Table 7 show that antibody 13 appears to bind primary blasts of at least three different FAB classifications (AML-M0, M4 and M5). Antibodies AT14-015 and AT14-016 are able to bind primary AML blasts of the M4 classification.

Example 3 In vitro activity of AML-specific antibodies of donors 59, 58 and 101 In Example 1, the breadth of g of the antibodies of donor 59 within the spectrum of AML subtypes was determined (Table 3). Using the same methods, this has also been determined for the dies of donor 58. The results are shown in Table 9A: all five antibodies of donor 58 (AT13-033, AT13-034, AT13-035, 36 and AT13-037) bound to the AML-M5 cell line THP-1, as well as to the AML-M5 cell line MonoMac6. These AML-specific antibodies did not significantly bind to freshly isolated AML blasts of newly diagnosed patients of FAB classification M0, M1 or M4. AT13-034 could only weakly bind M0 blasts. This indicates that these antibodies have a specificity for (at least) AML M5 blasts.

In Example 1, it was also determined that antibodies AT12-023 and 25 of donor 59 killed THP-1 cells (Table 5 and Figures 7-9). Subsequently, we have tested whether the other antibodies of donor 59, as well as the antibodies of donor 58, could also kill THP-1 cells, using the same Materials & Methods as in Example 1. As shown in Tables 9B-10, in addition to AT12-023 and AT12-025 also antibody AT13-031 (donor 59), as well as antibodies AT13-033, AT13-035, AT13-036 and 37 (donor 58) appear to be able to kill THP-1 cells.

The capability of ng death of primary AML blasts was also tested (Materials & Methods: see Example 1). Similar to some of the antibodies obtained from donor 59, some of the antibodies derived from donor 58 are also capable of inducing cell death of primary AML cells. This is shown in Figure 16 for antibody AT13-037, in both forms (purified B cell supernatant -037) and recombinant produced dy (rAT13-037); both in the IgG3 confirmation). The leukemic cells are derived from the bone marrow of a newly diagnosed AML patient, FAB classification AML-M5.

Example 4 In vitro activity of AML antibodies is rapid and involves a non-apoptotic cell death pathway To investigate the y through which several of the mentioned antibodies induced death of their target cells, we visualized death of target cells with apse microscopy (Figure 17a). We observed that within a few minutes after incubation with dy AT13-037, cells started to swell and then died. This suggested that antibodies according to the invention activated pathways other than the classical apoptosis pathways, as apoptotic cells shrink rather than swell. To further investigate this we med double staining with the cell death markers DiOC6 and iumiodide (PI). Cells engaged to undergo apoptosis first loose mitochondrial charge (which can be visualized by the loss of DiOC6 binding) before ne permeability increases (visualized by propidium iodide (PI) staining), while cells oing necrosis loose their membrane integrity (PI positive) but not immediately the mitochondrial membrane potential. As enac is known to induce apoptosis of THP-1 cells, we used diclofenac as a positive control.

Diclofenac-treated, tic THP-1 cells became negative (lost mitochondrial membrane potential), but maintained membrane integrity. Upon incubation with the AML-specific cytotoxic antibody AT12-023 mitochondrial membrane potential was ined (DiOC6-positive) while the membrane permeability of THP-1 cells increased (PI-positive). Thus, AML-antibody treated THP-1 cells became PI-positive while maintaining mitochondrial membrane potential (Figure 17b, right panel) indicating the activation of a non-apoptotic death pathway. Indeed, death of THP-1 cells by cytotoxic AML-specific antibody treatment could not be prevented by incubating the cells with the pan caspase inhibitors Z-VAD-fmk or QVD-OPh (Figure 17c).

Cell death mediated through interference with the target cell membrane Non-apoptotic death pathways include necroptosis and oncosis. Necroptosis is, similar to apoptosis, an active cell death pathway that depends on the activation of defined molecular pathways including the activation of receptor-interacting protein kinase 3 (RIPK3). To investigate whether AML-antibody-induced cell death was dependent on the activation of intracellular molecular pathways we tested whether antibody-induced cytotoxicity was dependent of temperature. We found that under these experimental conditions the xic activities of at least antibodies AT13-033, AT13-035, AT13-036, AT13-037, AT12-023 and AT12-025 were equally potent at 4°C as compared to their ties at 37°C (Figure 18), suggesting that at least these antibodies induced cell death by a e process. Of note, the cytotoxic activity of antibody AT13-031 was icantly more potent at 37°C as compared to 4°C. However, since dy AT13-031 does induce death of AML cells in the presence of sis inhibitors (such as the pan e inhibitors Q-VD-OPh or Z-VAD-fmk), it is clear that antibody 31 is also able to diminish proliferation of AML cells independently from apoptosis.

Oncosis is a mode of cell death characterized by swelling of the cell, through selective membrane injury, resulting in increased membrane permeability and ultimately cell death. Oncosis-inducing antibodies have been described that mediate cell death by g large pores in the membrane through ilization of the membrane (Hernandez et al, 2011). Cytocholasin D is an actin polymerization inhibitor that can stabilize the cytoskeleton. Treatment of the target cell line THP-1 with cytochalasin D did not prevent antibody binding to these cells (Figure 19a), however, it did prevent death of the target cells (Figure 19b ). Thus, membrane isation protects the target cells against the cytotoxic activity of our dies.

Example 5 One of the targets recognized by our antibodies is snRNP200 We then set out to determine the target recognized by several AML-specific antibodies. For this we used precipitation of cell membrane lysates of THP- 1 cells with AT12-023 and AT13-031. We found a clear protein band at 250 kD that was sent for mass-spectometry analysis which revealed snRNP200 as the target antigen which could be confirmed by Western blot analysis (Figure 20a). We developed an ELISA, to verify snRNP200 as the target of some of the AML antibodies. With this ELISA we found that in addition to AT12-023 and AT13-031, AT13-037 specifically recognizes snRNP200 (Figure 20b). Other AML specific antibodies like AT12-019 did not recognize snRNP200 as target antigen. snRNP200 is part of the spliceosome in all eukaryotic cells and is therefore expected to be located in the nucleus. To confirm that AML cells express this protein on their cell surface we stained the cell membrane of THP-1 cells with a commercially available, anti-snRNP200 antibody. Figure 21 shows that the anti snRNP200 antibody is indeed binding to the membrane of the AML cells, but not to the Jurkat cell line. As ed, as snRNP200 is a nuclear protein, it did bind intracellularly to the Jurkat and THP-1 cell lines (Figure 21).

All eukaryotic cells have snRNP200 (also known as U5-snRNP) protein in the nucleus, as part of the spliceosome (Kattah, 2010). The spliceosome consists of a number of proteins. At least one of these proteins, U1-snRNP, has been described to be expressed on apoptotic cells in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) leading to auto-immune responses (Kattah, 2010).

We e that 00 expression by AML cells has triggered an allo-immune response (graft vs ia response) that has kept the ts in durable remission. Therefore, this n can now be used as a new AML target. er, since antibodies AT12-023 and 31 specifically recognize 00 and also recognize B-NHL cells, snRNP200 can now also be used as a target for B-NHL.

