Biparatopic antibodies that specifically bind FMS related receptor tyrosine kinase 3

Abstract

Described and featured herein are biparatopic antibodies that specifically bind Fms Related Receptor Tyrosine Kinase 3 (FLT-3), antibody drug conjugates (ADC's) comprising such antibodies, as well as methods of using such antibodies and ADC for the treatment of diseases, such as cancer. Particularly effective are biparatopic antibodies in which one binding arm binds to an epitope of FLT3 that is located N-terminal of the D1 domain and the other binding arm binds to an epitope located on or includes a portion of domain D3.

Description

BIPARATOPIC ANTIBODIES THAT SPECIFICALLY BIND FMS RELATEDRECEPTOR TYROSINE KINASE 3Field of the inventionDescribed and featured herein are biparatopic antibodies that specifically bind Fms Related ReceptorTyrosine Kinase 3 (FLT3), antibody drug conjugates (ADC’s) comprising such antibodies, as well as methods of using such antibodies and ADC for the treatment of diseases, such as cancer. Particularly effective are biparatopic antibodies in which one binding arm binds to an epitope of FLT3 that is located N-terminal of the D1 domain and the other binding arm binds to an epitope located on or includes a portion of domain D3.Background of the inventionFms-like tyrosine kinase 3 (FLT3) is a receptor-tyrosine kinase playing a key role in hematopoietic cell maturation and proliferation in response to binding to its ligand (FL). Whilst FLT3 has minimal expression in healthy tissues, it is frequently overexpressed in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Due to its expression profile, agents targeting FLT3 are likely to be usefulfortreatment of ALL and AML. Such agents include antibody-drug conjugates (ADCs) targeting FLT3.However, FLT3 is present on the cells with less than 10,000 copies per cell, making it a difficult target, in particular in therapeutic approaches that require internalization, such as antibody drug conjugates (ADC’s). Several respective programs were unsuccessful in early phase clinical trials due to lack of efficacy.The inventors of the present application hypothesised that biparatopic antibodies could overcome this limitation by improving target crosslinking and hence internalization capacity. To test this hypothesis, several FLT3 monoparatopic antibodies (MPAs) were utilized to produce a matrix of biparatopic antibodies (BPAs). Surprisingly it was found that FLT3 internalization and payload delivery increased when BPAs were tested in comparison to the respective monoparatopic antibodies. Interestingly, increased internalization was even more pronounced in low FLT3-expressing cells.Several monoparatopic anti-FLT3 antibodies are known in the art, including those disclosed herein (WO2019 / 025484, WO2018 / 220584A1 , US20160272716, US20190389955,WO2017 / 021362, WO2018 / 119279, WO2018 / 220584, US20190183931). Also bi- and multispecific anti-FLT3 antibodies are described. Most commonly, the second specificity is towards CD3 (see e.g. WO2017 / 021356, WO2019 / 023097, WO2023 / 023489), but also other specificities were combined with anti-FLT3 antibodies, such as NKG2D (see e.g. WO2019 / 028027, WO2021 / 076564). No soluble biparatopic anti-FLT3 antibodies are however known in the art.The present disclosure characterized the epitopes of about 20 different monoparatopic anti- FLT3 antibodies. Based on this information, biparatopic antibodies were generated comprising binding domains of all possible combinations of epitopes. Further characterization then led to the identification of the preferred epitope combination for a biparatopic anti-FLT3 antibody.Figure legendsFigure 1 depicts the domains of human FLT3. Figure 1 was generated with BioRender.com.Figure 2 shows the results of affinity measurements of biparatopic antibodies (left) as compared to monoparatopic antibodies (right). It can be seen that essentially all biparatopic antibodies shown a strongly increased affinity to FLT3 compared to the monoparatopic antibodies.Figure 3 shows the principle of the assay for the measurement of the internalization capacity of antibodies as used in Example 6.Figure 4 shows in panel A the results of the internalization assay with MOLM13 cells for monoparatopic antibodies (left) and biparatopic antibodies (right). In panel B a heat map is shown.Figure 5 shows in panel A the results of the internalization assay with Ba / F3 cells cells for monoparatopic antibodies (left) and biparatopic antibodies (right). In panel B a heat map is shown.Figure 6 shows results of the internalization assay with MOLM13 cells for biparatopic antibodies grouped by the respective binding domains.Figure 7 shows results of the internalization assay with Ba / F3 cells for biparatopic antibodies grouped by the respective binding domains.Figure s shows results of the internalization assay with the AML cell line MV4-11 (DMSZ, ACC102).Figure 9 shows results of the internalization assay with the AML cell line NOMO-1 (DMSZ, ACC542).Figure 10 shows results of the proliferation data of Example 7, indicating that thebiparatopic antibodies do not have inhibitory or agonistic activity on Ba / F3 cells overexpressing human wildtype FLT3.Figure 11 shows that biparatopic anti-FLT3 antibodies improve payload delivery and have a superior cytotoxicity capacity compared to monoparatopic antibodies as measured in Baf3 hFTL3 cells.Figure 12 shows that biparatopic anti-FLT3 antibodies improve payload delivery and have a superior cytotoxicity capacity compared to monoparatopic antibodies as measured in MOLM13 cells.Figure 13 shows that biparatopic anti-FLT3 antibodies improve payload delivery and have a superior cytotoxicity capacity compared to monoparatopic antibodies as measured in MV4-11 cells.Figure 14 shows that biparatopic anti-FLT3 antibodies improve payload delivery and have a superior cytotoxicity capacity compared to monoparatopic antibodies as measured in NOMO1 cells.Figure 15 shows that biparatopic anti-FLT3 antibodies improve payload delivery and have a superior cytotoxicity capacity compared to monoparatopic antibodies as measured in OCIAML2 cells.Figure 16 shows that biparatopic anti-FLT3 antibodies improve payload delivery and have a superior cytotoxicity capacity compared to monoparatopic antibodies as measured in OCIAML5 cells.Figure 17 shows that biparatopic anti-FLT3 antibodies improve payload delivery compared to monoparatopic antibodies as measured in THP1 cells.Figure 18 shows the cytotoxic effect of antibody Broccoli / Tartufo conjugated to Tesirine. Panel A MOLM13 cells, panel B NOMO1 cells).Summary of the inventionThe present disclosure relates to a biparatopic antibody that specifically binds two epitopes of FLT3. The present disclosure also relates to a biparatopic antibody that specifically binds two epitopes on a polypeptide comprising SEQ ID No. 1 .In certain embodiments, said two epitopes are located on domains selected from an epitope N- terminal of the D1 domain of FLT3 (SEQ ID No. 143), D1 (SEQ ID No. 144), D2 SEQ ID No. 145), D3 SEQ ID No. 146), D4 (SEQ ID No. 147) and / or D5 (SEQ ID No. 148) of FLT3.In certain embodiments, said two epitopes on FLT3 is located on domain D1 (SEQ ID No. 144) and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146) or wherein one of said two epitopes on FLT3 is located N-terminal of the D1 domain (SEQ ID No. 143) and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146).In certain embodiments, said biparatopic antibody comprises two antigen binding fragments comprising CDRs selected from a) an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 5, an HCDR3 of SEQ ID No. 6, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 8, and an LCDR3 of SEQ ID No. 9, b) an HCDR1 of SEQ ID No. 12, an HCDR2 of SEQ ID No. 13, an HCDR3 of SEQ ID No. 14, an LCDR1 of SEQ ID No. 15, an LCDR2 of SEQ ID No. 16, and an LCDR3 of SEQ ID No. 17, c) an HCDR1 of SEQ ID No. 20, an HCDR2 of SEQ ID No. 21 , an HCDR3 of SEQ ID No. 22, an LCDR1 of SEQ ID No. 23, an LCDR2 of SEQ ID No. 24, and an LCDR3 of SEQ ID No. 25, d) an HCDR1 of SEQ ID No. 28, an HCDR2 of SEQ ID No. 29, an HCDR3 of SEQ ID No. 30, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 33, e) an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41 , f) an HCDR1 of SEQ ID No. 44, an HCDR2 of SEQ ID No. 45, an HCDR3 of SEQ ID No. 46, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 48, and an LCDR3 of SEQ ID No. 49, g) an HCDR1 of SEQ ID No. 52, an HCDR2 of SEQ ID No. 53, an HCDR3 of SEQ ID No. 54, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 55, and an LCDR3 of SEQ ID No. 56, h) an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 59, an HCDR3 of SEQ ID No. 60, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 61 , and an LCDR3 of SEQ ID No. 49, i) an HCDR1 of SEQ ID No. 64, an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 66, an LCDR1 of SEQ ID No. 67, an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 68, j) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75, k) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 78, an HCDR3 of SEQ ID No. 79, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 80, l) an HCDR1 of SEQ ID No. 83, an HCDR2 of SEQ ID No. 84, an HCDR3 of SEQ ID No. 85, an LCDR1 of SEQ ID No. 86, an LCDR2 of SEQ ID No. 87, and an LCDR3 of SEQ ID No. 88,m) an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96, n) an HCDR1 of SEQ ID No. 99, an HCDR2 of SEQ ID No. 100, an HCDR3 of SEQ ID No. 101 , an LCDR1 of SEQ ID No. 102, an LCDR2 of SEQ ID No. 103, and an LCDR3 of SEQ ID No. 104, o) an HCDR1 of SEQ ID No. 107, an HCDR2 of SEQ ID No. 108, an HCDR3 of SEQ ID No. 109, an LCDR1 of SEQ ID No. 110, an LCDR2 of SEQ ID No. 1 11 , and an LCDR3 of SEQ ID No. 112, p) an HCDR1 of SEQ ID No. 115, an HCDR2 of SEQ ID No. 1 16, an HCDR3 of SEQ ID No. 1 17, an LCDR1 of SEQ ID No. 118, an LCDR2 of SEQ ID No. 1 19, and an LCDR3 of SEQ ID No. 120, q) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 123, an HCDR3 of SEQ ID No. 124, an LCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126, r) an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No. 134, and s) an HCDR1 of SEQ ID No. 137, an HCDR2 of SEQ ID No. 138, an HCDR3 of SEQ ID No. 139, an LCDR1 of SEQ ID No. 140, an LCDR2 of SEQ ID No. 141 , and an LCDR3 of SEQ ID No. 142, wherein the CDRs of said two antigen binding fragments are different.In certain embodiments, said biparatopic antibody comprises a) a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96, b) a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96, c) a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 64, an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 66, an LCDR1 of SEQ ID No. 67, an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 68 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96, d) a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95,and an LCDR3 of SEQ ID No. 96 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No. 134, and e) a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 123, an HCDR3 of SEQ ID No. 124, an LCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126.In certain embodiments, said biparatopic antibody comprise two VH and VL pairs selected from a) the variable heavy chain of SEQ ID No. 2 and the variable light chain of SEQ ID No. 3, b) the variable heavy chain of SEQ ID No. 10 and the variable light chain of SEQ ID No. 1 1 , c) the variable heavy chain of SEQ ID No. 18 and the variable light chain of SEQ ID No. 19, d) the variable heavy chain of SEQ ID No. 26 and the variable light chain of SEQ ID No. 27, e) the variable heavy chain of SEQ ID No. 34 and the variable light chain of SEQ ID No. 35, f) the variable heavy chain of SEQ ID No. 42 and the variable light chain of SEQ ID No. 43, g) the variable heavy chain of SEQ ID No. 50 and the variable light chain of SEQ ID No. 51 , h) the variable heavy chain of SEQ ID No. 57 and the variable light chain of SEQ ID No. 58, i) the variable heavy chain of SEQ ID No. 62 and the variable light chain of SEQ ID No. 63, j) the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70, k) the variable heavy chain of SEQ ID No. 76 and the variable light chain of SEQ ID No. 77, l) the variable heavy chain of SEQ ID No. 81 and the variable light chain of SEQ ID No. 82, m) the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90, n) the variable heavy chain of SEQ ID No. 97 and the variable light chain of SEQ ID No. 98, o) the variable heavy chain of SEQ ID No. 105 and the variable light chain of SEQ ID No. 106, p) the variable heavy chain of SEQ ID No. 113 and the variable light chain of SEQ ID No. 1 14, q) the variable heavy chain of SEQ ID No. 121 and the variable light chain of SEQ ID No. 122, r) the variable heavy chain of SEQ ID No. 127 and the variable light chain of SEQ ID No. 128, and s) the variable heavy chain of SEQ ID No. 135 and the variable light chain of SEQ ID No. 136, wherein the VH / VL pairs of said two antigen binding fragments are different.In certain embodiments, said biparatopic antibody a comprises a) a first VH / VL pair comprising the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90,b) a first VH / VL pair comprising the variable heavy chain of SEQ ID No. 34 and the variable light chain of SEQ ID No. 35 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90, c) a first VH / VL pair comprising the variable heavy chain of SEQ ID No. 63 and the variable light chain of SEQ ID No. 63 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90, d) a first VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 127 and the variable light chain of SEQ ID No. 128, and e) a first VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 121 and the variable light chain of SEQ ID No. 122.In certain embodiments, said antigen binding fragments comprise VH and VL pairs having at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to aforementioned variable heavy chains sequences and variable light chain sequences.In certain embodiments, the present disclosure relates to a biparatopic antibody, wherein said biparatopic antibody binds to the same epitopes aforementioned biparatopic antibodies.In certain embodiments, the present disclosure relates to an antibody-drug conjugate comprising any of the aforementioned biparatopic