Table 1A. Preferred anti-AML antibodies according to the invention (CDR numbering according to Kabat et al. 1991) SEQ ID Antibody Identity Sequence 1 AT12-023 Heavy GYYWS chain CDR1 2 AT12-025 Heavy GYYWS chain CDR1 3 AT13-024 Heavy SYGMH chain CDR1 4 19 Heavy SYAMS chain CDR1 AT13-022 Heavy SYGMH chain CDR1 6 AT13-023 Heavy GYFWT chain CDR1 7 AT13-031 Heavy GYYWS chain CDR1 8 20 Heavy TYSMN chain CDR1 9 AT13-033 Heavy NYGMH chain CDR1 AT13-034 Heavy SHAIH chain CDR1 11 AT13-035 Heavy SYGMH chain CDR1 12 AT13-036 Heavy SYSMN chain CDR1 13 AT13-037 Heavy TYGMH chain CDR1 14 AT12-023 Heavy EINHSGSTNYNPSLKS chain CDR2 AT12-025 Heavy EINHSGSTNYNPSLKS chain CDR2 16 AT13-024 Heavy FIRYDGSNKYFADSVRG chain CDR2 17 AT12-019 Heavy GSTSYADSVKG chain CDR2 18 AT13-022 Heavy ISYDGSNKYYADSVKG chain CDR2 19 AT13-023 Heavy ETVHSGGTNYNPSLKS chain CDR2 AT13-031 Heavy EINHSGSTNYNPSLKS chain CDR2 21 AT12-020 Heavy SISSSSGYIYYADSVKG chain CDR2 22 AT13-033 Heavy VISHDGSKTYYGHSVKG chain CDR2 23 AT13-034 Heavy LIWYDGSNNYYADSVKG chain CDR2 24 AT13-035 Heavy VISYDGSNKYYADSVKG chain CDR2 AT13-036 Heavy SISSSSTYIYYADSVKG chain CDR2 26 AT13-037 Heavy VIWYDGSNTYYADSVKG chain CDR2 27 AT12-023 Heavy GRSTSPLDYYYYYMDV chain CDR3 28 AT12-025 Heavy KPFDY chain CDR3 29 AT13-024 Heavy DPQERIYYSDTSGYLDY chain CDR3 AT12-019 Heavy SPAMIRGVRGGDYFDY chain CDR3 31 AT13-022 Heavy DGKGIVVIYYYYGMDV chain CDR3 32 23 Heavy GLNSPFDY chain CDR3 33 AT13-031 Heavy GPRGMYSSSSGDY chain CDR3 34 AT12-020 Heavy DGTFSYYYYMDV chain CDR3 AT13-033 Heavy AGLNYYGNLLSNYFYYGMDV chain CDR3 36 AT13-034 Heavy ARDGCTGGSCCYFDN chain CDR3 37 AT13-035 Heavy AKDSYYYGSGRRWGYYFDY chain CDR3 38 AT13-036 Heavy GRDGYSLYPRGYHYGMDV chain CDR3 39 AT13-037 Heavy ARGRGYSAQGNRNRAYYFDY chain CDR3 40 AT12-023 Light QGDFLRSYYAS chain CDR1 41 AT12-025 Light RASQSISRYLN chain CDR1 42 AT13-024 Light RASQSISSWLA chain CDR1 43 AT12-019 Light RASQAFSSYLV chain CDR1 44 AT13-022 Light SGDKLGDKYAC chain CDR1 45 AT13-023 Light RASQGIRNVLG chain CDR1 46 AT13-031 Light RASQGIRNDLG chain CDR1 47 20 Light RASQDISSSLA chain CDR1 48 AT13-033 Light TGTSSDIGGYNYVS chain CDR1 49 AT13-034 Light RASQSISNNLG chain CDR1 50 AT13-035 Light QGDSLRSYYAS chain CDR1 51 AT13-036 Light TGTSSDVGGYNYVS chain CDR1 52 AT13-037 Light RASQSVSSNLA chain CDR1 53 AT12-023 Light GKNKRPS chain CDR2 54 AT12-025 Light AASSLQS chain CDR2 55 24 Light KASSLES chain CDR2 56 AT12-019 Light ATSTLQG chain CDR2 57 AT13-022 Light QDSKRPS chain CDR2 58 AT13-023 Light AASSLQS chain CDR2 59 AT13-031 Light AAVSLQS chain CDR2 60 AT12-020 Light AASTLQS chain CDR2 61 AT13-033 Light EVTKRPS chain CDR2 62 AT13-034 Light GASTRAT chain CDR2 63 AT13-035 Light S chain CDR2 64 AT13-036 Light DVNDRPS chain CDR2 65 37 Light GAFTRVT chain CDR2 66 AT12-023 Light NSRDRSGNHLV chain CDR3 67 AT12-025 Light QQSYSTPRT chain CDR3 68 AT13-024 Light QQYNTYPYT chain CDR3 69 AT12-019 Light PPT chain CDR3 70 AT13-022 Light QAWDSSTVVF chain CDR3 71 AT13-023 Light LQHNSHPRT chain CDR3 72 AT13-031 Light LQHNSYPRT chain CDR3 73 AT12-020 Light QQYYSYPPT chain CDR3 74 AT13-033 Light SSYAGSNDLL chain CDR3 75 34 Light QQYNNWPRLT chain CDR3 76 AT13-035 Light NSRDSSGNHVV chain CDR3 77 AT13-036 Light SSYTRSNTVI chain CDR3 78 AT13-037 Light QQYNDRPPYT chain CDR3 79 23 Heavy QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISV chain DTSKNQFSLKLSSVTAADTAVYYCARGRSTSPLDYYYYYMDVWAKGTTVTVSS 80 AT12-025 Heavy QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISV chain DTSKNQFSLKLSSVTAADTAVYYCARGSMARPKPFDYWGQGTLVTVSS 81 AT13-024 Heavy QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYFADSVRGRFTIS chain RDNSKNTLFLQMNSLRAEDTAVYYCAKDPQERIYYSDTSGYLDYWGQGTLVTVSS 82 AT12-019 Heavy EVHLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTIRASGGSTSYADSVKGRFTISR chain DNSQSRLYLQMNSLTAEDTAVYYCAKSPAMIRGVRGGDYFDYWGQGTLVTVSS 83 AT13-022 Heavy SGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTIS chain RDNSKNTLYLQMNSLRAEDTAVYYCAKDGKGIVVIYYYYGMDVWGQGTTVTVSS 84 AT13-023 Heavy QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYFWTWIRQPPGKGLEWIGETVHSGGTNYNPSLKSRVTISV chain DTSKNQFSLRLNSVTAADTAVYYCVRGLNSPFDYWGQGTLVTVSS 85 AT13-031 Heavy QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISV chain DTSKKQFSLKLSSVTAADTAVYYCARGPRGMYSSSSGDYWGQGTLVTVSS 86 AT12-020 Heavy EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISSSSGYIYYADSVKGRFTISR chain DNAKNSLYLQMNSLRAEDTAVYYCARDGTFSYYYYMDVWGKGTTVTVSS 87 33 Heavy QVQLVESGGGVVQPGRSLRLSCAVSGLSFRNYGMHWVRQAPGKGLEWVAVISHDGSKTYYGHSVKGRFTI chain SRDKSKTMLFLQMNSLRPEDTAVYYCAKAGLNYYGNLLSNYFYYGMDVWGQGTTVTVSS 88 AT13-034 Heavy QVHLVESGGGVVQPGTSLRLSCAASEFTFSSHAIHWVRQAPGKGLEWVALIWYDGSNNYYADSVKGRFTIS chain RDSSKNTVHLQMNSLRVEDTAVYYCARDGCTGGSCCYFDNWGQGTLVTVSS 89 AT13-035 Heavy QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTIS chain RDNSKNTLYLQMNSLRAEDTAVYYCAKDSYYYGSGRRWGYYFDYWGQGTLVTVSS 90 AT13-036 Heavy EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSTYIYYADSVKGRFTISR chain DNARNSLYLQMNSLRAEDTAVYYCARRREVGRDGYSLYPRGYHYGMDVWGQGTTVTVSS 91 AT13-037 Heavy QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWYDGSNTYYADSVKGRFTI chain SRDNSKNTLYLQIKSLRAEDTAVYYCARGRGYSAQGNRNRAYYFDYWGQGTLVTVSS 92 AT12-023 Light SSELTQDPAVSVALGQTVRITCQGDFLRSYYASWYQQKPGQAPVLVIFGKNKRPSGIPDRFSGSSSGNTASL chain TITGAQAEDEADYYCNSRDRSGNHLVFGGGTKLTVL 93 AT12-025 Light DIQMTQSPSSLSASVGDRVTITCRASQSISRYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTL chain TISSLQPEDFATYYCQQSYSTPRTFGPGTKVDIK 94 AT13-024 Light SPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGTGSGTEFTL chain TISSLQPDDFATYYCQQYNTYPYTFGQGTKLEIK 95 AT12-019 Light AIRLTQSPSSVSASTGDRVTITCRASQAFSSYLVWYQQKPGKAPNLLIYATSTLQGGVPSRFSGSGSGTDFTL chain TISNLQSEDFATYYCQQYYSYPPTFGQGTKLEIK 96 AT13-022 Light SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRPSGIPERFSGSNSGNTATL chain TISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVL 97 AT13-023 Light DIQMTQSPSSLSASVGDRVTITCRASQGIRNVLGWYQQKPGKAPKCLIYAASSLQSGVPSRFSGSGSGTEFTL chain TISSLQPEDFATYYCLQHNSHPRTFGQGTKVEIK 98 AT13-031 Light DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAAVSLQSGVPSRFSGSGSGTEFT chain LTISSLQPEDFATYYCLQHNSYPRTFGQGTKLEIK 99 AT12-020 Light AIRMTQSPSSFSASTGDRVTITCRASQDISSSLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFTL chain TISCLQSEDFATYYCQQYYSYPPTFGQGTRLEIK 100 AT13-033 Light QSALTQPPSASGSPGQSVTISCTGTSSDIGGYNYVSWYQHHPGKAPKLMIYEVTKRPSGVPDRFSGSKSGNT chain GLQAEDEAHYYCSSYAGSNDLLFGGGTKLTVL 101 AT13-034 Light EVVMTQSPATLSVSPGERATLSCRASQSISNNLGWYQQKPGQAPRLLIYGASTRATGIPGRFSGSGSGTEFT chain LTIYSLQSEDFAVYYCQQYNNWPRLTFGGGTKVEIK 102 AT13-035 Light SSELTQDPAVSVALGQTVRITCQGDSLRSYYASWYQQKPGQAPVLVIYGKNNRPSGIPDRFSGSSSGNTASL chain TITGAQAEDEADYYCNSRDSSGNHVVFGGGTKLTVL 103 AT13-036 Light QSALTQPASVSGSPRQSITISCTGTSSDVGGYNYVSWYQQLPGKAPKLMIYDVNDRPSGVSIRFSGSKSGNT chain ASLTISGLQAEDEADYYCSSYTRSNTVIFGGGTKLTVL 104 AT13-037 Light EIVMTQSPATLSVSPGERVILSCRASQSVSSNLAWYQQKPGQPPRLLIYGAFTRVTGVPARFSGSGSGTEFTL chain TISSLQSEDFAVYYCQQYNDRPPYTFGQGTKLEIK 105 AT12-023 Heavy ggt tac tac tgg agc chain CDR1 106 AT12-025 Heavy ggt tat tac tgg agc chain CDR1 107 AT13-024 Heavy agc tat ggc atg cac chain CDR1 108 19 Heavy agc tat gcc atg agt chain CDR1 109 AT13-022 Heavy agc tat ggc atg cac chain CDR1 110 AT13-023 Heavy ggt tac ttc tgg acc chain CDR1 111 AT13-031 Heavy ggt tac tac tgg agc chain CDR1 112 AT12-020 Heavy acc tat agc atg aac chain CDR1 113 AT13-033 Heavy aat tat ggc atg cac chain CDR1 114 AT13-034 Heavy tcc cat gcc ata cac chain CDR1 115 AT13-035 Heavy agc tat ggc atg cac chain CDR1 116 AT13-036 Heavy agt tat agc atg aac chain CDR1 117 AT13-037 Heavy acc tat ggc atg cac chain CDR1 118 AT12-023 Heavy gaa atc aat cat agt gga agc acc aac tac aac ccg tcc ctc aag agt chain CDR2 119 25 Heavy gaa atc aat cat agt gga agc acc aac tac aac ccg tcc ctc aag agt chain CDR2 120 AT13-024 Heavy ttt ata cgg tat gat gga agt aat aaa tac ttt gca gac tcc gtg agg ggc chain CDR2 121 AT12-019 Heavy act att agg gct agt ggt ggt agc aca agc tac gca gac tcc gtg aag ggc chain CDR2 122 AT13-022 Heavy ata tca tat gat gga agt aat aaa tac tat gca gac tcc gtg aag ggc chain CDR2 123 AT13-023 Heavy gaa acc gtt cat agt gga ggc acc aac tac aac ccg tcc ctc aag agt chain CDR2 124 AT13-031 Heavy gaa atc aat cat agt gga agc acc aac tac aac ccg tcc ctc aag agt chain CDR2 125 AT12-020 Heavy tcc att agt agt agt agt ggt tac ata tac tac gca gac tca gtg aag ggc chain CDR2 126 AT13-033 Heavy gtc att tcg cat gat gga agt aag aca tac tat gga cac tcc gtg aag ggc chain CDR2 127 AT13-034 Heavy ctt ata tgg tat gat gga agt aat aat tat tat gca gac tcc gtg aag ggc chain CDR2 128 AT13-035 Heavy gtt ata tca tat gat gga agt aat aaa tac tat gca gac tcc gtg aag ggc chain CDR2 129 AT13-036 Heavy tcc att agt agt agt agt act tac ata tac tac gca gac tca gtg aag ggc chain CDR2 130 AT13-037 Heavy gtt ata tgg tat gat gga agt aat aca tac tat gca gac tcc gtg aag ggc chain CDR2 131 AT12-023 Heavy ggc cgt agt acc agc ccg ctc gac tac tac tac tac tac atg gac gtc chain CDR3 132 AT12-025 Heavy ggc tca atg gca aga ccc aag cca ttt gac tac chain CDR3 133 AT13-024 Heavy gcg aaa gat ccc caa gag cgt att tat tac tct gat act agt ggt tac ctt gac tac chain CDR3 134 19 Heavy tct cct gct atg att cgg gga gtt agg ggg ggt gac tac ttt gac tac chain CDR3 135 AT13-022 Heavy gat ggg aag ggg att gta gtt att tac tac tac tac ggt atg gac gtc chain CDR3 136 AT13-023 Heavy ggc ctt aac agc ccc ttt gac tac chain CDR3 137 AT13-031 Heavy ccc cgg ggc atg tat agc agc tcg tcc ggg gac tac chain CDR3 138 AT12-020 Heavy gat ggg act ttc tcc tac tac tac tac atg gac gtc chain CDR3 139 AT13-033 Heavy gcc ggg ttg aac tac tat gga aac cta tta tca aac tac ttc tac tac gga atg gac gtc chain CDR3 140 AT13-034 Heavy gcg aga gat ggt tgt act ggt ggt agc tgc tgc tat ttt gac aac chain CDR3 141 AT13-035 Heavy gcg aaa gac tcg tat tac tat ggt tcg ggg aga cga tgg ggc tac tac ttt gac tac chain CDR3 142 AT13-036 Heavy gcg aga agg agg gag gtc ggt aga gat ggc tac agt ttg tac ccc cgg ggg tac cac tac ggt atg gac gtc chain CDR3 143 AT13-037 Heavy gcg aga ggc cgt gga tat agt gcc caa ggg aat cgg aat agg gct tac tac ttt gac tac chain CDR3 144 23 Light caa gga gac ttc ctc aga agc tat tat gca agc chain CDR1 145 AT12-025 Light cgg gca agt cag agc att agc agg tat tta aat chain CDR1 146 AT13-024 Light cgg gcc agt cag agt att agt agc tgg ttg gcc chain CDR1 147 AT12-019 Light cgg gcg agt cag gct ttt agc agt tat tta gtc chain CDR1 148 AT13-022 Light tct gga gat aaa ttg ggg gat aaa tat gct tgc chain CDR1 149 AT13-023 Light cgg gca agt cag ggc att aga aat gtt tta ggc chain CDR1 150 AT13-031 Light cgg gca agt cag ggc att aga aat gat tta ggc chain CDR1 151 AT12-020 Light cgg gcg agt cag gat att agc agt tct tta gcc chain CDR1 152 33 Light act ggg acc agc agt gac att ggt ggt tat aac tat gtc tcc chain CDR1 153 AT13-034 Light agg gcc agt cag agc att agc aac aac tta ggc chain CDR1 154 AT13-035 Light caa gga gac agc ctc aga agc tat tat gca agc chain CDR1 155 AT13-036 Light act gga acc agc agt gac gtt ggt ggt tat aac tat gtc tcc chain CDR1 156 AT13-037 Light agg gcc agt cag agt gtt agc agc aac tta gcc chain CDR1 157 AT12-023 Light ggt aaa aac aag cgg ccc tca chain CDR2 158 AT12-025 Light gct gca tcc agt ttg caa agt chain CDR2 159 AT13-024 Light aag gcg tct agt tta gaa agt chain CDR2 160 AT12-019 Light gct aca tcc act ttg caa ggt chain CDR2 161 AT13-022 Light caa gat agc aag cgg ccc tca chain CDR2 162 23 Light gct gca tcc agt ttg caa agt chain CDR2 163 AT13-031 Light gct gca gtc agt ttg caa agt chain CDR2 164 AT12-020 Light gct gca tcc act ttg caa agt chain CDR2 165 AT13-033 Light gag gtc act aag cgg ccc tca chain CDR2 166 AT13-034 Light ggt gca tcc acc agg gcc act chain CDR2 167 AT13-035 Light ggt aaa aac aac cgg ccc tca chain CDR2 168 AT13-036 Light gat gtc aat gat cgg ccc tca chain CDR2 169 AT13-037 Light ggt gca ttc acg agg gtc act chain CDR2 170 AT12-023 Light aac tcc cgg gac cgc agt ggt aac cac ctg gtg chain CDR3 171 AT12-025 Light caa cag agt tac agt acc cct cgc act chain CDR3 172 AT13-024 Light caa cag tat aat act tac ccg tac act chain CDR3 173 AT12-019 Light caa cag tat tat agt tac cct ccg act chain CDR3 174 22 Light cag gcg tgg gac agc agc act gtg gta ttc chain CDR3 175 AT13-023 Light cta cag cat aat agt cac ccc cgg acg chain CDR3 176 AT13-031 Light cta cag cat aat agt tac cct cgg act chain CDR3 177 AT12-020 Light caa cag tat tat agt tac cct ccg acg chain CDR3 178 AT13-033 Light agc tca tat gca ggc agc aac gat ttg cta chain CDR3 179 AT13-034 Light caa caa tat aat aac tgg cct cgg ctc act chain CDR3 180 AT13-035 Light aac tcc cgg gac agc agt ggt aac cat gtg gta chain CDR3 181 AT13-036 Light agc tca tat aca aga agc aac act gtg ata chain CDR3 182 AT13-037 Light cag cag tac aat gac cgg ccc ccg tac act chain CDR3 183 AT12-023 Heavy cag gtg cag cta cag cag tgg ggc gca gga ctg ttg aag cct tcg gag acc ctg tcc ctc acc tgc gct gtc tat ggt ggg tcc ttc chain agt ggt tac tac tgg agc tgg atc cgc cag ccc cca ggg aag ggg ctg gag tgg att ggg gaa atc aat cat agt gga agc acc aac tac aac ccg tcc ctc aag agt cga gtc acc ata tca gta gac acg tcc aag aac cag ttc tcc ctg aag ctg agc tct gtg acc gcc gcg gac acg gct gtg tat tac tgt gcg agg ggc cgt agt acc agc ccg ctc gac tac tac tac tac tac atg gac gtc tgg gcc aaa ggg acc acg gtc acc gtc tcc tca 184 AT12-025 Heavy cag gtg cag cta cag cag tgg ggc gca gga ctg ttg aag cct tcg gag acc ctg tcc ctc acc tgc gct gtc tat ggt ggg tcc ttc chain agt ggt tat tac tgg agc tgg atc cgc cag ccc cca ggg aag ggg ctg gag tgg att ggg gaa atc aat cat agt gga agc acc aac tac aac ccg tcc ctc aag agt cga gtc acc ata tca gta gac acg tcc aag aac cag ttc tcc ctg aag ctg agc tct gtg acc gcc gcg gac acg gct gtg tat tac tgt gcg aga ggc tca atg gca aga ccc aag cca ttt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc tca 185 24 Heavy cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg agg tcc ctg aga ctc tcc tgt gca gcg tct gga ttc acc ttc chain agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg gag tgg gtg gca ttt ata cgg tat gat gga agt aat aaa tac ttt gca gac tcc gtg agg ggc cga ttc acc atc tcc aga gac aat tcc aag aac acg ctg ttt ctg caa atg aac agc ctg aga gct gag gac acg gct gtg tat tac tgt gcg aaa gat ccc caa gag cgt att tat tac tct gat act agt ggt tac ctt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc tca 186 AT12-019 Heavy gag gtg cac ctg ttg gag tct ggg gga ggc ttg gta cag cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt chain agc agc tat gcc atg agt tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtc tca act att agg gct agt ggt ggt agc aca agc tac gca gac tcc gtg aag ggc cgg ttc acc atc tcc aga gac aat tcc cag agc agg ttg tat ctg caa atg aac agt ctg aca gcc gag gac acg gcc gta tat tac tgt gcg aaa tct cct gct atg att cgg gga gtt agg ggg ggt gac tac ttt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc tca 187 AT13-022 Heavy cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc chain agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg gag tgg gtg gca gtt ata tca tat gat gga agt aat aaa tac tat gca gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg tat tac tgt gcg aaa gat ggg aag ggg att gta gtt att tac tac tac tac ggt atg gac gtc tgg ggc caa ggg acc acg gtc acc gtc tcc tca 188 AT13-023 Heavy cag gta cag cta cag cag tgg ggc gca gga ctg ttg aag cct tcg gag acc ctg tcc ctc acc tgc gct gtc tat ggt ggg tcc ttc chain agt ggt tac ttc tgg acc tgg atc cgc cag ccc cca ggg aag ggg ctg gag tgg att ggg gaa acc gtt cat agt gga ggc acc aac tac aac ccg tcc ctc aag agt cga gtc acc ata tca gtc gac acg tcc aag aac cag ttc tcc ctg agg ctg aac tct gtg acc gcc gcg gac acg gct gtg tat tac tgt gtg aga ggc ctt aac agc ccc ttt gac tac tgg ggc cag gga acc cta gtc acc gtc tcc tca 189 AT13-031 Heavy cag gtg cag cta cag cag tgg ggc gca gga ctg ttg aag cct tcg gag acc ctg tcc ctc acc tgc gct gtc tat ggt ggg tcc ttc chain agt ggt tac tac tgg agc tgg atc cgc cag ccc cca ggg aag ggg ctg gag tgg att ggg gaa atc aat cat agt gga agc acc aac tac aac ccg tcc ctc aag agt cga gtc acc ata tca gta gac acg tcc aag aag cag ttc tcc ctg aag ctg agc tct gtg acc gcc gcg gac acg gct gtg tat tat tgt gcg aga ggc ccc cgg ggc atg tat agc agc tcg tcc ggg gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc tca 190 AT12-020 Heavy gag gtg cag ctg gtg gag tct ggg gga ggc ctg gtc aag cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc chain agt acc tat agc atg aac tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtc tca tcc att agt agt agt agt ggt tac ata tac tac gca gac tca gtg aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tca ctg tat ctg caa atg aac agc ctg aga gcc gag gac acg gct gtg tat tac tgt gcg aga gat ggg act ttc tcc tac tac tac tac atg gac gtc tgg ggc aaa ggg acc acg gtc acc gtc tcc tca 191 AT13-033 Heavy cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg agg tcc ctg aga ctc tcc tgt gca gtc tct gga ctc agt ttc chain agg aat tat ggc atg cac tgg gtc cgc cag gct ccc ggc aag ggg ctg gag tgg gtg gca gtc att tcg cat gat gga agt aag aca tac tat gga cac tcc gtg aag ggc cga ttc acc ata tcc aga gac aaa tcc aag act atg ttg ttt ctc caa atg aac agc ctg aga cct gag gac acg gct gtt tat tac tgt gcg aaa gcc ggg ttg aac tac tat gga aac cta tta tca aac tac ttc tac tac gga atg gac gtc tgg ggc caa ggg acc aca gtc acc gtc tcg tca 192 34 Heavy cag gtg cac ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg acg tcc ctg aga ctc tcc tgt gca gcg tct gaa ttc acc ttc chain agt tcc cat gcc ata cac tgg gtc cgc cag gct cca ggc aag ggg ctg gag tgg gtg gca ctt ata tgg tat gat gga agt aat aat tat tat gca gac tcc gtg aag ggc cga ttc acc atc tcc aga gac agt tcc aag aac acg gtg cat ctg caa atg aac agc ctg aga gtc gag gac acg gct gtg tat tac tgt gcg aga gat ggt tgt act ggt ggt agc tgc tgc tat ttt gac aac tgg ggc cag gga acc cta gtc acc gtc tcc tcg 193 AT13-035 Heavy cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg agg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc chain agt agc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg gag tgg gtg gca gtt ata tca tat gat gga agt aat aaa tac tat gca gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac acg ctg tat ctg caa atg aac agc ctg aga gct gag gac acg gct gtg tat tac tgt gcg aaa gac tcg tat tac tat ggt tcg ggg aga cga tgg ggc tac tac ttt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc tca 194 AT13-036 Heavy gag gtg cag ctg gtg gag tct ggg gga ggc ctg gtc aag cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttc chain agt agt tat agc atg aac tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtc tca tcc att agt agt agt agt act tac ata tac tac gca gac tca gtg aag ggc cga ttc acc atc tcc aga gac aac gcc agg aac tca ctg tat ctg caa atg aac agc ctg aga gcc gag gac acg gct gtg tat tat tgt gcg aga agg agg gag gtc ggt aga gat ggc tac agt ttg tac ccc cgg ggg tac cac tac ggt atg gac gtc tgg ggc caa ggg acc acg gtc acc gtc tcc tca 195 AT13-037 Heavy cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg agg tcc ctg aga ctc tcc tgt gca gcg tct gga ttc acc ttc chain agt acc tat ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctt gag tgg gtg gca gtt ata tgg tat gat gga agt aat aca tac tat gca gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac aca ctg tat ctg caa ata aag agc ctg aga gcc gag gac acg gct gtc tat tac tgt gcg aga ggc cgt gga tat agt gcc caa ggg aat cgg aat agg gct tac tac ttt gac tac tgg ggc cag gga acc ctg gtc acc gtc tcc tca 196 AT12-023 Light tct tct gag ctg act cag gac cct gct gtg tct gtg gcc ttg gga cag aca gtc agg atc aca tgc caa gga gac ttc ctc aga agc chain tat tat gca agc tgg tac cag cag aag cca gga cag gcc cct gta ctt gtc atc ttt ggt aaa aac aag cgg ccc tca ggg atc cca gac cga ttc tct ggc tcc agc tca gga aac aca gct tcc ttg acc atc act ggg gct cag gcg gaa gat gag gct gac tat tac tgt aac tcc cgg gac cgc agt ggt aac cac ctg gtg ttc ggc gga ggg acc aag ctg acc gtc cta 197 25 Light gac atc cag atg acc cag tct cca tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg gca agt cag agc att chain agc agg tat tta aat tgg tat cag cag aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc agt ttg caa agt ggg gtc cca tca agg ttc agt ggc agt gga tct ggg aca gat ttc act ctc acc atc agc agt ctg caa cct gaa gat ttt gca act tac tac tgt caa cag agt tac agt acc cct cgc act ttc ggc cct ggg acc aaa gtg gat atc aaa 198 AT13-024 Light gac atc cag atg acc cag tct cct tcc acc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg gcc agt cag agt att chain agt agc tgg ttg gcc tgg tat cag cag aaa cca ggg aaa gcc cct aag ctc ctg atc tat aag gcg tct agt tta gaa agt ggg gtc cca tca agg ttc agc ggc act gga tct ggg aca gaa ttc act ctc acc atc agc agc ctg cag cct gat gat ttt gca act tat tac tgc caa cag tat aat act tac ccg tac act ttt ggc cag ggg acc aag ctg gag atc aaa 199 AT12-019 Light gcc atc cgg ttg acc cag tct cca tcc tca gtc tct gca tct aca gga gac aga gtc acc atc act tgt cgg gcg agt cag gct ttt agc chain agt tat tta gtc tgg tat cag caa aaa cca ggg aaa gcc cct aac ctc ctg atc tac gct aca tcc act ttg caa ggt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gat ttc act ctc acc atc agc aac ctg cag tct gaa gat ttt gca act tat tac tgt caa cag tat tat agt tac cct ccg act ttt ggc cag ggg acc aag ttg gag atc aaa 200 AT13-022 Light tcc tat gag ctg act cag cca ccc tca gtg tcc gtg tcc cca gga cag aca gcc agc atc acc tgc tct gga gat aaa ttg ggg gat chain aaa tat gct tgc tgg tat cag cag aag cca ggc cag tcc cct gtg ctg gtc atc tat caa gat agc aag cgg ccc tca ggg atc cct gag cga ttc tct ggc tcc aac tct ggg aac aca gcc act ctg acc atc agc ggg acc cag gct atg gat gag gct gac tat tac tgt cag gcg tgg gac agc agc act gtg gta ttc ggc gga ggg acc aag ctg acc gtc cta 201 AT13-023 Light gac atc cag atg acc cag tct cca tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg gca agt cag ggc att chain aga aat gtt tta ggc tgg tat cag cag aaa cca ggg aaa gcc cct aag tgc ctg atc tat gct gca tcc agt ttg caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gaa ttc act ctc aca atc agc agc ctg cag cct gaa gat ttt gca act tat tac tgt cta cag cat aat agt cac ccc cgg acg ttc ggc caa ggg acc aag gtg gaa atc aaa 202 AT13-031 Light gac atc cag atg acc cag tct cca tcc tcc ctg tct gca tct gta gga gac aga gtc acc atc act tgc cgg gca agt cag ggc att chain aga aat gat tta ggc tgg tat cag cag aaa cca ggg aaa gcc cct aag cgc ctg atc tat gct gca gtc agt ttg caa agt ggg gtc cca tca agg ttc agc ggc agt gga tct ggg aca gaa ttc act ctc aca atc agc agc ctg cag cct gaa gat ttt gca act tat tac tgt cta cag cat aat agt tac cct cgg act ttt ggc cag ggg acc aag ctg gag atc aaa 203 AT12-020 Light gcc atc cgg atg acc cag tct cca tcc tca ttc tct gca tct aca gga gac aga gtc acc atc act tgt cgg gcg agt cag gat att chain agc agt tct tta gcc tgg tat cag caa aaa cca ggg aaa gcc cct aag ctc ctg atc tat gct gca tcc act ttg caa agt gga gtc cca tca agg ttc agc ggc agt gga tct ggg aca gac ttc act ctc acc atc agc tgc ctg cag tct gaa gat ttt gca act tat tac tgt caa cag tat tat agt tac cct ccg acg ttc ggc caa ggg acc agg ttg gaa atc aaa 204 AT13-033 Light cag tct gcc ctg act cag cct ccc tcc gcg tcc ggg tct cct ggt cag tca gtc acc atc tcc tgt act ggg acc agc agt gac att ggt chain ggt tat aac tat gtc tcc tgg tac caa cac cac cca ggc aaa gcc ccc aaa ttg atg att tat gag gtc act aag cgg ccc tca ggg gtc cct gat cgt ttc tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc gtc tct gga ctc cag gct gag gat gag gct cat tat tac tgc agc tca tat gca ggc agc aac gat ttg cta ttc ggc gga ggg acc aag ctg acc gtc ctg 205 AT13-034 Light gaa gta gtg atg acg cag tct cca gcc acc ctg tct gtg tct cca ggg gaa aga gcc acc ctc tcc tgc agg gcc agt cag agc att chain agc aac aac tta ggc tgg tat cag cag aaa cct ggc cag gct ccc agg ctc ctc atc tac ggt gca tcc acc agg gcc act ggt atc cca ggc agg ttc agt ggc agt ggg tct ggg aca gag ttc act ctc acc atc tac agc ctg cag tct gag gat ttt gca gtt tat tac tgt caa caa tat aat aac tgg cct cgg ctc act ttc ggc gga ggg acc aag gtg gag atc aaa 206 35 Light tct tct gag ctg act cag gac cct gct gtg tct gtg gcc ttg gga cag aca gtc agg atc aca tgc caa gga gac agc ctc aga agc chain tat tat gca agc tgg tac cag cag aag cca gga cag gcc cct gta ctt gtc atc tat ggt aaa aac aac cgg ccc tca ggg atc cca gac cga ttc tct ggc tcc agc tca gga aac aca gct tcc ttg acc atc act ggg gct cag gcg gaa gat gag gct gac tat tac tgt aac tcc cgg gac agc agt ggt aac cat gtg gta ttc ggc gga ggg acc aag ctg acc gtc cta 207 AT13-036 Light cag tct gcc ctg act cag cct gcc tcc gtg tct ggg tct cct aga cag tcg atc acc atc tcc tgc act gga acc agc agt gac gtt ggt chain ggt tat aac tat gtc tcc tgg tac caa caa ctc cca ggc aaa gcc ccc aaa ctc atg att tat gat gtc aat gat cgg ccc tca ggg gtt tct att cgc ttc tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc atc tct ggg ctc cag gct gag gac gag gct gat tat tac tgc agc tca tat aca aga agc aac act gtg ata ttc ggc gga ggg acc aaa ctg acc gtc cta 208 AT13-037 Light gaa ata gtg atg acg cag tct cca gcc acc ctg tct gtg tct cca ggg gaa agg gtc atc ctc tcc tgc agg gcc agt cag agt gtt chain agc agc aac tta gcc tgg tac cag cag aaa cct ggc cag cct ccc agg ctc ctc atc tat ggt gca ttc acg agg gtc act ggt gtc cca gcc agg ttc agt ggc agt ggg tct ggg aca gaa ttc act ctc acc atc agc agc ctg cag tct gaa gat ttt gca gtt tat tac tgt cag cag tac aat gac cgg ccc ccg tac act ttt ggc cag ggg acc aag ctg gag atc aaa Table 1B. Preferred anti-AML antibodies according to the invention (CDR numbering according to Kabat et al. 1991) SEQ ID Antibody Identity ce 209 AT14-013 Heavy SPNWWT chain CDR1 210 AT14-014 Heavy DAWMS chain CDR1 211 AT14-015 Heavy DFAMS chain CDR1 212 AT14-016 Heavy SYAMT chain CDR1 213 13 Heavy EIYYGGRVSYNSALRS chain CDR2 214 AT14-014 Heavy HINTKVDGGTTEYAAPVKG chain CDR2 215 AT14-015 Heavy FIRTKANDGTTEYAASVKG chain CDR2 216 AT14-016 Heavy SISGSGGSTYYADSVRG chain CDR2 217 AT14-013 Heavy AGQKNIGCGYSSCFISWFDT chain CDR3 218 AT14-014 Heavy TTEAIYDSSGYFHDY chain CDR3 219 15 Heavy ASDPFMTTDYYYYYMDV chain CDR3 220 AT14-016 Heavy AKGYVGCSGGNCYSGGAFDI chain CDR3 221 AT14-013 Light KSSQTILQRSNHLNYLA chain CDR1 222 AT14-014 Light KSSRSVLYSSNNKNYLA chain CDR1 223 AT14-015 Light VGGYNSVS chain CDR1 224 AT14-016 Light GGNNIGSESVH chain CDR1 225 AT14-013 Light WASTRES chain CDR2 226 AT14-014 Light WASIRES chain CDR2 227 AT14-015 Light EVYKRPL chain CDR2 228 AT14-016 Light YDTDRPS chain CDR2 229 AT14-013 Light HQYYTTPQT chain CDR3 230 AT14-014 Light QQYSRPPT chain CDR3 231 AT14-015 Light SSYGGTVLF chain CDR3 232 AT14-016 Light QVWDNTSDHPVVF chain CDR3 233 AT14-013 Heavy QGRLQESGPGLVKPSETLTLTCAVSGGSSVSSPNWWTWVRQAPGKGLEWIGEIYYGGRVSYNSALRSRVTI chain SSDRSKEEFSLKLRSVTAADTAIYYCAGQKNIGCGYSSCFISWFDTWGQGIAVTVSS 234 AT14-014 Heavy EVQLVESGGGLVKPGGSLRLSCAASGFTFSDAWMSWVRQAPGKGLEWVGHINTKVDGGTTEYAAPVKGR chain FTISRDDSKNSLYLHMDSLKTEDTAVYYCTTEAIYDSSGYFHDYWGQGSLVTVSS 235 AT14-015 Heavy EVQLVESGGGLAQPGRSLRLSCTASGFRFGDFAMSWVRQAPGKGLEWVGFIRTKANDGTTEYAASVKGRF chain SKSIAYLQMNSLKTEDTAVYYCASDPFMTTDYYYYYMDVWGKGTTVTVSS 236 AT14-016 Heavy EVQVLESGGDSVQPGGSLRLSCAASGFTFSSYAMTWVRQAPGKGLKWVSSISGSGGSTYYADSVRGRFTISR chain DNSKNTLYVQMNSLRAEDTAVYYCAKGYVGCSGGNCYSGGAFDIWGQGTVVTVSS 237 AT14-013 Light DIVMTQSPDSLAVSLGERATIACKSSQTILQRSNHLNYLAWYQQKPGQPPKVLIYWASTRESGVPDRFSGSG chain SGTDFTLTINSLQAEDVAVYYCHQYYTTPQTFGQGTKVEIK 238 14 Light DIVMTQSPDSLAVSLGERATINCKSSRSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASIRESGVPDRFSGSG chain SGTDFTLTINSLQAEDVAVYYCQQYSRPPTFGQGTKVEIK 239 AT14-015 Light PPSASGSPGQSVTISCTGTSSDVGGYNSVSWYQHHPGKAPKLMIYEVYKRPLGVPDRFSGSKSGN chain TASLTVSGLQAEDEAYYYCSSYGGTVLFGGGTKLTVL 240 AT14-016 Light SYVLTQPPSVSVAPGKTARITCGGNNIGSESVHWYQQKPGQAPVVVIYYDTDRPSGIPERFSGSNSGNTATL TISRVEAGDEADYYCQVWDNTSDHPVVFGGGTKLTVL chain 241 AT14-013 Heavy agt cct aac tgg tgg act chain CDR1 242 AT14-014 Heavy gac gcc tgg atg agc chain CDR1 243 AT14-015 Heavy gat ttt gct atg agt chain CDR1 244 16 Heavy agc tat gcc atg acc chain CDR1 245 AT14-013 Heavy gaa atc tat tat ggt ggg aga gtg agc tac aac tcg gcc ctc agg agt chain CDR2 246 AT14-014 Heavy cat att aac acc aaa gtt gat ggt ggg aca aca gag tac gct gca ccc gtg aaa ggc chain CDR2 247 AT14-015 Heavy ttc att aga acc aaa gct aat gat ggg aca aca gaa tac gcc gcg tct gtg aaa ggc chain CDR2 248 AT14-016 Heavy agt att agt ggt agt ggt ggt agc aca tac tac gca gac tcc gtg agg ggc chain CDR2 249 AT14-013 Heavy gcg ggt caa aaa aat att ggc tgt ggt tac agc agt tgc ttt atc agt tgg ttc gac acc chain CDR3 250 AT14-014 Heavy acc aca gag gcg ata tat gat agt agt ggt tat ttc cat gac tat chain CDR3 251 AT14-015 Heavy gct agc gat ccc ttc atg act aca gac tat tac tac tac tac atg gac gtc chain CDR3 252 16 Heavy gcg aaa gga tat gtg ggg tgt agt ggt ggg aac tgc tac tcg ggg ggt gct ttt gat atc chain CDR3 253 AT14-013 Light aag tcc agc cag act att tta caa agg tcc aac cat ttg aac tac tta gct chain CDR1 254 AT14-014 Light aag tcc agc cgg agt gtt tta tac agc tcc aac aat aag aac tac tta gct chain CDR1 255 AT14-015 Light act ggg acc agc agt gac gtt ggt ggt tat aac tct gtc tcc chain CDR1 256 AT14-016 Light ggg ggg aac aac att gga agt gaa agt gtt cac chain CDR1 257 AT14-013 Light tgg gca tct acc cgg gaa tcc chain CDR2 258 AT14-014 Light tgg gca tct atc cgg gaa tcc chain CDR2 259 AT14-015 Light gag gtc tat aag cgg ccc tta chain CDR2 260 AT14-016 Light tat gat acc gac cgg ccc tca chain CDR2 261 AT14-013 Light cac caa tat tat act act ccg cag act chain CDR3 262 AT14-014 Light cag caa tat tct cgt cct ccg acg chain CDR3 263 AT14-015 Light agc tca tat gga ggc acc gtg cta ttc chain CDR3 264 AT14-016 Light cag gtg tgg gat aac act agt gat cat cct gtg gta ttc chain CDR3 265 AT14-013 Heavy cag ggg cga ctg cag gag tcg ggc cca gga ctg gtg aag cct tcg gag acc ctg acc ctc acg tgc gct gtg tcc ggt ggc tcc tcc chain gtc agc agt cct aac tgg tgg act tgg gtc cgc cag gcc ccc ggg aag ggg ctg gag tgg att gga gaa atc tat tat ggt ggg aga gtg agc tac aac tcg gcc ctc agg agt cga gtc acc att tca tca gac agg tcc aaa gag gag ttc tcc ctg aaa ctg agg tct gtg acc gcc gcg gac acg gcc ata tat tat tgt gcg ggt caa aaa aat att ggc tgt ggt tac agc agt tgc ttt atc agt tgg ttc gac acc tgg gga cag gga att gcg gtc acc gtc tcc tca 266 AT14-014 Heavy gag gtg cag ctg gtg gag tct ggg gga ggt ttg gta aag cct ggg ggg tcc ctt aga ctc tcc tgt gca gcc tct gga ttc act ttc chain agt gac gcc tgg atg agc tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtt ggc cat att aac acc aaa gtt gat ggt ggg aca aca gag tac gct gca ccc gtg aaa ggc aga ttc acc atc tca aga gat gat tca aaa aat tcg ctg tat ctg cac atg gac agc ctg aaa acc gag gac aca gcc gtg tat tac tgt acc aca gag gcg ata tat gat agt agt ggt tat ttc cat gac tat tgg ggc cag gga tcc ctg gtc acc gtc tcc tca 267 15 Heavy gag gtg cag ctg gtg gag tcg ggg gga ggc ttg gca cag cca ggg cgg tcc ctg aga ctc tcc tgt aca gct tct gga ttc agg ttt chain ggt gat ttt gct atg agt tgg gtc cgc cag gct cca ggg aag gga ctg gag tgg gta ggt ttc att aga acc aaa gct aat gat ggg aca aca gaa tac gcc gcg tct gtg aaa ggc aga ttc atc atc tca aga gat gat tcc aaa agt atc gcc tat ctg caa atg aac agc ctg aaa acc gag gac aca gcc gtt tat tac tgt gct agc gat ccc ttc atg act aca gac tat tac tac tac tac atg gac gtc tgg ggc aaa ggg acc acg gtc acc gtc tcc tca 268 AT14-016 Heavy gag gtg caa gtg ttg gag tct ggg gga gac tcg gta cag cct ggg ggg tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt chain agc agc tat gcc atg acc tgg gtc cgc cag gct cca ggg aag ggg ctg aaa tgg gtc tca agt att agt ggt agt ggt ggt agc aca tac tac gca gac tcc gtg agg ggc cgg ttc acc atc tcc aga gac aat tcc aag aac acg ctg tat gtg cag atg aac agc ctg aga gcc gag gac acg gcc gta tat tac tgt gcg aaa gga tat gtg ggg tgt agt ggt ggg aac tgc tac tcg ggg ggt gct ttt gat atc tgg ggc caa ggg aca gtg gtc acc gtc tct tca 269 AT14-013 Light gac atc gtg atg acc cag tct cca gac tcc ctg gct gtg tct ctg ggc gag agg gcc acc atc gcc tgc aag tcc agc cag act att chain tta caa agg tcc aac cat ttg aac tac tta gct tgg tac cag cag aaa cca gga cag cct cct aaa gtg ctc att tat tgg gca tct acc cgg gaa tcc ggg gtc cct gac cga ttc agt ggc agc ggg tct ggg aca gat ttc act ctc acc atc aac agc ctg cag gct gag gat gtg gca gtt tat tac tgt cac caa tat tat act act ccg cag act ttt ggc cag ggg acc aag gtg gag atc aaa 270 14 Light gac atc gtg atg acc cag tct cca gac tcc ctg gct gtg tct ctg ggc gag agg gcc acc atc aac tgc aag tcc agc cgg agt gtt chain tta tac agc tcc aac aat aag aac tac tta gct tgg tac cag cag aaa cca gga cag cct cct aag ctg ctc att tac tgg gca tct atc cgg gaa tcc ggg gtc cct gac cga ttc agt ggc agc ggg tct ggg aca gat ttc act ctc acc atc aac agc ctg cag gct gaa gat gtg gca gtt tat tac tgt cag caa tat tct cgt cct ccg acg ttc ggc caa ggg acc aag gtg gaa atc aaa 271 AT14-015 Light cag tct gcc ctg act cag cct ccc tcc gcg tcc ggg tct cct gga cag tca gtc acc atc tcc tgc act ggg acc agc agt gac gtt ggt chain ggt tat aac tct gtc tcc tgg tac caa cat cac cca ggc aaa gcc ccc aaa ctc atg att tat gag gtc tat aag cgg ccc tta ggg gtc cct gat cgc ttc tct ggc tcc aag tct ggc aac acg gcc tcc ctg acc gtc tct ggg ctc cag gct gag gat gag gct tat tat tac tgc agc tca tat gga ggc acc gtg cta ttc ggc gga ggg acc aag ctg acc gtc cta 272 AT14-016 Light tcc tat gtg ctg act cag cca ccc tca gtg tca gtg gcc cca gga aag acg gcc cgg att acc tgt ggg ggg aac aac att gga agt chain gaa agt gtt cac tgg tac cag cag aag cca ggc cag gcc cct gtg gtg gtc atc tat tat gat acc gac cgg ccc tca ggg atc cct gag cgc ttc tct ggc tcc aac tct ggg aac acg gcc acc ctg acc atc agc agg gtc gaa gcc ggg gat gag gcc gac tat tac tgt cag gtg tgg gat aac act agt gat cat cct gtg gta ttc ggc gga ggg acc aag ctg acc gtc cta Tabel 2 mAbare specificforAML mAbs Cell lines Prim cells Name Ig class Mel1 Mel2 Mel3 BJ FB Col1 Col2 Col3 Vero HUVEC HepG2 PBMC BM AT12-019 IgG1 κ - - - - - - - - - - - - - AT13-023 IgG1 κ - - - - - - - - - - - - - AT13-031 IgG1 κ - - - - - - AT12-020 IgG3 κ - - - - - - - - - - - - - AT12-023 IgG3 λ - - - - - - - - - - - - - IgG3 κ - - - - - - - - - - - - - AT13-022 IgG3 λ - - - - - - - - - - - - - AT13-024 IgG3 κ - - - - - - - - - - - - - Mel1: Mel 126.2; Mel2: Mel BLM; Mel3: Mel WBO; BJ: Fibroblast cell line; FB: primary fibroblasts (skin); Col1: Colo205; Col2: Caco-2; Col3 HT29; Vero: nonhuman kidney; PBMC: peripheral blood mononuclear cells; BM: bone marrow.