antibodies and a payload.In certain embodiments, the present disclosure relates to a nucleic acid encoding aforementioned biparatopic antibodies.In certain embodiments, the present disclosure relates to a vector comprising aforementioned nucleic acids.In certain embodiments, the present disclosure relates to a host cell comprising aforementioned nucleic acids or vectors.In certain embodiments, the present disclosure relates to aforementioned biparatopic antibodies or antibody-drug conjugates for use in medicine, preferably wherein said use in medicine is the treatment of cancer, such as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).Embodiments of the inventionUnless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which the aspects and embodiments described herein belong. The following references provide one of skill with a general definition of many of the terms used in the described aspects and embodiments: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Veriag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.Fms Related ReceptorTyrosine Kinase 3The terms “FLT3” and “Fms Related Receptor Tyrosine Kinase 3” refer to a receptor tyrosine kinase involved in the regulation of hematopoiesis. (UniProt: P36888). Human FLT3 has the following amino acid sequence (SEQ ID No. 1 ):MPALARDGGQLPLLVVFSAMIFGTITNQDLPVIKCVLINHKNNDSSVGKSSSYPMVSESPEDL GCALRPQSSGTVYEAAAVEVDVSASITLQVLVDAPGNISCLWVFKHSSLNCQPHFDLQNRGVV SMVILKMTETQAGEYLLFIQSEATNYTILFTVSIRNTLLYTLRRPYFRKMENQDALVCISESV PEPIVEWVLCDSQGESCKEESPAVVKKEEKVLHELFGTDIRCCARNELGRECTRLFTIDLNQT PQTTLPQLFLKVGEPLWIRCKAVHVNHGFGLTWELENKALEEGNYFEMSTYSTNRTMIRILFA FVSSVARNDTGYYTCSSSKHPSQSALVTIVEKGFINATNSSEDYEIDQYEEFCFSVRFKAYPQ IRCTWTFSRKSFPCEQKGLDNGYSISKFCNHKHQPGEYIFHAENDDAQFTKMFTLNIRRKPQV LAEASASQASCFSDGYPLPSWTWKKCSDKSPNCTEEITEGVWNRKANRKVFGQWVSSSTLNMS EAIKGFLVKCCAYNSLGTSCETILLNSPGPFPFIQDNISFYATIGVCLLFIVVLTLLICHKYK KQFRYESQLQMVQVTGSSDNEYFYVDFREYEYDLKWEFPRENLEFGKVLGSGAFGKVMNATAY GISKTGVSIQVAVKMLKEKADSSEREALMSELKMMTQLGSHENIVNLLGACTLSGPIYLI FEY CCYGDLLNYLRSKREKFHRTWTEIFKEHNFSFYPTFQSHPNSSMPGSREVQIHPDSDQISGLH GNSFHSEDEIEYENQKRLEEEEDLNVLTFEDLLCFAYQVAKGMEFLEFKSCVHRDLAARNVLV THGKVVKICDFGLARDIMSDSNYVVRGNARLPVKWMAPESLFEGIYTIKSDVWSYGILLWEI F SLGVNPYPGIPVDANFYKLIQNGFKMDQPFYATEEIYIIMQSCWAFDSRKRPSFPNLTSFLGC QLADAEEAMYQNVDGRVSECPHTYQNRRPFSREMDLGLLSPQAQVEDSFLT3 consists of various domains (Blood (2011) 118 : 60-68) which are summarized in the following table.Table 1 :The terms “specifically binds" and “specific for” as used herein, refer to a polypeptide or antibody that recognizes and binds a polypeptide of interest (e.g., FLT3), but which does not substantially recognize and bind other molecules in a sample. An antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a KD of less than 100 nM. For example, an antibody or antigen-binding fragment thereof that specifically binds to an antigen will bind to the antigen with a KD of up to 100 nM (e.g., between 1 pM and 100 nM). An antibody or antigen-binding fragment thereof that does not exhibit specific binding to a particular antigen or epitope thereofwill exhibit a KD of greaterthan 100 nM (e.g., greaterthan 500 nm, 1 uM, 100 uM, 500 uM, or 1 mM) for that particular antigen or epitope thereof. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein or carbohydrate. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein or carbohydrate. See, Harlow and Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1988) and Harlow and Lane, Using Antibodies, A Laboratory Manual, Cold Spring Harbor Press, New York (1999), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.Antibodies and agentsAs used herein, the term "agent" refers to any molecule, including small molecules (SMOL’s), proteins, nucleic acid molecules, or fragment thereof. Preferred agents of the present disclosure are proteins, including biparatopic antibodies and fragments thereof.As used herein, the term "antibody" refers to a soluble immunoglobulin molecule that specifically binds to, or is immunologically reactive with, a particular antigen, and includes polyclonal, monoclonal, genetically and molecularly engineered and otherwise modified forms of antibodies, including but not limited to chimeric antibodies, humanized antibodies, heteroconjugate antibodies (e.g., bi- tri- and quad-specific antibodies, diabodies, triabodies, and tetrabodies), and antigen-binding fragments of antibodies, including e.g., Fab', F(ab')2, Fab, Fv, rlgG, and scFv fragments. Antibodies may also be used to generate cell-based therapeutics, suchas CAR T cells (i.e., T cells carrying a chimeric antigen receptor). Such cell-based therapeutics incorporate antibodies, but are not “antibodies” in the sense of the present disclosure.The terms "antigen-binding fragment" and “antibody fragment” as used herein, refer to one or more fragments of an antibody that retain the ability to specifically bind to a target antigen. The antigen binding function of an antibody can be performed by fragments of a full-length antibody. The antibody fragments can be a Fab, F(ab')2, scFv, SMIP, diabody, a triabody, an affibody, a nanobody, an aptamer, ora domain antibody. Examples of binding fragments encompassed of the term "antigen-binding fragment" of an antibody include, but are not limited to: (i) a Fab fragment, a monovalent fragment consisting of the VL,VH,CL, and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb including VH and VL domains; (vi) a dAb fragment (Ward etal., Nature 341 :544-546, 1989), which consists of aVH domain; (vii) a dAb which consists of a VH or aVL domain; (viii) an isolated complementarity determining region (CDR); and (ix) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., Science 242:423-426, 1988, and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988). These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments can be screened for utility in the same manner as intact antibodies. Antigen-binding fragments can be produced by recombinant DNA techniques, enzymatic or chemical cleavage of intact immunoglobulins, or, in some embodiments, by chemical peptide synthesis procedures known in the art. In some embodiments, antigen-binding fragments (e.g.,.g., Fab', F(ab')2, Fab, scFab, Fv, rlgG, and scFv fragments) of a biparatopic antibody, which are joined by a synthetic linker, are provided.As used herein, the term " VH" refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, or Fab. References to " VL" refer to the variable region of an immunoglobulin light chain, including the light chain of an Fv, scFv, dsFv or Fab. Antibodies (Abs) and immunoglobulins (Igs) are glycoproteins having the same structural characteristics. While antibodies exhibit binding specificity to a specific target, immunoglobulins include both antibodies and other antibody-like molecules which lack target specificity. Native antibodies and immunoglobulins are usually heterotetra meric glycoproteins of about 150,000Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain of a native antibody has at the amino terminus a variable domain (VH) followed by a number of constant domains. Each light chain of a native antibody has a variable domain at the amino terminus (VL) and a constant domain at the carboxy terminus.As used herein, the terms "complementarity determining region" and “CDR” refer to a hypervariable region found both in the light chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FRs). As is appreciated in the art, the amino acid positions that delineate a hypervariable region of an antibody can vary, depending on the context and the various definitions known in the art. Some positions within a variable domain may be viewed as hybrid hypervariable positions in that these positions can be deemed to be within a hypervariable region under one set of criteria while being deemed to be outside a hypervariable region under a different set of criteria. One or more of these positions can also be found in extended hypervariable regions. In various aspects and embodiments, antibodies comprising modifications in these hybrid hypervariable positions are provided. The variable domains of native heavy and light chains each comprise four framework regions that primarily adopt a beta-sheet configuration, connected by three CDRs, which form loops that connect, and in some cases form part of, the beta -sheet structure. The CDRs in each chain are held together in close proximity by the FR regions in the order FR 1 -CDR 1 -FR2-CDR2- FR3 -CDR3 -FR4 and, with the CDRs from the other antibody chains, contribute to the formation of the target binding site of antibodies (see Kabat et al, Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md. 1987; incorporated herein by reference). As used herein, numbering of immunoglobulin amino acid residues is done according to the immunoglobulin amino acid residue numbering system of Kabat et al, unless otherwise indicated.As used herein, the term "framework region" or "FW region" refers to amino acid residues that are adjacent to the CDRs. FW region residues may be present in, for example, human antibodies, rodent-derived antibodies (e.g., murine antibodies), humanized antibodies, primatized antibodies, chimeric antibodies, antibody fragments (e.g., Fab fragments), singlechain antibody fragments (e.g., scFv fragments), antibody domains, and bispecific antibodies, among others.A “bispecific antibody” as used herein refers to an antibody comprising two Fab variable domains each of which binds a distinct antigen.The terms "biparatopic antibody" or “BPA” refer to an antibody comprising two Fab variable domains that bind to two distinct epitopes on the same antigen. The biparatopic antibodies of the present disclosure bind to two different epitopes on FLT3.In contractto biparatopic antibodies, a “monoparatopic antibody” or“MPA” is an antibody that comprises two Fab variable domains that bind to only one epitope on the antigen. Conventional antibodies, by way of their two identical heavy chains and light chains, are monoparatopic antibodies.The biparatopic antibodies of the present disclosure may contain modifications in the Fc part of the antibody. Such additional modifications include so-called silencing mutations. The inventive contribution of the biparatopic anti-FLT3 antibodies is however not linked to the presence of such additional modifications. The terms “silent”, “silenced” as used in this context refer to a mutation in the Fc domain of such antibody which decreases, partially or wholly, bindingto one or more cell surface Fcgamma receptors, thereby reducing or dampening, and in some embodiments abrogating substantially completely, one or more Fc-mediated antibody effector functions, such as ADCC, ADCP, and CDC complement response (see, e.g., Kang and Jung, Experimental and Molecular Medicine (2019) 51 :138). Silenced effector functions can be obtained by mutation in the Fc region of the antibody and have been described in the Art (e.g., Strohl, Biotechnology 20: 685-91 for LALAand N297A; Baudino etal., J. Immunol. 181 : 6664-69 for D265A). Other exemplary Fc silencing mutations include amino acid substitutions at one of more of positions E233, L234, L235, G236, N297, P331 and P329 (see e.g. U.S. Pat. Nos.6,737,056, 7,332,581 ; WO 2004 / 056312, WO2021 / 234402, and Shields, R. L. et al., J. Biol. Chem.276 (2001) 6591-6604). Silencing mutations also include (numbering according EU index) the LALA (L234A / L235A), the PA-LALA (L234A / L235A / P329A) and the PG-LALA (L234A / L235A / P329G) mutations, as well as the AEASS mutations (L234A / L235E / G237A / A330S / P331 S).Anti-FLT3 antibodies19 antibodies, as further defined below, were utilized to exemplify the present disclosure. These antibodies were used to generate a panel of biparatopic antibodies. Biparatopic antibodies comprise antigen binding sites (paratopes) that provide the ability to recognize and bind to two different epitopes or antigenic sites on the same target antigen.In certain embodiments, the antibodies of the present disclosure are soluble antibodies. In certain embodiments, the antibodies of the present disclosure are not a cellular therapeutic.In certain embodiments, the antigen binding domains of the biparatopic anti-FLT3 antibodies recognize and bind unique, non-overlapping epitopes on the same target antigen.In certain embodiments, the antibodies of the present disclosure bind to an epitope located N- terminal of the D1 domain of FLT3 (SEQ ID No. 143).In certain embodiments, the antibodies of the present disclosure bind to an epitope located on the D1 domain of FLT3 (SEQ ID No. 144).In certain embodiments, the antibodies of the present disclosure bind to an epitope located on the D2 domain of FLT3 (SEQ ID No. 145).In certain embodiments, the antibodies of the present disclosure bind to an epitope located on the D3 domain of FLT3 (SEQ ID No. 146).In certain embodiments, the antibodies of the present disclosure bind to an epitope, wherein said epitope includes a portion of domain D3 (SEQ ID No. 146).In certain embodiments, the antibodies of the present disclosure bind to an epitope located on or includes a portion of the D3 domain of FLT3 (SEQ ID No. 146).In certain embodiments, the antibodies of the present disclosure bind to an epitope located on the D4 domain of FLT3 (SEQ ID No. 147).In certain embodiments, the antibodies of the present disclosure bind to an epitope located on the D5 domain of FLT3 (SEQ ID No. 148).In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids K374, L397, N399 and K405 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids R174, 1185 and K219 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids Y359 and R372 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids P69, Y76, E77 and V81 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids Y76, L104, W105, S111, L142 and F144 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids D62, Y76 and Y77 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids D62, E191 , 1193, E217 and R234 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids V75, E77, V106, F107, K108, E140, L142, F144 and T153 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids D62 and E77 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids D62, P69, Y76 and E77 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids D62, L63, Y76 and E77 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids F118, D119, L120 and R123 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids H276, N278, H279, Y303, R307 and M309 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids Y359, R372, K374, L397 and K405 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids N488, R489, W495 and S497 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids Y359 and R372 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids D62, L63 and Y76 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acids L63, Y76 and E77 of FLT3.In certain embodiments, the antibodies of the present disclosure bind to an epitope comprising amino acid Y359 of FLT3.Antibody Margherita refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 2 and the variable light chain of SEQ ID No. 3. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 2 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 3. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 5, an HCDR3 of SEQ ID No. 6, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 8, and an LCDR3 of SEQ ID No. 9. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 5, an HCDR3 of SEQ ID No. 6, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 8, and an LCDR3 of SEQ ID No. 9. In certain embodiments, the present disclosure relates to an antibody orantigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 5, an HCDR3 of SEQ ID No. 6, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 8, and an LCDR3 of SEQ ID No. 9.Antibody Marinara refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 10 and the variable light chain of SEQ ID No. 11 . In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 10 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 1 1. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 12, an HCDR2 of SEQ ID No. 13, an HCDR3 of SEQ ID No. 14, an LCDR1 of SEQ ID No. 15, an LCDR2 of SEQ ID No. 16, and an LCDR3 of SEQ ID No. 17. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 12, an HCDR2 of SEQ ID No. 13, an HCDR3 of SEQ ID No. 14, an LCDR1 of SEQ ID No. 15, an LCDR2 of SEQ ID No. 16, and an LCDR3 of SEQ ID No. 17. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 12, an HCDR2 of SEQ ID No. 13, an HCDR3 of SEQ ID No. 14, an LCDR1 of SEQ ID No. 15, an LCDR2 of SEQ ID No. 16, and an LCDR3 of SEQ ID No. 17.Antibody Funghi refers to an antibody or antigen bindingfragment comprisingthe variable heavy chain of SEQ ID No. 18 and the variable light chain of SEQ ID No. 19. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 18 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 19. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 20, an HCDR2 of SEQ ID No. 21 , an HCDR3 of SEQ ID No. 22, an LCDR1 of SEQ ID No. 23, an LCDR2 of SEQ ID No. 24, and an LCDR3 of SEQ ID No. 25. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 20, an HCDR2 of SEQ ID No. 21 , an HCDR3 of SEQ ID No. 22, an LCDR1 of SEQ ID No. 23, an LCDR2 of SEQ ID No. 24, and an LCDR3 of SEQ ID No. 25. In certain embodiments, the present disclosure relates to an antibodyor antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 20, an HCDR2 of SEQ ID No. 21 , an HCDR3 of SEQ ID No. 22, an LCDR1 of SEQ ID No. 23, an LCDR2 of SEQ ID No. 24, and an LCDR3 of SEQ ID No. 25.Antibody Regina refers to an antibody or antigen bindingfragment comprising the variable heavy chain of SEQ ID No. 26 and the variable light chain of SEQ ID No. 27. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 26 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 27. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 28, an HCDR2 of SEQ ID No. 29, an HCDR3 of SEQ ID No. 30, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 33. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 28, an HCDR2 of SEQ ID No. 29, an HCDR3 of SEQ ID No. 30, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 33. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 28, an HCDR2 of SEQ ID No. 29, an HCDR3 of SEQ ID No. 30, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 33.Antibody Caprese refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 34 and the variable light chain of SEQ ID No. 35. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 34 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 35. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41 . In certain embodiments, the present disclosurerelates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41 .Antibody Cipolla refers to an antibody or antigen binding fragment com prising the variable heavy chain of SEQ ID No. 42 and the variable light chain of SEQ ID No. 43. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 42 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 43. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 44, an HCDR2 of SEQ ID No. 45, an HCDR3 of SEQ ID No. 46, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 48, and an LCDR3 of SEQ ID No. 49. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 44, an HCDR2 of SEQ ID No. 45, an HCDR3 of SEQ ID No. 46, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 48, and an LCDR3 of SEQ ID No. 49. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 44, an HCDR2 of SEQ ID No. 45, an HCDR3 of SEQ ID No. 46, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 48, and an LCDR3 of SEQ ID No. 49.Antibody Sicilia refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 50 and the variable light chain of SEQ ID No. 51 . In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 50 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 51 . In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 52, an HCDR2 of SEQ ID No. 53, an HCDR3 of SEQ ID No. 54, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 55, and an LCDR3 of SEQ ID No. 56. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 52, an HCDR2 of SEQ ID No. 53, an HCDR3 of SEQ ID No. 54, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 55, and an LCDR3 of SEQ ID No. 56. In certain embodiments, the present disclosure relates to an antibodyor antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 52, an HCDR2 of SEQ ID No. 53, an HCDR3 of SEQ ID No. 54, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 55, and an LCDR3 of SEQ ID No. 56.Antibody Paesana refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 57 and the variable light chain of SEQ ID No. 58. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 57 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 58. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 59, an HCDR3 of SEQ ID No. 60, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 61 , and an LCDR3 of SEQ ID No. 49. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 59, an HCDR3 of SEQ ID No. 60, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 61 , and an LCDR3 of SEQ ID No. 49. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 4, an HCDR2 of SEQ ID No. 59, an HCDR3 of SEQ ID No. 60, an LCDR1 of SEQ ID No. 47, an LCDR2 of SEQ ID No. 61 , and an LCDR3 of SEQ ID No. 49.Antibody Sicula refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 62 and the variable light chain of SEQ ID No. 63. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 62 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 63. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 64, an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 66, an LCDR1 of SEQ ID No. 67, an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 68. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 64, an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 66, an LCDR1 of SEQ ID No. 67, an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 68. In certain embodiments, the present disclosure relates to an antibodyor antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 64, an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 66, an LCDR1 of SEQ ID No. 67, an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 68.Antibody Broccoli refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 69 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 70. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75.Antibody Rucola refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 76 and the variable light chain of SEQ ID No. 77. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 76 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 77. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 78, an HCDR3 of SEQ ID No. 78, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 80. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 78, an HCDR3 of SEQ ID No. 79, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 80. In certain embodiments, the present disclosure relates to an antibodyor antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 78, an HCDR3 of SEQ ID No. 79, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 80.Antibody Patata refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 81 and the variable light chain of SEQ ID No. 82. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 81 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 82. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 84, an HCDR2 of SEQ ID No. 84, an HCDR3 of SEQ ID No. 85, an LCDR1 of SEQ ID No. 86, an LCDR2 of SEQ ID No. 87, and an LCDR3 of SEQ ID No. 88. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 83, an HCDR2 of SEQ ID No. 84, an HCDR3 of SEQ ID No. 85, an LCDR1 of SEQ ID No. 86, an LCDR2 of SEQ ID No. 87, and an LCDR3 of SEQ ID No. 88. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 83, an HCDR2 of SEQ ID No. 84, an HCDR3 of SEQ ID No. 85, an LCDR1 of SEQ ID No. 86, an LCDR2 of SEQ ID No. 87, and an LCDR3 of SEQ ID No. 88.Antibody Tartufo refers to an antibody or antigen bindingfragment com prising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 89 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 90. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96. In certain embodiments, the present disclosure relates to an antibodyor antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96.Antibody Neapolitana refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 97 and the variable light chain of SEQ ID No. 98. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 97 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percentor99 percent sequence identityto SEQ ID No. 98. In certain embodiments, the present disclosure relates to an antibody or antigen bindingfragment comprisingan HCDR1 of SEQ ID No. 99, an HCDR2 of SEQ ID No. 100, an HCDR3 of SEQ ID No. 101 , an LCDR1 of SEQ ID No. 102, an LCDR2 of SEQ ID No. 103, and an LCDR3 of SEQ ID No. 104. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprisingan HCDR1 of SEQ ID No. 99, an HCDR2 of SEQ ID No. 100, an HCDR3 of SEQ ID No. 101 , an LCDR1 of SEQ ID No. 102, an LCDR2 of SEQ ID No. 103, and an LCDR3 of SEQ ID No. 104. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 99, an HCDR2 of SEQ ID No. 100, an HCDR3 of SEQ ID No. 101 , an LCDR1 of SEQ ID No. 102, an LCDR2 of SEQ ID No. 103, and an LCDR3 of SEQ ID No. 104.Antibody Vongole refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 105 and the variable light chain of SEQ ID No. 106. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 105 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percentor99 percent sequence identityto SEQ ID No. 106. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 107, an HCDR2 of SEQ ID No. 108, an HCDR3 of SEQ ID No. 109, an LCDR1 of SEQ ID No. 110, an LCDR2 of SEQ ID No. 111 , and an LCDR3 of SEQ ID No. 112. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 107, an HCDR2 of SEQ ID No. 108, an HCDR3 of SEQ ID No. 109, an LCDR1 of SEQ ID No. 110, an LCDR2 of SEQ ID No. 111 , and an LCDR3 of SEQ ID No. 112. In certain embodiments,the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 107, an HCDR2 of SEQ ID No. 108, an HCDR3 of SEQ ID No. 109, an LCDR1 of SEQ ID No. 1 10, an LCDR2 of SEQ ID No. 11 1 , and an LCDR3 of SEQ ID No. 112.Antibody Carbonara refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 1 13 and the variable light chain of SEQ ID No. 1 14. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 113 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 1 14. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 115, an HCDR2 of SEQ ID No. 1 16, an HCDR3 of SEQ ID No. 117, an LCDR1 of SEQ ID No. 118, an LCDR2 of SEQ ID No. 119, and an LCDR3 of SEQ ID No. 120. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 115, an HCDR2 of SEQ ID No. 1 16, an HCDR3 of SEQ ID No. 1 17, an LCDR1 of SEQ ID No. 1 18, an LCDR2 of SEQ ID No. 119, and an LCDR3 of SEQ ID No. 120. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 1 15, an HCDR2 of SEQ ID No. 116, an HCDR3 of SEQ ID No. 117, an LCDR1 of SEQ ID No. 1 18, an LCDR2 of SEQ ID No. 119, and an LCDR3 of SEQ ID No. 120.Antibody Carciofi refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 121 and the variable light chain of SEQ ID No. 122. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 121 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 122. In certain embodiments, the present disclosure relates to an antibody or antigen bindingfragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 123, an HCDR3 of SEQ ID No. 124, an LCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 123, an HCDR3 of SEQ ID No. 124, an LCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126. In certain embodiments, the presentdisclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an LCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126.Antibody Diavola refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 127 and the variable light chain of SEQ ID No. 128. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 127 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 128. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No. 134. In certain embodiments, the present disclosure relates to an antibodyorantigen bindingfragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No. 134. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No. 134.Antibody Prosciuto refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 135 and the variable light chain of SEQ ID No. 136. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 135 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percentor99 percent sequence identityto SEQ ID No. 136. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 137, an HCDR2 of SEQ ID No. 138, an HCDR3 of SEQ ID No. 139, an LCDR1 of SEQ ID No. 140, an LCDR2 of SEQ ID No. 141 , and an LCDR3 of SEQ ID No. 142. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 137, an HCDR2 of SEQ ID No. 138, an HCDR3 of SEQ ID No. 139, an LCDR1 of SEQ ID No. 140, an LCDR2 of SEQ ID No. 141 , and an LCDR3 of SEQ ID No. 142. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibodyor antibody fragment competes for binding to FLT3 with an antibody com rising an HCDR1 of SEQ ID No. 137, an HCDR2 of SEQ ID No. 138, an HCDR3 of SEQ ID No. 139, an LCDR1 of SEQ ID No. 140, an LCDR2 of SEQ ID No. 141 , and an LCDR3 of SEQ ID No. 142.Antibody Siciliana refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 151 and the variable light chain of SEQ ID No. 152. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 151 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 152. In certain embodiments, the present disclosure relates to an antibody or antigen bindingfragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 153, an HCDR3 of SEQ ID No. 154, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 155, and an LCDR3 of SEQ ID No. 156. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 153, an HCDR3 of SEQ ID No. 154, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 155, and an LCDR3 of SEQ ID No. 156. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibody fragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 153, an HCDR3 of SEQ ID No. 154, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 155, and an LCDR3 of SEQ ID No. 156.Antibody Tirolese refers to an antibody or antigen binding fragment comprising the variable heavy chain of SEQ ID No. 157 and the variable light chain of SEQ ID No. 158. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising a variable heavy chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to SEQ ID No. 157 and a variable light chain with at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or99 percent sequence identityto SEQ ID No. 158. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 159, an HCDR3 of SEQ ID No. 160, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 80. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment binding to the same epitope as an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 159, an HCDR3 of SEQ ID No. 160, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 80. In certain embodiments, the present disclosure relates to an antibody or antigen binding fragment, wherein said antibody or antibodyfragment competes for binding to FLT3 with an antibody comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 159, an HCDR3 of SEQ ID No. 160, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 80.Biparatopic antibodiesThe present disclosure relates to biparatopic antibodies that specifically bind and inhibit FLT3. and to methods of using such antibodies for the treatment of cancers, including include acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Such biparatopic anti-FLT3 antibodies have several unexpected, advantageous properties compared to monoparatopic anti- FLT3 antibodies.In certain embodiments, the biparatopic antibodies of the present disclosure are soluble biparatopic antibodies. In certain embodiments, the biparatopic antibodies of the present disclosure are not a cellular therapeutic.Biparatopic antibodies based on aforementioned monoparatopic antibodies may be generated by any applicable technology, such as a controlled Fab-arm exchange (DuoBody technology) or the knob-into-hole technology.The term "knob-into-hole" or "KiH" technology as used herein refers to the technology directing the pairing of two polypeptides together in vitro or in vivo by introducing a protuberance (knob) into one polypeptide and a cavity (hole) into the other polypeptide at an interface in which they interact. For example, KiHs have been introduced in the Fc:Fc binding interfaces, CL:CH1 interfaces or VH / VL interfaces of antibodies (e.g., US2007 / 0178552, WO 96 / 027011 , WO 98 / 050431 and Zhu et al. (1997) The KiH technology another technology useful in driving the pairing of two different heavy chains together during the manufacture of biparatopic antibodies. For example, biparatopic antibodies having KiH in their Fc regions can further comprise single variable domains linked to each Fc region, or further comprise different heavy chain variable domains that pair with similar ordifferent light chain domains. KiH technology can be also be used to pair two different receptor extracellular domains together or any other polypeptide sequences that comprises different target recognition sequences (e.g., including affibodies, peptibodies and other Fc fusions).Another technologies for the generation of biparatopic antibodies includes the controlled Fab arm exchange (Labrijn, et al.; Nature Protocols 9: 2450-2463, 2014), which involves the following: (i) separate expression of two parental IgGs containing single matching point mutations in theCH3 domain; (ii) mixing of parental IgGs under permissive redox conditions in vitro to enable recombination of half-molecules; (iii) removal of the reductant to allow reoxidation of interchain disulfide bonds; and (iv) analysis of exchange efficiency and final product using chromatographybased or mass spectrometry (MS)-based methods. The protocol generates bsAbs with regular IgG architecture, characteristics and quality attributes both at bench scale (micrograms to milligrams) and at a mini-bioreactor scale (milligrams to grams) that is designed to model large- scale manufacturing (kilograms). Other methods useful for the generation biparatopic antibodies are described, for example, in US9212230, US9150663 and US10344050.The terms "isolated" and "purified" refer to material that is free to varying degrees from components which normally accompany it as found in its native state. "Isolate" denotes a degree of separation from original source or surroundings. "Purify" denotes a degree of separation that is higher than isolation. A "purified" protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of some aspects and embodiments is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography.Nucleic acid molecules useful in the methods of some aspects and embodiments of the present disclosure include any nucleic acid molecule that encodes a polypeptide of some aspects and embodiments herein ora fragment thereof. Such nucleic acid molecules need not be 100 percent identical with an endogenous nucleic acid sequence, but will typically exhibit substantial identity. Polynucleotides having "substantial identity" to an endogenous sequence are typically capable of hybridizing with at least one strand of a double-stranded nucleic acid molecule. By "hybridize" is meant pair to form a double-stranded molecule between complementary polynucleotide sequences (e.g., a gene described herein), or portions thereof, under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol. 152:507).As used herein, the term "vector" includes a nucleic acid vector, e.g., a DNA vector, such as a plasmid, a RNA vector, virus or other suitable replicon (e.g., viral vector). A variety of vectors have been developed for the delivery of polynucleotides encoding exogenous proteins into a prokaryotic or eukaryotic cell. Examples of such expression vectors are disclosed in, e.g., WO 1994 / 11026. Expression vectors of some aspects and embodiments herein contain apolynucleotide sequence as well as, e.g., additional sequence elements used for the expression of proteins and / or the integration of these polynucleotide sequences into the genome of a mammalian cell. Certain vectors that can be used for the expression of antibodies and antibody fragments of some aspects and embodiments herein include plasmids that contain regulatory sequences, such as promoter and enhancer regions, which direct gene transcription. Other useful vectors for expression of antibodies and antibody fragments contain polynucleotide sequences that enhance the rate of translation of these genes or improve the stability or nuclear export of the mRNAthat results from gene transcription. These sequence elements include, e.g., 5' and 3' untranslated regions, an internal ribosomal entry site (IRES), and polyadenylation signal site in order to direct efficient transcription of the gene carried on the expression vector. The expression vectors of some aspects and embodiments herein may also contain a polynucleotide encoding a marker for selection of cells that contain such a vector. Examples of a suitable marker include genes that encode resistance to antibiotics, such as ampicillin, chloramphenicol, kanamycin, or nourseothricin.The biparatopic antibodies of the present disclosure bind to two epitopes of FLT3. In certain embodiments, said two epitopes on FLT3 are non overlapping epitopes. In other embodiments, said two epitopes are located on two different domains of FLT3.In certain embodiments, said two epitopes are located on domains selected from the N- terminal part of D1 (SEQ ID No. 143), D1 (SEQ ID No. 144), D2 SEQ ID No. 145), D3 SEQ ID No. 146), D4 (SEQ ID No. 147) and / or D5 (SEQ ID No. 148) of FLT3.In certain embodiments, said two epitopes are located on or include portions of domains selected from the N-terminal part of D1 (SEQ ID No. 143), D1 (SEQ ID No. 144), D2 SEQ ID No. 145), D3 SEQ ID No. 146), D4 (SEQ ID No. 147) and / or D5 (SEQ ID No. 148) of FLT3.In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 is located on domain D1 (SEQ ID No. 144).In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 is located on domain D2 (SEQ ID No. 145).In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 is located on domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 includes a portion of domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 is located on domain D4 (SEQ ID No. 147).In certain embodiments, one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143), and the other one of said two epitopes on FLT3 is located on domain D5 (SEQ ID No. 148).In certain embodiments, one of said two epitopes on FLT3 is located on domain D1 (SEQ ID No.144), and the other one of said two epitopes on FLT3 is located on domain D2 (SEQ ID No. 145).In certain embodiments, one of said two epitopes on FLT3 is located on domain D1 (SEQ ID No. 144), and the other one of said two epitopes on FLT3 is located on domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located on domain D1 (SEQ ID No. 144), and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located on domain D1 (SEQ ID No. 144), and the other one of said two epitopes on FLT3 is located on domain D4 (SEQ ID No. 147).In certain embodiments, one of said two epitopes on FLT3 is located on domain D1 (SEQ ID No.144), and the other one of said two epitopes on FLT3 is located on domain D5 (SEQ ID No. 148).In certain embodiments, one of said two epitopes on FLT3 is located on domain D2 (SEQ ID No.145), and the other one of said two epitopes on FLT3 is located on domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located on or includes a portion of domain D2 (SEQ ID No. 145), and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146).In certain embodiments, one of said two epitopes on FLT3 is located on domain D2 (SEQ ID No. 145), and the other one of said two epitopes on FLT3 is located on domain D4 (SEQ ID No. 147).In certain embodiments, one of said two epitopes on FLT3 is located on domain D2 (SEQ ID No.145), and the other one of said two epitopes on FLT3 is located on domain D5 (SEQ ID No. 148).In certain embodiments, one of said two epitopes on FLT3 is located on domain D3 (SEQ ID No.146), and the other one of said two epitopes on FLT3 is located on domain D4 (SEQ ID No. 147).In certain embodiments, one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146), and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D4 (SEQ ID No. 147).In certain embodiments, one of said two epitopes on FLT3 is located on domain D3 (SEQ ID No.146), and the other one of said two epitopes on FLT3 is located on domain D5 (SEQ ID No. 148).In certain embodiments, one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146), and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D5 (SEQ ID No. 148).In certain embodiments, one of said two epitopes on FLT3 is located on domain D4 (SEQ ID No.147), and the other one of said two epitopes on FLT3 is located on domain D5 (SEQ ID No. 148).In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, P69, Y76 andY77, and the other one of said two epitopes comprises one or more amino acids of selected from L104, W105, V106, F107, K108, S111, F118, D119, L120, R123,E14O, L142 and F144.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, P69, Y76 andY77, and the other one of said two epitopes comprises one or more amino acids of selected from D62, E191 , 1193, E217 and R234.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, P69, Y76 andY77, and the other one of said two epitopes comprises one or more amino acids of selected from R174, 1185 and K219.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, P69, Y76 andY77, and the other one of said two epitopes comprises one or more amino acids of selected from H276, N278, H279, Y303, R307 and M309.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, P69, Y76 andY77, and the other one of said two epitopes comprises one or more amino acids of selected from Y359, R372, K374, L397, N399 and K405.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, P69, Y76 andY77, and the other one of said two epitopes comprises one or more amino acids of selected from N488, R489, W495 and S497.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids Of selected from L104, W105, V106, F107, K108, S11 1 , F118, D1 19, L120, R123, E140, L142 and F144, and the other one of said two epitopes comprises one or more amino acids of selected from D62, E191 , 1193, E217 and R234.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids Of selected from L104, W105, V106, F107, K108, S11 1 , F118, D1 19, L120, R123, E140, L142 and F144, and the other one of said two epitopes comprises one or more amino acids of selected from R174, 1185 and K219.