Tabel 3 Overview AML-specific mAbsderived from a patient with a potent GvLresponse (donor 59) mAbs AML Primary AML* Name Ig class CD27 SHM VH/VL THP-1 MM6 M0 M1 M1 M1 M4 AT12-019 IgG1 κ + 10/ 9 ++ + + + ++ +/- - AT13-023 IgG1 κ + 8/4 ++ ++ + AT13-031 IgG1 κ + 1/1 ++ + - + - - +/- AT12-020 IgG3 κ + 4/2 ++ AT12-023 IgG3 λ - Germline/6 +++ ++ + ++ ++ +/- ++ AT12-025 IgG3 κ - 1/1 ++ ++ - +/- + - - AT13-022 IgG3 λ + ne ++ ++ ++ AT13-024 IgG3 κ - 6/3 ++ ++ ++ ++ ++ MM6: MonoMac6; M0: donor 77; M1 donor 69, 79, 86 respectively; M4 donor 78 * AML according to the FAB fication; SHM: number of somatic hypermutations Tabel 4 SomemAbbind otherhematologictumors mAbs Other hematologic tumor cell lines Primary tumors Name Ig class OCI-Ly1 OCI-Ly7 U266 NCI-H929 NHL pt ALL pt 19 IgG1 κ + - - - - - AT13-023 IgG1 κ AT13-031 IgG1 κ ++ + - +/- ++ - AT12-020 IgG3 κ AT12-023 IgG3 λ - - +/- - ++ - AT12-025 IgG3 κ - - + - - - AT13-022 IgG3 λ AT13-024 IgG3 κ ++ + - - - - OCI-Ly1 and OCI-Ly7: diffuse large B cell lymphoma cell lines; U266 and NCI-H929: multiple myeloma cell lines; NHL pt: B-non n ma cells freshly isolated from a newly diagnosed patient ; ALL pt: B-acute lymphatic leukemia cells freshly isolated from a newly diagnosed patient.

Tabel 5 SomemAbshow in vitro activity mAbs Killing Name Ig class CD27 SHM VH/VL THP-1 M0/5 19 IgG1 κ + 10/ 9 no no AT13-023 IgG1 κ + 8/4 AT13-031 IgG1 κ + 1/1 AT12-020 IgG3 κ + 4/2 AT12-023 IgG3 λ - Germline/6 yes AT12-025 IgG3 κ - 1/1 yes yes AT13-022 IgG3 λ + Germline AT13-024 IgG3 κ - 6/3 no yes AT13-023, AT13-031, AT12-020 and AT13-022 were not yet tested for in vitro activity Tabel 6 2nd AML twithGvLresponse (donor 58) mAbs AML Not binding to Clone CD27 Ig class SHM VH/VL THP-1 MM6 PBMC Caco HT-29 HepG2 AT13-033 + IgG3 λ 18/5 ++ ++ - - - - AT13-034 + IgG3 κ 14/6 ++ ++ - - - - AT13-035 - IgG3 λ 0/0 ++ ++ - - - - AT13-036 - IgG3 λ 4/9 ++ ++ - - - - AT13-037 + IgG3 κ 4/8 ++ ++ - - - - SHM: number of somatic hypermutations 135135 Table 7 Overview of AM L-specific mAbs derived from a 3rd t with a potent GvL response (donor 101) AT14-013 +++ +++ AT14-014 ++ - AT14-015 AT14-016 ++ - M1: donor 77; M4: donor BL-046; M51: donor BL-034, M52: donor BL-038 * AML according to the FAB classification; SHM: number of somatic hypermutations 136136 Table 8 mAb are specific for AML (donor 101) “s-l—C-—ellli-nes-—BMC5 P__imarycells AT14-014 AT14-015 AT14-016 FB: primary fibroblasts (skin); Col: Caco-Z; Liv1: Huh7 liver cell line; Livz: HepGZ liver cell line PBMC: eral blood mononuclear cells; 137137 Tabel 9A Overview of AM L-specific mAbs derived from a 2'“ patient with a potentAGvL se (donor 58) mAbs Primary AML* AT13-033 AT13-034 AT13—035 AT13-036 AT13-037 MM6: MonoMac6; M0: donor 77, BL-030; M1 donor 69, respectively; M4 donor 78 * AML according to the FAB classification; SHM: number of somatic hypermutations 138138 Tabel 98 Some mAb show in vitro activity (donor 59) THP-l AT12-019 10/ 9 AT13-023 8/4 AT13-031 1/1 AT12-020 4/2 AT12-023 Germline/6 AT12-025 1/1 22 Germline AT13-024 6/3 * Only at 37 C; nd = not determined 139139 Tabel 10 Some mAb show in vitro activity (donor 58) AT13-O33 AT13-034 AT13-035 AT13-037 References Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA, eelen MA, Visser TJ, Bijl N, Geuijen CA, Marissen WE, vic K, Throsby M, Schuurhuis GJ, Ossenkoppele GJ, de Kruif J, Goudsmit J, Kruisbeek AM. 2004. C-type -like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res 64:8443-50.

Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. 1976. Proposals for the classification of the acute leukaemias. French-American- British (FAB) co-operative group. Br J Haematol 33:451–458.

Bhat NM, Bieber MM, Hsu FJ, Chapman CJ, Spellerberg M, Stevenson FK, Teng NNH. 1997. Rapid cytotoxicity of human B lymphocytes induced by VH4-34 (VH4.21) gene-encoded monoclonal dies. Clin Exp Immunol 108: 151-159 Biernacki MA, Marina O, Zhang W, Liu F, Bruns I, Cai A, Neuberg D, Canning CM, Alyea EP, Soiffer RJ, Brusic V, Ritz J, Wu CJ. 2010. Efficacious immune therapy in chronic myelogenous leukemia (CML) recognizes antigens that are expressed on CML progenitor cells. Cancer Research 70:906–915.

Chen Y, Wiesmann C, Fuh G, Li B, Christinger HW, McKay P, de Vos AM, Lowman HB. 1999. ion and analysis of an optimized anti-VEGF dy: l structure of an affinity-matured Fab in complex with antigen. J Mol Biol 293:865-881.

Diehl SA, Schmidlin H, Nagasawa M, van Haren SD, Kwakkenbos MJ, Yasuda E, Beaumont T, Scheeren FA, Spits H. 2008. mediated up-regulation of BLIMP1 Is coordinated with BCL6 down-regulation to control human plasma cell differentiation. J Immunol 180:4805-4815.

Drexler HG, Minowada J. 1998. History and classification of human leukemia- lymphoma cell lines. Leuk Lymphoma 31:305–316.

Hernandez AM, Rodriguez N, Gonzalez JE, et al. euGcGM3 Antibodies, Actively Elicited by Idiotypic Vaccination in Nonsmall Cell Lung Cancer Patients, Induce Tumor Cell Death by an Oncosis-Like Mechanism. J Immunol 2011;186(6):3735–3744.

Hugh J. M et al, 2004 Methods in lar biology Vol. 282 Kattah NH, Kattah MG, Utz PJ. The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Reviews. 33(1):126–145.

Kepp O, Galluzzi L, Lipinski M, Yuan J, Kroemer G. Cell death assays for drug discovery. Nat Rev Drug Discov 2011;1–17.

Kwakkenbos MJ, Diehl SA, Yasuda E, Bakker AQ, Van Geelen CMM, Lukens MV, Van Bleek GM, Widjojoatmodjo MN, Bogers WMJM, Mei H, ch A, Scheeren FA, Spits H, Beaumont T. 2010. Generation of stable monoclonal antibodyproducing B cell receptor-positive human memory B cells by genetic programming.

Nat Med 16:123–128.

Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, Van n N, Weissman IL. 2009. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid ia stem cells. Cell 138:286-299 k RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H, German-Austrian Acute Myeloid Leukemia Study Group. 2008.

Mutations and treatment outcome in cytogenetically normal acute myeloid ia. N Engl J Med 358:1909–1918.

Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, Volin L, Gürman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin N-C, Kolb H-J, Rocha V, EBMT Acute Leukemia Working Party. Donor lymphocyte infusion in the treatment of first logical relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. Journal of Clinical Oncology 25:4938–4945.

Schmiedel BJ, Werner A, Steinbacher J, et al. Generation and nical Characterization of a Fc-optimized GITR-Ig Fusion Protein for Induction of NK Cell Reactivity Against Leukemia. Mol Ther. 2013;21(4):877–886.