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids Of selected from L104, W105, V106, F107, K108, S11 1 , F118, D1 19, L120, R123, E140, L142 and F144, and the other one of said two epitopes comprises one or more amino acids of selected from H276, N278, H279, Y303, R307 and M309.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids Of selected from L104, W105, V106, F107, K108, S11 1 , F118, D1 19, L120, R123, E140, L142 and F144, and the other one of said two epitopes comprises one or more amino acids of selected from Y359, R372, K374, L397, N399 and K405.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids Of selected from L104, W105, V106, F107, K108, S11 1 , F118, D1 19, L120, R123, E140, L142 and F144, and the other one of said two epitopes comprises one or more amino acids of selected from N488, R489, W495 and S497.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, E191 , 1193, E217 and R234, and the other one of said two epitopes comprises one or more amino acids of selected from R174, 1185 and K219.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, E191 , 1193, E217 and R234, and the other one of said two epitopes comprises one or more amino acids of selected from H276, N278, H279, Y303, R307 and M309.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, E191 , 1193, E217 and R234, and the other one of said two epitopes comprises one or more amino acids of selected from Y359, R372, K374, L397, N399 and K405.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from D62, E191 , 1193, E217 and R234, and the other one of said two epitopes comprises one or more amino acids of selected from N488, R489, W495 and S497.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from R174, 1185 and K219, and the other one of said two epitopes comprises one or more amino acids of selected from H276, N278, H279, Y303, R307 and M309.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from R174, 1185 and K219, and the other one of said two epitopes comprises one or more amino acids of selected from Y359, R372, K374, L397, N399 and K405.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from R174, 1185 and K219, and the other one of said two epitopes comprises one or more amino acids of selected from N488, R489, W495 and S497.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from H276, N278, H279, Y303, R307 and M309, and the other one of said two epitopes comprises one or more amino acids of selected from Y359, R372, K374, L397, N399 and K405.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from H276, N278, H279, Y303, R307 and M309, and the other one of said two epitopes comprises one or more amino acids of selected from N488, R489, W495 and S497.In certain embodiments, one of said two epitopes on FLT3 comprises one or more amino acids of selected from Y359, R372, K374, L397, N399 and K405, and the other one of said two epitopes comprises one or more amino acids of selected from N488, R489, W495 and S497.In certain embodiments, the present disclosure relates to a biparatopic antibody that specifically binds two epitopes of FLT3, wherein said biparatopic antibody comprises a first antigen binding fragment comprising CDRs selected from a) an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41 , b) an HCDR1 of SEQ ID No. 52, an HCDR2 of SEQ ID No. 53, an HCDR3 of SEQ ID No. 54, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 55, and an LCDR3 of SEQ ID No. 56, c) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75, d) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 78, an HCDR3 of SEQ ID No. 79, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 80, e) an HCDR1 of SEQ ID No. 1 15, an HCDR2 of SEQ ID No. 116, an HCDR3 of SEQ ID No. 1 17, an LCDR1 of SEQ ID No. 1 18, an LCDR2 of SEQ ID No. 119, and an LCDR3 of SEQ ID No. 120, f) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 123, an HCDR3 of SEQ ID No. 124, anLCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126,g) an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No. 134, and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96.In certain embodiments, the present disclosure relates to a biparatopic antibody that specifically binds two epitopes of FLT3, wherein said biparatopic antibody comprises a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96.In certain embodiments, the present disclosure relates to a biparatopic antibody that specifically binds two epitopes of FLT3, wherein said biparatopic antibody comprises a first VH and VL pair selected from a) the variable heavy chain of SEQ ID No. 34 and the variable light chain of SEQ ID No. 35, b) the variable heavy chain of SEQ ID No. 50 and the variable light chain of SEQ ID No. 51 , c) the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70, d) the variable heavy chain of SEQ ID No. 76 and the variable light chain of SEQ ID No. 77, e) the variable heavy chain of SEQ ID No. 113 and the variable light chain of SEQ ID No. 114, f) the variable heavy chain of SEQ ID No. 121 and the variable light chain of SEQ ID No. 122, g) the variable heavy chain of SEQ ID No. 127 and the variable light chain of SEQ ID No. 128, and a second VH and VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90.In certain embodiments, the present disclosure relates to a biparatopic antibody that specifically binds two epitopes of FLT3, wherein said biparatopic antibody comprises a first VH / VL pair comprising the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90.In certain embodiments, the biparatopic antibody of the present disclosure are internalized more rapidly than a corresponding monoparatopic antibody.Payloads and ADCsThe biparatopic antibodies of the present disclosure may also be linked to a payload. In its broadest sense, the term “payload” as used herein refers to any molecule that is linked, conjugated or attached to a biparatopic antibody of the present disclosure. After internalization of the biparatopic antibody into the cell, the payload may exert its action, which may vary, depend on the nature of the payload. The biparatopic antibody, when linked, conjugated or attached to a payload, is also referred to as “antibody drug conjugate” or “ADC”.The payload may be a cell killing agent, an immune-modulating payload, a macrophage class switching agent, or a light activatable payload. The cell killing agent may comprise a cytotoxin. The cytotoxin may be a peptide toxin or a chemical toxin. The cytotoxin may also be an inhibitor of Bcl-2 or Bcl-axl, an RNA Polymerase inhibitor such as a-amanitin, a spliceosome inhibitor, a microtubule-targeting payload, or DNA- damaging payload.Immune-modulating payloads include moieties that modulates the immune system, for example which stimulates the immune system and / or kills the target cell. Thus, a moiety that has immuno-activating and / or antineoplastic activities can be used. Such moieties may be synthetic peptides that recognise the specific target and trigger (agonist) or block (antagonist) inflammatory responses. The target may be a pattern recognition receptor (PRR), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-l-like receptors (RLRs), C-type lectin receptors (CLRs) and cytosolic dsDNA sensors (CDSs). Examples of payloads also include agonists for the stimulator of interferon genes protein (STING; transmembrane protein 173; TMEM173). Light activatable payloads, such as IRDye(R) 700DX orlR700, may also be used. Light activation of the non-toxic payload results in the generation of singlet oxygen species that damage the cell membrane integrity, resulting in necrotic and immunogenic cell death of tumour cells, resulting in minimal damage to surrounding normaltissue.The composition may further comprise a linker for linking the payload, e.g. the cell killing agent to the agent, e.g. cell inhibiting agent and / or antibody or antibody fragment, that binds to the pair of proteins expressed on the cell surface. The linker may be a cleavable linkeror a a non-cleavable linker.Antibody screeningAnti-FLT3 antibodies, and antigen-binding fragments thereof, can be principally be obtained by screening libraries of polypeptides (e.g., antibodies and antigen-binding fragments thereof) for functional molecules that are capable of binding epitopes within FLT3. Numerous technologies are known in the art. For example, peptides comprising amino acid stretches of FLT3 can be immobilized on a solid surface and screened for molecules that bind to such peptides, e.g., using ELISA-based screening platforms. Since such peptides act as surrogates for epitopes within FLT3, antibodies can be identifies that bind to specific epitopes on FLT3.Methods for high throughput screening of polypeptide (e.g., biparatopic antibody, or antibody fragment) libraries for molecules capable of binding epitopes within FLT3 include, without limitation, display techniques including phage display, bacterial display, yeast display, mammalian display, ribosome display, mRNA display, and cDNA display. The use of phage display to isolate ligands that bind biologically relevant molecules has been reviewed, e g., in Felici et al. (Biotechnol. Annual Rev. 1 : 149-183, 1995), Katz (Annual Rev. Biophys. Biomol. Struct. 26:27-45, 1997), and Hoogenboom etal. (Immunotechnology 4:1 -20, 1998). Fully human synthetic antibody libraries are disclosed in J Mol Biol (2000), 296:57-86 and Mabs (2013), 5:445-70. Several randomized combinatorial peptide libraries have been constructed to select for polypeptides that bind different targets, e.g., cell surface receptors or DNA (reviewed by Kay (Perspect. Drug Discovery Des. 2, 251 -268, 1995), Kay et al., (Mol. Divers. 1 :139-140, 1996)). Proteins and multimeric proteins have been successfully phage-displayed as functional molecules (see EP 0349578, EP 4527839, EP 0589877; Chiswell and McCafferty (Trends Biotechnol. 10, 80-84 1992)). In addition, functional antibody fragments (e.g. Fab, single-chain Fv [scFv]) have been expressed (McCafferty et al. (Nature 348: 552-554, 1990), Barbas et al. (Proc. Natl. Acad Sci. USA 88:7978-7982, 1991 ), Clackson et al. (Nature 352:624-628, 1991 )).Various other screening technologies exist, such as assembling libraries of polynucleotides encoding antibodies or antigen-binding fragments that encode random mutations only at particular sites within hypervariable regions. Such polynucleotides can then be expressed in, e.g., filamentous phage, bacterial cells, yeast cells, mammalian cells, or in vitro using, e.g., ribosomedisplay, mRNA display, or cDNA display techniques in order to screen for antibodies or antigenbinding fragments thereof that specifically bind FLT3 epitopes with improved binding affinity. Yeast display, for instance, is well-suited for affinity maturation.Combinatorial antibody libraries can be obtained, e.g., by expression of polynucleotides encoding randomized hypervariable regions of an antibody or antigen-binding fragment thereof in a eukaryotic or prokaryotic cell. Heterogeneous mixtures of antibodies can be purified, e.g., by Protein A or Protein G selection, sizing column chromatography), centrifugation, differential solubility, and / or by any other standard technique for the purification of proteins. Libraries of combinatorial libraries thus obtained can be screened, e.g., by incubating a heterogeneous mixture of these antibodies with a peptide derived from FLT3 that has been immobilized to a surface for a period of time sufficient to allow antibody-antigen binding. Non-binding antibodies or fragments thereof can be removed by washing the surface with an appropriate buffer (e.g., a solution buffered at physiological pH (approximately 7.4) and containing physiological salt concentrations and ionic strength, and optionally containing a detergent, such as TWEEN-20). Antibodies that remain bound can subsequently be detected, e.g., using an ELISA-based detection protocol (see, e.g., U.S. Pat. No. 4,661 ,445; incorporated herein by reference).Additional techniques for screening combinatorial libraries of polypeptides (e.g., antibodies, and antigen-binding fragments thereof) for those that specifically bind FLT3- derived peptides include the screening of one-bead-one-compound libraries of antibody fragments. Antibody fragments can be chemically synthesized on a solid bead (e.g., using established split-and-pool solid phase peptide synthesis protocols) composed of a hydrophilic, water-swellable material such that each bead displays a single antibody fragment. Heterogeneous bead mixtures can then be incubated with a FLT3-derived peptide that is optionally labeled with a detectable moiety (e.g., a fluorescent dye) or that is conjugated to an epitope tag (e.g., biotin, avidin, FLAG tag, HA tag) that can later be detected by treatment with a complementary tag (e.g., avidin, biotin, anti-FLAG antibody, anti-HA antibody, respectively). Beads containing antibody fragments that specifically bind a FLT3-derived peptide can be identified by analyzingthe fluorescent properties of the beads following incubation with a fluorescently-labeled antigen or complementary tag (e.g., by confocal fluorescent microscopy or by fluorescence-activated bead sorting; see, e.g., Muller et al. ( / . Biol. Chem., 16500-16505, 1996); incorporated herein by reference). Beads containing antibody fragments that specifically bind FLT3-derived peptides can thus be separated from those that do not contain high-affinity antibody fragments. The sequence of an antibody fragment that specifically binds a FLT3-derived peptide can be determined by techniques known in the art, including, e.g., Edman degradation, tandem mass spectrometry, matrix-assisted laser-desorption time-of-flight mass spectrometry (MALDI-TOF MS), nuclear magnetic resonance (NMR), and 2D gel electrophoresis, among others (see, e.g., WO 2004 / 062553).Antibody productionMammalian cells can be co- transfected with polynucleotides encoding the antibodies of some aspects and embodiments herein, which are expressed as recombinant polypeptides, and assembled into biparatopic antibodies by the host cell. In one embodiment, a mammalian cell is co-transfected with polynucleotides encoding four chains of a biparatopic antibody, which expression results in the correct assembly of a biparatopic antibody.

[0162] It is possible to express antibodies (e.g., biparatopic antibodies, or antigen-binding fragments thereof) in either prokaryotic or eukaryotic host cells. In certain embodiments, expression of polypeptides (e.g., biparatopic antibodies, or antigen-binding fragments thereof) is performed in eukaryotic cells, e.g., mammalian host cells, for optimal secretion of a properly folded and immunologically active antibody. Exemplary mammalian host cells for expressing the recombinant antibodies or antigen-bindingfragments thereof of some aspects and embodiments herein include Chinese Hamster Ovary (CHO cells) (including DHFR CHO cells, described in Urlaub and Chasin (1980, Proc. Natl. Acad. Sci. USA 77:4216-4220), used with a DHFR selectable marker, e.g., as described in Kaufman and Sharp (1982, Mol. Biol. 159:601-621), NSO myeloma cells, COS cells, HEK293T cells, SP2 / 0, N1 H3T3, and BaF3 cells. Additional cell types that may be useful for the expression of antibodies and fragments thereof include bacterial cells, such as BL- 21 (DE3) E. coli cells, which can be transformed with vectors containing foreign DNA according to established protocols. Additional eukaryotic cells that may be useful for expression of antibodies include yeast cells, such as auxotrophic strains of S. cerevisiae, which can be transformed and selectively grown in incomplete media according to established procedures known in the art. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells for a period of time sufficient to allow for expression of the antibody in the host cells or secretion of the antibody into the culture medium in which the host cells are grown.

[0163] Polypeptides (e.g., biparatopic antibodies, or antigen-binding fragments thereof) can be recovered from the culture medium using standard protein purification methods. Host cells can also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. Also included in some aspects and embodiments herein are methods in which the above procedure is varied according to established protocols known in the art. For example, it can bedesirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an anti-FLT3 antibody of some aspects and embodiments herein in order to produce an antigen-binding fragment of the antibody.Once an anti-FLT3 polypeptide (e.g., biparatopic antibodies, or antigen-binding fragments thereof) of some aspects and embodiments herein has been produced by recombinant expression, it can be purified by any method known in the art, such as a method useful for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for FLT3 after Protein A or Protein G selection, and sizing column chromatography), centrifugation, differential solubility, or byany other standard technique forthe purification of proteins. Further, the anti-FLT3 polypeptides of some aspects and embodiments described herein, orantigen-bindingfragments thereof, can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification or to produce therapeutic conjugates.

[0165] Once isolated, an anti-FLT3 biparatopic antibody, or antigen-binding fragments thereof can, if desired, be further purified, e.g., by high performance liquid chromatography (see, e.g., Fisher, Laboratory Techniques in Biochemistry and Molecular Biology (Work and Burdon, eds., Elsevier, 1980); incorporated herein by reference), or by gel filtration chromatography, such as on a Superdex.TM. 75 column (Pharmacia Biotech AB, Uppsala, Sweden).Therapeutic methodsAs used herein, the terms "disease" refers to any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include cancer. The biparatopic antibodies of the present disclosure are useful in the treatment or prophylaxis if diseases associated with the aberrant expression or activity of FLT3, such as cancers or tumors. Such diseases include acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).As used herein, the term "effective amount" refers to an agent, such as a biparatopic anti_FLT3 antibody, that is required to treat a disease or to ameliorate the symptoms associated with a disease relative to an untreated patient. The effective amount of active compound(s) used to practice methods for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen.As used herein, the terms "treat," treating," "treatment," and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.In one therapeutic approach, an antibody identified as described herein is administered to a patient, such administration may be local or systemic. The dosage of the administered agent depends on a number of factors, including the size and health of the individual patient. For any particular subject, the specific dosage regimes should be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions.Pharmaceutical formulationsFor therapeutic uses, the antibodies identified using the methods disclosed herein may be administered systemically, for example, formulated in a pharmaceutically-acceptable buffer such as physiological saline. Preferable routes of administration include, for example, subcutaneous, intravenous, interperitoneally, intramuscular, or intradermal injections that provide continuous, sustained levels of the drug in the patient Treatment of human patients or other animals will be carried out using a therapeutically effective amount of a therapeutic identified herein in a physiologically-acceptable carrier. Suitable carriers and their formulation are described, for example, in Remington's Pharmaceutical Sciences by E. W. Martin. The amount of the therapeutic agent to be administered varies depending upon the manner of administration, the age and bodyweightof the patient, and with the clinical symptoms of the neoplasia. Generally, amounts will be in the range of those used for other agents used in the treatment of other diseases associated with neoplasia, although in certain instances lower amounts will be needed because of the increased specificity of the compound. An agent of some aspects and embodiments herein is administered at a dosage that blocks ligand binding to a receptor and / or that inhibits receptor activity.The administration of a biparatopic antibody may be by any suitable means that results in a concentration of the therapeutic that, combined with other components, is effective in ameliorating, reducing, or stabilizing a neoplasia. The compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1- 95 percent by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for parenteral (e.g., subcutaneously, intravenously, intramuscularly,or intraperitoneally) administration route. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams and Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).The pharmaceutical composition may be administered parenterally by injection, infusion or implantation (subcutaneous, intravenous, intramuscular, intraperitoneal, or the like) in dosage forms, formulations, or via suitable delivery devices or implants containing conventional, nontoxic pharmaceutically acceptable carriers and adjuvants. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. Formulations can be found in Remington: The Science and Practice of Pharmacy, supra.ExamplesExample 1: Generation of monoparatopic anti-FLT3 antibodiesThe following 19 monoparatopic antibodies were generated according to standard procedures based on publicly available sequence information. All antibodies were generated with PG-LALA Fc modifications.Table 2:Example 2: Characterization of monoparatopic anti-FLT3 antibodiesAffinities of all 19 monoparatopic anti-FLT3 antibodies to FLT3 was measured by BLI and MSD- SET. In brief, in a BLI experiment antibodies are captured on a sensor tip by an anti-IgG-Fc molecule using an Octet instrument. Then the tips containing the antibodies are moved in wells containing the interaction partner of interest called the analyte (FLT3 ECD) at different concentrations. In this way the curve generated, called sensorgrams, can be fitted to a 1 :1 interaction model and kinetic rates and affinity KDs be derived. Also, monoparatopic antibody affinities were additionally characterised by MSD-SET. This is an orthogonal binding interaction technique where the antigen of interest (FLT3 ECD) is coated on an MSD plate. Then a mix of titrated antigen and constant antibody, previously incubated overnight to reach equilibrium, is moved into the coated MSD plate to finally measure the free concentration of antibody. The binding curve is then fitted to binding equation to derive affinity KD. Furthermore, all 19 monoparatoic anti-FLT3 antibodies were subjected to epitope binning experiments. The epitope binning was performed using the Octet (BLI). Every antibody was tested against each other to generate a matrix. In short, biotinylated FLT3 ECD was immobilised on streptavidin tips, then tips were moved into Ab1 (also called saturating antibody) for Ab 1 to saturate the immobilised antigen. Finally, tips were moved into Ab2 (also called competing antibody) to check if there was binding (therefore no competition) or binding in the same (or overlapping) epitope.The following table shows the affinity measurements, the domains to which the respective antibodies bind on FLT3, as well as the epitope bins to which the antibodies were assigned.Table 3:Figure 1 furthermore depicts the domains of FLT3 indicated in Table 3. Overall there was a relatively good correlation between the epitope binning data and the alanine scanning data, whereby antibodies binding different domains did not show competition in epitope binning experiments. The antibodies tested bind to various regions of FLT3, covering all accessible domains.Example 3: Epitope mapping of monoparatopic anti-FLT3 antibodies by alanine scanningAn alanine scan was performed to determine the residues that are essential for binding of the monoparatopic antibodies to human Flt3. The alanine scan was performed via shotgun mutagenesis epitope mapping (Integral Molecular, Philadelphia / PA, USA) as described in Immunology (2014) 143, 13-20. Briefly, a mutation library of Flt3 was created by high-throughput, site-directed mutagenesis. Each residue was individually mutated to alanine, with alanine codons mutated to serine. The mutant library was arrayed in 384-well microplates and transiently transfected into HEK293-T. Following transfection, cells were incubated with the indicated antibodies (IgG or Fab) at concentrations pre-determined using an independentimmunofluorescence titration curve on wild type Flt3. Antibodies were detected using an Alexa Fluor 488-conjugated secondary antibody and mean cellular fluorescence was determined using Intellicyt iQue flow cytometry platform (Intellicyt / Sartorius). Normally, mutated residues were identified as being critical to the antibody epitope if they did not support the reactivity of the test antibody but did support the reactivity of a control antibody (BV10A4H2, RRID: AB_10596974). This counterscreen strategy facilitates the exclusion of mutants that are locally misfolded or that have an expression defect. Binding of each antibody to each mutant clone was determined in duplicates. For each point, background fluorescence was subtracted from the raw data, which were then normalized to antibody reactivity with wild type Flt3.The result of the alanine scan is shown in Tables 4a-4d: below. Mean binding reactivities (and ranges) are listed for all identified critical residues.Table 4a:K49A 119.5 8,9 48,0 87,1 117,0 13,6 143.6 32,5 127,5 32,4S50A 115,0 6,0 47.8 89,8 103.3 9,1 96,4 24,4 102.4 0,5S51A 113.5 15,6 97,0 26,0 110.6 32,6 92.7 10,3 106.1 32,1S52A 114,0 4,7 99.6 20,8 120.7 54,8 117,0 12,8 123.7 5,4Y53A 113.2 8,9 93.1 18,5 126.5 9,9 84.2 14,2 119.7 0,9P54A 102.6 7,4 82.1 32,8 109.1 46,0 106.5 20,4 114.5 5,2M55A 105.6 12,5 46.9 87,3 119.5 27,3 96.6 15,8 95.7 21 ,7V56A 103.5 5,4 62,5 109,1 133.3 3,4 79.5 18,7 98.7 46,1S57A 108.4 7,0 115.9 31 ,6 130.2 8,8 140,0 49,9 144.1 3,7E58A 98.1 13,2 144.3 36,4 110.1 6,0 85.9 0,2 125.2 47,5S59A 103.8 12,1 141.4 78,5 138.8 0,3 122,0 4,8 120.9 13,4P60A 102.9 33,9 103.7 44,7 113.6 0,6 99,0 29,4 122.2 37,9E61A 96.1 30,5 94,0 13,7 105.2 1 ,0 76.6 3,0 144,0 9,9D62A 64.5 6,9 4.9 1 ,7 62.5 6,1 56.5 12,6 61.6 29,1L63A 62,7 11 ,8 9.9 7,5 40.7 21 ,5 79.9 30,5 67.9 5,8G64A 106.2 4,3 122.6 20,8 114.5 2,8 95.5 6,2 107.7 8,0C65A 1.1 1 ,4 1.4 0,7 11.3 1 ,2 37.3 31 ,9 8,0 2,3A66S 95.4 12,0 88.7 28,1 100.5 28,6 77.8 6,7 106.6 38,7L67A 113.3 11 ,7 104.7 3,7 136.3 30,1 112.8 22,9 124,0 16,2R68A 62.7 33,4 78.4 11 ,8 100.2 31 ,9 104,0 3,5 73.9 19,0P69A 108.7 18,1 38,8 13,4 94.8 28,9 88,0 38,9 95.7 46,6Q70A 102,0 7,3 76.7 29,7 91 ,0 34,7 55.3 10,4 84.2 6,5S71A 107,6 11 ,4 102.3 20,6 107.3 7,7 101 ,0 43,3 143.1 49,0S72A 100.5 3,9 105.2 9,9 115.6 12,9 44.7 13,4 60,4 2,3G73A 94.1 5,4 72.1 12,2 85,2 8,3 87.4 12,7 105.5 30,4T74A 95.5 21 ,3 98.2 8,0 103.1 11 ,1 108,0 37,2 153.7 11 ,7V75A 1.7 0,7 99.7 28,4 92.1 3,5 87.4 6,6 124,0 2,5Y76A 41.3 10,8 24.5 10,4 35.6 10,7 94.9 15,8 52.7 3,3E77A 14.1 1 ,1 10.3 13,7 101.7 9,4 96.7 61 ,8 115.5 10,0A79S 67.7 13,3 44.4 13,2 61.8 13,3 39.6 19,6 57.9 11 ,3A80S 98.6 0,2 75.6 2,7 101 ,2 48,0 86.1 14,1 113.8 5,8V81A 87.9 3,6 54.3 14,5 89.1 25,2 92.5 36,9 74.3 16,8E82A 94.9 9,4 103.2 41 ,0 108.7 4,2 114.9 48,7 109.7 20,8V83A 82,0 9,7 76.5 29,2 85.7 12,5 83,4 22,4 86.4 0,4D84A 97.6 3,2 66,0 23,2 105.5 4,3 85.9 26,3 101.9 3,4V85A 86,0 32,9 87.7 13,8 136,0 6,3 71.1 11 ,7 118.5 9,8S86A 110.4 37,1 174.2 45,5 89,0 16,3 104,0 45,7 131.1 28,4A87S 109,2 7,5 146,1 104,0 91.5 8,6 101 ,8 7,4 100.8 24,9S88A 88.6 9,2 52,0 3,0 108.1 64,9 43.7 10,0 71.4 35,4I89A 92.9 1 ,2 79.3 0,9 118.7 29,3 111.6 18,6 132,4 1 ,6T90A 77.7 3,7 48.4 1 ,3 77,9 8,5 94,0 59,2 91.5 4,2L91A 1 ,0 1 ,4 0,7 3,2 0,0 1 ,1 33.4 37,5 1 ,0 2,5Q92A 85,6 0,8 81.3 10,3 55.1 32,8 58.1 19,6 60.7 27,6V93A 85.9 9,4 95.8 6,2 97.7 65,2 103.6 65,4 102.2 11 ,1L94A 98,5 8,0 64,0 5,8 45.6 7,2 46.1 1 ,9 69.1 39,4V95A 52,3 13,9 44.6 24,7 34.6 4,0 82,8 13,4 57.3 7,6D96A 105.4 3,8 94.9 8,9 121.8 37,5 80.7 12,8 84.5 0,7A97S 109.5 6,6 101.6 12,1 90.3 40,5 78.8 87,6 114.5 41 ,3G99A 72.8 18,3 58.9 14,1 85.8 11 ,1 62.5 27,0 76,0 69,61101 A 68.1 15,5 48,0 11 ,6 31.2 8,9 71.1 7,7 47.8 30,6C103A 3,0 0,2 17.5 28,0 3,0 1 ,8 31.3 11 ,2 31 ,0 7,2L104A 69.5 2,1 100.6 13,1 135.3 0,5 84.6 13,1 57.5 9,6W105A 52.4 17,3 88.1 6,0 71.9 22,5 99.5 24,4 108,0 8,7V106A 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40,3 115.7 28,8 115.1 11 ,3 78.1 65,0 123,0 19,0N306A 72.8 2,4 33.5 56,2 75.2 21 ,8 61.2 0,3 53.3 7,0R307A 102.3 2,4 58.2 101 ,4 139.6 26,3 77.5 3,3 115,0 60,4T308A 83.8 5,3 91.7 51 ,7 96.4 28,9 55.6 4,2 82.1 3,2M309A 105.1 0,0 90.7 15,4 126.1 41 ,7 94.6 10,6 137,0 32,4131 OA 105.2 1 ,8 102.1 22,7 77.9 38,8 112.9 26,2 67.4 33,4R311A 62.6 3,5 72.7 0,4 69.3 6,1 98.7 34,4 37.6 4,9F314A 28.9 7,7 39.5 5,0 27.6 1 ,4 33.2 3,4 16.1 3,2A315S 47,4 29.7 51 ,6 47.2 21 ,1 71.3 0,2 34.4 5,7F316A 106,0 10,7 84.4 13,5 87.5 27,6 109.6 18,4 121.9 0,4V317A 87,0 0,2 72.2 2,8 91.3 35,9 81.6 12,1 76.6 14,0S318A 118,5 103.9 0,3 121.8 14,7 149,0 66,1 104.6 8,4S319A 103.9 18,6 110.2 17,1 131 ,2 21 ,8 113.8 35,7 124.7 23,1V320A 108.5 0,7 84,3 4,3 113.4 38,5 84.8 20,4 98,0 8,9A321 S 11 