Singh R, u R-P, Fröbel J, et al. The non-steroidal anti-inflammatory drugs Sulindac sulfide and Diclofenac induce apoptosis and differentiation in human acute d leukemia cells through an AP-1 dependent y. Apoptosis. 2011;16(9):889–901.

Tsuchiya S, Yamabe M, Yamaguchi Y, Kobayashi Y, Konno K, Tada K. 1988.

Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer 26:171–176.

Walter RB, Appelbaum FR, Estey EH, Bernstein ID. Acute myeloid ia stem cells and CD33-targeted immunotherapy. 2012. Blood 119: 6198-208.

Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, l S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a eutic target for human solid tumors. Proc Natl Acad Sci USA 109:6662- Wu CJ, Yang XF, McLaughlin S, g D, Canning C, Stein B, Alyea EP, Soiffer RJ, Dranoff G, Ritz J. 2000. Detection of a potent humoral response associated with immune-induced remission of c myelogenous leukemia. J Clin Invest 106:705–714.

The following numbered paragraphs define particular s of the present invention: 1. An isolated, synthetic or recombinant human antibody, or a functional part or a onal equivalent thereof, which is able to bind a cell surface component of acute myeloid leukemia (AML) cells and which is able to diminish proliferation of AML cells essentially independently from antibody-dependent cellmediated xicity (ADCC), complement-dependent cytotoxicity (CDC), apoptosis, or phagocytosis by macrophages or dendritic cells. 2. An antibody or functional part or functional equivalent ing to paragraph 1, which is able to bind a cell surface component that is ic for AML cells. 3. An antibody or functional part or functional equivalent according to paragraph 1 or 2, which is able to induce death of primary AML blasts essentially independently from antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), apoptosis, or phagocytosis by macrophages or tic cells. 4. An antibody or functional part or functional equivalent according to any one of paragraphs 1-3, which is able to diminish proliferation of AML cells in vitro within 3 days.

. An antibody or functional part or functional equivalent according to any one of paragraphs 1-4, wherein said AML cells belong to a French-American- British (FAB) classification selected from the group consisting of M5, M0, M1, M2, M3 and M4. 6. An dy or onal part or functional equivalent according to any one of paragraphs 1-5, n said AML cells belong to the FAB classification M5 or M1 or M0 or M4, ably M5. 7. An antibody or functional part or functional lent according to any one of paragraphs 1-6, which is able to bind a cell surface component of different AML cells of at least two, preferably at least three, more preferably at least four FAB classifications. 8. An antibody or functional part or functional equivalent according to any one of paragraphs 1-7, which is able to bind snRNP200. 9. An antibody or functional part or functional equivalent according to any one of paragraphs 1-8, wherein said antibody is of the IgG isotype, preferably IgG1 or IgG3.

. An isolated, synthetic or recombinant dy, or a functional part or a functional equivalent thereof, which ses at least a heavy chain CDR3 sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 27-39, and a light chain CDR3 sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 66-78. 11. An isolated, synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises: - a heavy chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with a sequence ed from the group consisting of SEQ ID NOs: 1-13; and - a heavy chain CDR2 sequence comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 14-26; and - a heavy chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 27-39; and - a light chain CDR1 sequence comprising a sequence which has at least 80% sequence identity with a sequence selected from the group ting of SEQ ID NOs: 40-52; and - a light chain CDR2 sequence comprising a ce which has at least 80% ce identity with a sequence selected from the group consisting of SEQ ID NOs: 53-65; and - a light chain CDR3 sequence comprising a sequence which has at least 80% sequence identity with a ce selected from the group consisting of SEQ ID NOs: 66-78. 12. An antibody or functional part or functional equivalent according to aph 10 or 11, comprising a variable heavy chain sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 79-91. 13. An antibody or onal part or functional equivalent according to any one of paragraphs 10-12, comprising a variable light chain sequence having at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 92-104. 14. An antibody or functional part or functional equivalent according to any one of aphs 1-13, which is coupled to another compound.

. An antibody or functional part or functional equivalent according to paragraph 14, wherein said other compound is a detectable label, a chemotherapeutic drug, a toxic moiety, an immunomodulatory molecule, another ecific binding compound, or a radioactive compound. 16. An isolated, synthetic or inant nucleic acid molecule with a length of at least 15 nucleotides, or a functional equivalent thereof, encoding at least one CDR sequence of an antibody or functional part or functional equivalent according to any one of paragraphs 1-15. 17. A nucleic acid molecule or functional equivalent according to paragraph 16, which encodes at least the variable heavy chain sequence and/or the variable light chain sequence of an antibody or functional part or functional equivalent according to any one of paragraphs 1-15 18. A nucleic acid molecule or functional equivalent according to paragraph 16 or 17, sing a sequence which has at least 80% ce identity with a sequence selected from the group ting of SEQ ID NOs: 105-182 19. A nucleic acid molecule or functional equivalent according to any one of paragraphs 16-18, comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 183-195 and/or comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 196-208.

. A nucleic acid molecule or functional equivalent thereof, encoding an antibody or functional part or onal equivalent according to any one of paragraphs 1-15. 21. A nucleic acid molecule ing to any one of paragraphs 16-20, which comprises cDNA, peptide nucleic acid (PNA), locked c acid (LNA), or a DNA/RNA helix. 22. A vector comprising a nucleic acid molecule or onal equivalent according to any one of paragraphs 16-21. 23. An isolated or recombinant cell, or a non-human animal, comprising a nucleic acid molecule or functional equivalent according to any one of aphs 16-21 or a vector according to paragraph 22. 24. A composition sing an antibody or functional part or functional equivalent according to any one of paragraphs 1-15, or a nucleic acid molecule or functional equivalent according to any one of paragraphs 16-21, or a vector according to paragraph 22, or a cell ing to paragraph 23.

. A ition according to paragraph 24, wherein said composition is a pharmaceutical composition which comprises a pharmaceutically acceptable carrier, diluent or excipient. 26. A composition according to aph 25, which comprises at least two antibodies, onal parts or functional equivalents ing to any one of paragraphs 1-15. 27. An antibody or functional part or functional equivalent according to any one of paragraphs 1-15, or a nucleic acid molecule or onal equivalent ing to any one of paragraphs 16-21, or a vector according to aph 22, or a cell according to paragraph 23, for use as a medicament or prophylactic agent. 28. An antibody or functional part or functional equivalent according to any one of paragraphs 1-15, or a nucleic acid le or functional equivalent according to any one of paragraphs 16-21, or a vector according to paragraph 22, or a cell ing to paragraph 23, for use in a method for at least in part treating or preventing a myeloproliferative or lymphoproliferative disorder. 29. An antibody or functional part or functional equivalent according to any one of paragraphs 1-15, or a nucleic acid molecule or functional equivalent according to any one of aphs 16-21, or a vector according to paragraph 22, or a cell according to paragraph 23, for use in diagnosis of a myeloproliferative or lymphoproliferative disorder.

. An antibody or functional part or functional equivalent or nucleic acid molecule or functional equivalent or vector or cell for use according to paragraph 28 or 29, wherein said roliferative disorder is acute myeloid leukemia (AML). 31. An antibody or functional part or functional equivalent or nucleic acid molecule or functional equivalent or vector or cell for use according to paragraph 28 or 29, wherein said lymphoproliferative disorder is lymphoma, B- non-Hodgkin lymphoma or multiple myeloma. 32. Use of an dy or functional part or functional equivalent according to any one of paragraphs 1-15, or a nucleic acid molecule or functional equivalent according to any one of paragraphs 16-21, or a vector ing to paragraph 22, or a cell according to paragraph 23, for determining whether a sample comprises myeloproliferative or proliferative cells. 33. A method for producing an dy or functional part or functional lent according to any one of paragraphs 1-15, the method comprising providing a cell with a nucleic acid le or onal equivalent or a vector according to any one of paragraphs 16-22, and allowing said cell to translate said nucleic acid molecule or functional equivalent or vector, thereby producing said antibody or functional part or functional equivalent according to any one of paragraphs 1-15, the method preferably further comprising harvesting, ing and/or isolating said antibody or functional part or functional equivalent according to any one of aphs 1-15. 34. A method for detecting myeloproliferative or lymphoproliferative cells using an antibody or functional part or functional equivalent according to any one of paragraphs 1-15.

. A method for determining whether a myeloid cell or lymphoid cell is a myeloproliferative cell or lymphoproliferative cell, the method comprising determining whether snRNP200 is present on the surface of said cell, wherein the presence of snRNP200 on the surface of said cell indicates that said cell is myeloproliferative or lymphoproliferative. 36. A method for identifying myeloproliferative or lymphoproliferative cells, comprising detecting the presence of snRNP200 on the surface of said cells. 37. A method for ining whether myeloproliferative or lymphoproliferative cells are present in a sample comprising: - contacting said sample with an antibody or functional part or functional equivalent according to any one of paragraphs 1-15, and - allowing said antibody or functional part or functional lent to bind myeloproliferative cells or lymphoproliferative cells, if present, and - determining whether or not myeloproliferative cells or lymphoproliferative cells are bound to said antibody or functional part or functional equivalent, thereby determining whether or not myeloproliferative cells or lymphoproliferative cells are present in said sample. 38. A use according to paragraph 32 or a method according to any one of paragraphs 33-37, wherein said myeloproliferative cells are AML cells. 39. A use according to paragraph 32 or a method according to any one of aphs 33-37, wherein said lymphoproliferative cells are lymphoma, B- non- Hodgkin lymphoma or multiple myeloma cells. 40. A method for at least in part ng and/or preventing a myeloproliferative or proliferative disorder, comprising administering to an individual in need thereof a therapeutically effective amount of an antibody or functional part or functional equivalent according to any one of paragraphs 1-15, or a nucleic acid molecule or functional equivalent ing to any one of paragraphs 16-21, or a vector according to paragraph 22, or a cell according to paragraph 23, or a composition according to any one of paragraphs 24-26. 41. A method for determining whether an individual is suffering from a myeloproliferative or lymphoproliferative disorder, comprising: - ting a sample from said dual with an antibody or functional part or functional equivalent according to any one of paragraphs 1-15, and - allowing said antibody or functional part or onal equivalent to bind myeloproliferative cells or lymphoproliferative cells, if present, and - determining whether or not myeloproliferative cells or lymphoproliferative cells are bound to said antibody or functional part or functional lent, thereby determining r or nor said individual is suffering from a myeloproliferative er or a lymphoproliferative disorder. 42. A method for determining whether an individual is suffering from a myeloproliferative or proliferative disorder, comprising determining whether a sample from said dual comprises antibodies that are specific for snRNP200. 43. A method according to paragraph 42, the method comprising: - contacting a sample from said dual with snRNP200 or an epitope thereof; - ng said snRNP200 or epitope to bind snRNP200-specific dies from said sample, if present, and - determining r or not said snRNP200 or epitope is bound to snRNP200- specific antibodies, wherein binding of said snRNP200 or epitope to snRNP200- specific antibodies indicates that said individual is ing from a myeloproliferative or lymphoproliferative disorder. 44. A method for typing a myeloid cell-containing sample or a lymphoid cellcontaining sample of an individual, the method comprising determining whether snRNP200 is present on the surface of cells in said sample. 45. A method for determining whether a patient suffering from a myeloproliferative or proliferative disorder has an improved chance of a positive outcome of treatment with an antibody, functional part or functional equivalent according to any one of paragraphs 1-15, as compared to the mean population of patients suffering from a myeloproliferative or lymphoproliferative disorder, the method comprising determining whether 00 is present on the surface of myeloproliferative cells or lymphoproliferative cells of said patient. 46. A method according to paragraph 45, the method comprising: - contacting a myeloproliferative cell- or lymphoproliferative cell-containing sample from said individual with an antibody or functional part or functional equivalent that is specific for snRNP200; - allowing said antibody or functional part or onal lent to bind myeloproliferative cells or lymphoproliferative cells of said sample, and - determining whether or not said snRNP200-specific antibody or functional part or functional equivalent is bound to myeloproliferative cells or lymphoproliferative cells of said , wherein binding of said snRNP200-specific antibody or functional part or functional equivalent to myeloproliferative cells or lymphoproliferative cells of said sample indicates that said patient has an improved chance of a positive outcome of treatment with an antibody, functional part or functional equivalent according to any one of paragraphs 1-15, as compared to the mean population of patients suffering from a roliferative or lymphoproliferative disorder. 47. A method according to any one of paragraphs 40-46, wherein said myeloproliferative disorder is AML and wherein said myeloproliferative cells are AML cells. 48. A method according to any one of paragraphs 40-46, wherein said lymphoproliferative disorder is lymphoma, B- non-Hodgkin lymphoma or multiple myeloma and wherein said lymphoproliferative cells are lymphoma, B- non- Hodgkin lymphoma or multiple a cells. 49. An dy according to any one of paragraphs 1-15, or an antibody for use according to any one of paragraphs 27-31, or a use according to 32, or a method according to any one of paragraphs 33-48, wherein said dy is selected from the group consisting of AT12-023, AT13-031, AT13-037, AT13-024, 25 and AT12-019, and functional parts and functional equivalents thereof. 50. A method for determining whether a patient suffering from a myeloproliferative disorder or lymphoproliferative disorder is a candidate for treatment with antibody AT12-023, AT13-031 and/or AT13-037, or a functional part or a onal equivalent thereof, the method comprising determining whether snRNP200 is present on the surface of myeloproliferative cells or lymphoproliferative cells of said patient. 51. Use of an antibody or onal part or functional equivalent according to any one of paragraphs 1-15 for determining r an AML patient has a Graft versus ia response.

Claims

1. An isolated, synthetic or recombinant human dy, or a functional part or a functional equivalent f, which is able to bind acute myeloid leukemia (AML) cells and which comprises: - a heavy chain CDR1 sequence comprising the sequence of SEQ ID NO: 209; - a heavy chain CDR2 sequence comprising the sequence of SEQ ID NO: 213; - a heavy chain CDR3 sequence comprising the sequence of SEQ ID NO: 217; - a light chain CDR1 sequence comprising the sequence of SEQ ID NO: 221; - a light chain CDR2 sequence comprising the sequence of SEQ ID NO: 225; and - a light chain CDR3 sequence comprising the sequence of SEQ ID NO: 229.

2. An antibody or functional part or functional equivalent according to claim 1, wherein said AML cells belong to a French-American-British (FAB) classification ed from the group ting of M5, M0, M1, M2, M3 and M4.

3. An antibody or functional part or functional equivalent according to any one of claims 1-2, wherein said AML cells belong to the FAB classification M5 or M1 or M0 or M4.

4. An antibody or functional part or functional equivalent according to any one of claims 1-3, which is able to bind a cell e component of different AML cells of at least two, or at least three, or at least four FAB classifications.

5. An antibody or onal part or functional equivalent according to any one of claims 1-4, wherein said antibody is of the IgG e.

6. An antibody or functional part or functional equivalent according to any one of claims 1-5, wherein said antibody is of the IgG1 or IgG3 e.

7. An antibody or functional part or functional equivalent according to any one of claims 1-6, comprising a variable heavy chain sequence having at least 80% sequence identity with the sequence of SEQ ID NO: 233.

8. An antibody or functional part or onal equivalent according to any one of claims 1-7, comprising a variable light chain sequence having at least 80% sequence identity with the sequence of SEQ ID NO: 237.

9. An antibody or functional part or functional equivalent according to any one of claims 1-8, which is coupled to another nd.

10. An antibody or functional part or functional equivalent ing to claim 9, wherein said other compound is a detectable label, a chemotherapeutic drug, a toxic moiety, an immunomodulatory molecule, another AML-specific binding compound, or a radioactive compound.

11. An isolated, synthetic or recombinant nucleic acid molecule with a length of at least 15 nucleotides, or a functional equivalent thereof, or a vector, encoding at least the six CDR sequences of an antibody or functional part or functional equivalent according to any one of claims 1-10.

12. A c acid le or functional equivalent or vector according to claim 11, which encodes at least a variable heavy chain sequence and/or a variable light chain sequence of an antibody or functional part or functional equivalent according to any one of claims 1-10.

13. A nucleic acid le or functional equivalent or vector according to claim 11 or 12, comprising a sequence which has at least 80% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 241, 245, 249, 253, 257 and 261.

14. A nucleic acid molecule or functional equivalent or vector ing to any one of claims 11-13, comprising a sequence which has at least 80% sequence ty with the sequence of SEQ ID NO: 265; and/or comprising a sequence which has at least 80% sequence identity with the sequence of SEQ ID NO: 269.

15. A c acid molecule or functional equivalent thereof, or a vector, encoding an antibody or functional part or functional equivalent according to any one of claims 1-10.

16. A nucleic acid molecule or functional equivalent or vector according to any one of claims 11-15, which comprises cDNA, peptide nucleic acid (PNA), locked nucleic acid (LNA), or a DNA/RNA helix.

17. An isolated or recombinant cell, or a non-human animal, comprising a nucleic acid molecule or onal equivalent or vector according to any one of claims 11-16, with the proviso that said cell is not present in a human being.

18. A composition comprising an antibody or functional part or functional equivalent ing to any one of claims 1-10, or a nucleic acid molecule or functional equivalent or vector according to any one of claims 11-16, or a cell ing to claim 17.

19. A composition according to claim 18, wherein said ition is a pharmaceutical composition which comprises a pharmaceutically acceptable carrier, diluent or excipient.

20. A ition according to claim 19, which comprises at least two antibodies, functional parts or functional lents according to any one of claims 1-10.

21. Use of an antibody or functional part or functional equivalent according to any one of claims 1-10, or a nucleic acid molecule or functional equivalent or a vector according to any one of claims 11-16, or a cell ing to claim 17, in the manufacture of a medicament or prophylactic agent.

22. Use of an antibody or functional part or functional equivalent according to any one of claims 1-10, or a nucleic acid molecule or onal equivalent or a vector according to any one of claims 11-16, or a cell according to claim 17, in the manufacture of a medicament or prophylactic agent for treating or preventing acute myeloid leukemia (AML).

23. Use of an antibody or functional part or functional equivalent according to any one of claims 1-10, or a nucleic acid molecule or functional equivalent or a vector according to any one of claims 11-16, or a cell ing to claim 17, in the manufacture of a diagnostic agent for acute myeloid leukemia (AML).

24. A method for ing an antibody or functional part or functional equivalent according to any one of claims 1-10, the method comprising providing a cell with a c acid molecule or functional equivalent or a vector according to any one of claims 11-16, and allowing said cell to translate said nucleic acid molecule or functional equivalent or vector, thereby producing said antibody or functional part or functional equivalent according to any one of claims 1-10, with the proviso that said method is not carried out in a human being.

25. A method according to claim 24, wherein the method r comprises harvesting, purifying and/or isolating said antibody or functional part or functional equivalent according to any one of claims 1-10.

26. A method for determining whether AML cells are present in a sample comprising: - contacting said sample with an antibody or functional part or functional equivalent according to any one of claims 1-10, and - allowing said dy or functional part or functional equivalent to bind AML cells, if present, and - determining whether or not AML cells are bound to said antibody or functional part or functional equivalent, thereby determining whether or not AML cells are present in said sample.

27. A method for determining whether an AML t has a Graft versus Leukemia response, comprising contacting a sample from said AML t with an antibody or functional part or functional equivalent ing to any one of claims 1-10, and ng said dy or functional part or functional equivalent to bind AML cells, if present, and determining r or not AML cells are bound to said antibody or functional part or functional equivalent, y determining whether or nor said individual has a GvL response, whereby the absence of AML cells is indicative for a GvL response.

28. A bispecific or multispecific g compound, comprising an antibody or a functional part or a functional equivalent according to any one of claims 1-8 and an immunomodulatory molecule.

29. A ific or multispecific binding compound according to claim 28, wherein said immunomodulatory molecule comprises a ecific binding compound.

30. A synthetic or recombinant antibody, or a functional part or a functional equivalent thereof, which comprises one Fab fragment of an antibody according to any one of claims 1-8, and one Fab fragment of another antibody.

31. A chimeric antigen or (CAR) T cell comprising an antibody or a functional part or a functional lent according to any one of claims 1-

32. An antibody or functional part or functional equivalent according to any one of claims 1-10 substantially as herein described with nce to any example thereof.

33. A nucleic acid molecule or functional equivalent or vector according to any one of claims 11-16 substantially as herein described with reference to any example thereof.

34. A cell as claimed in claim 17 substantially as herein described with reference to any example thereof, with the proviso that said cell is not present in a human being.

35. A non-human animal as claimed in claim 17 substantially as herein bed.

36. A composition as claimed in any one of claims 18-20 substantially as herein described with nce to any example thereof.

37. A use as claimed in any one of claims 21-23 substantially as herein bed with reference to any example thereof.

38. A method as claimed in any one of claims 24-27 substantially as herein bed with reference to any example thereof.

39. A bispecific or multispecific binding compound as claimed in claim 28 or 29 substantially as herein described.

40. A synthetic or recombinant antibody, or a functional part or a functional equivalent thereof as claimed in claim 30 substantially as herein described.

41. A chimeric antigen receptor (CAR) T cell as claimed in claim 31 substantially as herein described.