1.6 12,2 103.4 35,1 118.8 4,3 103.8 29,7 121.4 34,8R322A 100.9 21 ,6 92,0 26,7 126.6 10,1 82.8 60,9 122.7 14,1D324A 94.3 4,7 139,0 85,8 93.9 12,3 94.8 34,0 121.2 29,7G326A 63,0 13,2 66.7 3,8 78.4 18,4 49.8 9,1 73.4 4,9Y327A 107.1 10,2 72.6 6,1 103.8 6,9 92.5 1 ,3 81.7 8,7T329A 39.5 1 ,2 39.8 0,3 49.1 0,9 37,0 21 ,8 23.4 0,2C330A 6.4 0,0 15.8 1 ,9 23,9 3,5 45.6 4,9 8,8 8,0S331A 116.5 15,7 105.9 1 ,2 149,4 35,0 75.2 11 ,2 83.7 67,3S332A 10.4 6,5 17.1 11 ,8 15.3 7,9 11 ,4 4,4 5.1 3,6S333A 68,0 0,3 72.9 1 ,8 79.8 7,1 66.3 13,8 74.3 7,9S333A 75,0 6,6 55.6 10,0 74,0 24,2 29.2 47,8 38.5 15,1K334A 118.6 16,6 107.7 8,3 128,0 26,0 64.3 8,0 88.1 1 ,8H335A 18.3 4,9 21.2 1 ,0 18.5 10,2 21.6 4,8 12,0 7,2P336A 107.4 7,9 104.8 20,5 115.5 28,6 67.8 17,5 83.7 22,6S337A 96.1 3,6 83.8 2,7 108.3 23,6 112.5 9,1 92.4 10,1S339A 85.6 7,2 78.4 1 ,5 96.6 11 ,7 88.6 13,4 76.9 2,5A340S 55.3 6,5 31.3 20,4 47.5 16,1 76.8 8,4 36.9 10,7L341A 86.2 8,2 59.8 7,7 76.3 15,2 57.8 11 ,6 98.1 6,1V342A 30.8 2,0 30.5 17,9 30.7 13,0 69,0 12,9 22.9 0,8T343A 35.6 1 ,5 34.2 1 ,7 26.7 53,0 40.7 0,3 23,3 0,0I344A 42.1 0,4 53.8 2,3 46.7 36,7 46.8 7,5 15.7 19,2V345A 34.2 7,1 38.8 32,0 36.1 1 ,6 54,0 4,2 17.5 2,8E346A 51.1 4,5 60.2 9,3 81 ,0 22,2 101.8 6,7 68.2 11 ,8G348A 15.7 1 ,5 23.6 14,0 21.8 8,2 58.9 3,4 19.3 15,4F349A 8.3 0,5 17.5 8,6 19,7 5,4 53.1 28,3 6.4 3,6I350A 14.4 2,6 16.7 1 ,9 52.3 66,0 36,0 2,3 8,0 0,7N351A 100.7 20,8 70.7 17,6 105.8 9,6 115.5 20,6 114.5 0,9A352S 70.9 8,6 79,0 6,0 77.3 19,8 74.5 8,6 49.5 13,9T353A 99.3 17,3 77.5 38,5 112.4 23,0 77.9 19,4 82.3 0,4N354A 121.4 9,1 95.3 5,3 133.5 52,2 69.6 13,6 108.5 4,1S355A 100.9 2,6 85.6 5,4 103.6 33,4 119,5 16,4 81.8 30,3S356A 104.6 3,6 84.5 20,5 88,4 25,8 132,0 5,6 101.1 7,5E357A 105.4 1 ,9 92.4 5,5 117.7 17,7 104,4 16,8 113.1 48,0D358A 114.7 19,9 58.9 98,5 118.9 18,9 113.3 6,4 104.1 56,0Y359A 70.6 16,4 26,2 40,1 65.9 13,5 98.9 4,1 13.4 11 ,1E360A 89.2 10,7 56.7 10,4 82.7 12,3 90,0 16,9 72.5 31 ,11361 A 58.6 6,1 61.1 2,1 62.8 9,6 63,0 19,0 50.1 1 ,8D362A 79.9 0,2 56,0 5,9 80,7 3,0 38.9 2,9 36.8 2,1Q363A 101.3 15,4 71.6 15,6 113.3 2,0 116.1 24,1 75.9 13,7Y364A 115.6 3,9 88.7 0,5 101.4 53,4 161.4 53,5 99,8 13,1E365A 73.4 0,7 67.4 8,8 78,5 12,1 114.1 36,6 67.4 12,4E366A 106.6 0,6 94.4 0,4 162.8 18,6 74.4 33,6 119,2 9,7F367A 38,8 12,8 34.2 8,9 54.8 3,7 80.7 5,8 20.6 4,3C368A 5,7 1 ,9 10.5 1 ,8 11.9 5,7 13.1 21 ,7 -5,5 1 ,1F369A 7.5 1 ,2 7.5 0,2 9,5 1 ,5 11.4 11 ,9 -2,3 1 ,0S370A 99,3 6,6 108.5 16,1 89.3 27,9 97.2 27,9 83.6 15,3V371A 29.5 2,0 47.3 1 ,2 41.4 2,4 42.6 14,3 0,7 3,4R372A 108.4 6,0 88,0 4,5 111 ,3 7,7 117.2 20,1 15.8 12,8K374A 53.6 23,9 42.8 62,6 82,8 30,8 71.4 4,8 26.2 41 ,2A375S 55.4 7,1 55.1 8,9 71.1 0,2 56.8 12,8 34.4 12,9Y376A 36.4 3,2 35.5 12,7 42.7 18,8 54.8 1 ,9 21.8 5,0P377A 5.3 0,7 16.6 9,1 19.4 7,6 48,3 16,8 13.4 6,6P377A 7,1 0,0 15.6 2,0 22.2 8,7 27.1 3,3 3,9 4,8Q378A 104,3 16,8 162.3 81 ,4 108.9 8,5 130.4 31 ,9 119.2 17,8I379A 124.8 10,0 128.4 2,0 110.9 16,4 74.7 12,5 143,1 20,9R380A 72.2 7,2 52.2 4,4 87.9 14,2 72.2 9,4 64.2 4,4C381A 6.4 2,6 10.8 1 ,4 22.4 10,7 45.7 6,4 11.4 6,4T382A 101.8 7,1 96.3 38,4 90.8 25,7 92.5 4,3 112.4 55,8W383A 5.5 0,5 10.5 1 ,2 14.2 0,8 24.5 5,1 6.1 4,8T384A 91.9 8,1 79.9 5,8 91.4 21 ,3 95.9 28,8 98.5 16,4F385A 94.9 28,4 100,0 28,9 91.7 31 ,4 118.2 16,7 112.6 8,7S386A 120.5 19,7 87.1 45,6 105.2 7,6 122.8 14,1 151 ,0 49,7R387A 120,0 5,2 85,0 18,6 99,0 6,5 159.3 53,7 78,7 4,9K388A 88.8 20,3 55.6 1 ,2 118.2 23,2 95.2 18,4 87.6 39,7S389A 95.6 29,8 90.8 2,8 159,0 124,8 74.2 9,9 88.7 41 ,5C392A 8.6 1 ,5 15.8 16,1 20.2 1 ,8 33.3 4,3 11.6 2,1E393A 79.6 13,5 72.2 1 ,7 92.5 17,6 83.1 20,3 73.1 1 ,9Q394A 120.8 22,2 97,5 38,9 109.3 3,7 88.2 1 ,5 131.1 18,9G396A 134.8 17,4 112.1 2,5 138.4 8,0 103,0 23,6 150.3 9,0L397A 105.2 0,2 85.8 31 ,8 116.8 5,3 101.9 3,7 96,5 9,5D398A 11 1.2 3,1 104.1 4,5 98.8 6,4 108,0 28,7 102.8 3,3N399A 80.8 6,6 75.9 7,6 89.2 12,2 76.7 29,7 61.4 7,3G400A 48,0 13,7 30.8 0,5 74.7 27,5 48,0 7,4 42,0 8,5Y401A 61.5 16,1 46.8 36,8 69.6 6,3 58.3 23,4 19.8 4,6S402A 102.6 1 ,1 84.7 12,2 129.2 7,9 64.4 30,9 97.5 19,7I403A 49.7 19,0 49.1 17,3 57.5 1 ,1 65.9 27,5 28.4 6,2S404A 94.7 6,7 65.3 27,6 96.5 9,2 82.5 28,4 90.4 56,1K405A 71.2 3,9 68.3 14,9 77.7 7,8 70,4 13,5 62.7 2,4F406A 6,6 1 ,3 15,0 9,3 18,0 5,4 12.6 11 ,3 5,1 0,3C407A 5.2 0,7 20.4 3,2 19.8 9,9 38.1 1 ,1 18,0 12,3N408A 90.7 4,2 77.4 32,4 83,3 31 ,8 86.2 22,6 69.3 4,9H409A 20.7 4,0 J,1 HA 24.2 17,3 56.6 19,1 16.5 4,3K410A 93,9 1 ,5 86.8 2,6 73.1 5,1 53.1 4,3 78.2 11 ,1H411A 46,0 10,3 50.6 3,6 55,6 J,1 56.3 0,0 41 ,7 22,3Q412A 86.3 17,0 79.4 4,5 73.5 19,9 104.6 12,6 76.3 2,4P413A 95.1 2,8 90,0 37,5 110.8 68,5 92.5 5,8 99.2 23,5G414A 9.3 3,4 16.6 2,5 15,0 3,1 23,0 11 ,1 1 ,0 1 ,8E415A 99.1 0,2 95.7 3,9 144.5 3,8 53.7 20,7 92.2 37,9Y416A 57.7 21 ,5 45.4 19,3 59.2 0,7 92,9 19,9 46.1 15,71417A 74.6 4,2 73.9 12,7 74.3 15,5 76.2 26,5 82.4 16,8F418A 10.6 3,8 15.5 14,7 21.2 5,4 30.5 39,4 3,8 0,9A420S 17.2 0,0 29,0 19,5 30.5 6,6 41.4 2,1 17.6 10,2E421A 79.2 9,9 60.1 2,4 94.3 9,3 51.8 12,0 94.2 10,2N422A 19.6 2,6 21.6 12,9 28,0 3,5 40.1 1 ,7 13.7 7,6D423A 91.8 10,0 136,0 73,5 106.5 12,9 60.1 3,1 95.2 8,1D424A 50.8 9,7 42.8 30,7 58.2 7,8 66.8 1 ,8 23.7 17,7Q426A 104.8 28,5 70.9 3,5 106.6 9,0 107.6 13,5 96.5 17,5F427A 12,0 2,8 18.6 6,4 35.4 7,1 61.5 0,4 9,0 2,1T428A 54.1 4,2 68,8 9,9 63.5 2,7 68.8 10,2 49.1 9,6K429A 59.4 16,3 73.4 49,9 76.4 6,5 69.8 4,5 6.5 0,3M430A 117.4 8,6 100.4 20,4 97,0 1 ,9 87.1 42,3 130.5 7,3F431A 7.6 1 ,1 17.6 13,2 16.2 6,9 30,0 7,7 3,0 3,7T432A 41.7 1 ,8 48.2 1 ,4 56.6 18,3 54,8 42,0 8,1L433A 13,0 7,3 20,0 21 ,1 24.8 3,4 58.2 15,5 10.3 1 ,1N434A 100.2 2,6 93.7 5,5 95.6 4,3 93.2 4,1 123.5 11 ,1I435A 20.2 3,8 21.5 9,3 25.4 8,8 39,0 20,3 15.8 1 ,4R436A 28.3 7,9 24.4 6,5 36.6 8,3 66,7 27,1 13.9 1 ,7R437A 91.8 15,3 38.3 61 ,4 99.9 8,5 64.6 28,6 90.3 13,3K438A 102.5 0,8 124.4 68,7 114.1 10,3 125.8 30,9 102.6 0,5P439A 11 ,0 1 ,9 19.8 15,6 23.2 5,0 38.8 5,6 13.2 1 ,8V441A 30.4 4,2 19.5 2,3 79.3 85,5 25.3 2,1 15.2 0,8L442A 115.6 20,0 109.5 0,7 121.1 6,7 154.8 9,3 101.6 25,9A443S 93.4 21 ,6 59.7 8,6 84.4 27,5 67.8 11 ,2 55,8 1 ,7E444A 72.4 8,7 74.6 6,3 97.9 6,0 44.2 30,8 63.1 10,5A445S 108,3 10,7 11 1.4 22,4 116,8 20,8 84.2 0,7 89,7 11 ,5S446A 93.7 1 ,5 78.3 2,9 104.4 10,5 59.6 7,9 88.4 2,1A447S 114.1 9,9 93.6 20,1 95.3 20,3 99,0 10,5 129,3 8,6S448A 102,9 0,1 83.6 36,2 108.1 11 ,1 81.1 4,8 91.5 13,7Q449A 108.8 6,5 96,2 23,0 111.3 10,6 113,0 2,2 115.9 15,8A450S 46.7 5,6 52.8 19,7 59.9 10,0 36.2 8,1 44.2 18,3S451A 102,5 0,5 105.4 0,3 123.6 21 ,6 108,1 18,7 107.6 48,0C452A 6.2 1 ,1 16.5 4,9 23.2 0,0 I ,2 14,0 4.5 3,9F453A 70.8 6,0 61.3 24,1 90,4 19,5 25.4 5,0 85,0 33,4S454A 101.8 7,7 92.5 15,9 100.5 1 ,4 120.2 16,1 129.1 46,3D455A 97.2 5,0 90.5 8,5 79,7 21 ,4 99,3 1 ,9 84.4 4,2G456A 102.5 14,7 84.5 30,8 103.8 11 ,5 140.4 15,0 81.8 16,2Y457A 27.1 5,8 23.5 12,8 34.3 10,6 23.4 13,3 18.9 2,1P458A 5.3 1 ,0 13.6 7,4 16.2 4,1 I I ,5 7,6 11 ,6 0,1L459A 125.2 3,9 126.8 1 ,5 126.6 3,1 56.2 1 ,7 100.2 2,1P460A 76.2 7,7 64.4 26,3 105.7 50,7 61.6 11 ,1 88,0 12,4S461A 107.6 7,2 96.1 8,5 108,0 26,8 82.1 15,8 11 1.3 45,1W462A 6.4 1 ,4 12.3 7,0 25,5 12,2 22.4 20,2 9.7 5,7T463A 96.1 3,3 82.8 6,9 114,0 1 ,6 101.5 52,0 87.1 5,3W464A 5.5 1 ,2 16.2 1 ,5 45.1 54,4 17.6 28,3 9.5 3,5K465A 100.5 14,7 124.3 18,1 135,4 32,3 70.5 9,4 76.7 15,2K466A 101.8 3,3 50.2 16,1 69.8 19,8 77.5 39,5 96.7 26,2C467A 18.4 1 ,4 29.7 0,5 32.9 7,8 10,0 7,1 13.7 5,5S468A 103.6 21 ,4 57.2 87,1 116,0 12,3 77.9 15,3 121.3 4,2D469A 107.9 13,3 56.1 92,3 128.2 60,7 97.9 19,1 99,6 11 ,2K470A 114.9 18,9 75.5 3,4 161 ,0 27,0 77.6 18,2 127.1 7,2S471A 98.6 5,7 32.2 64,1 107.1 4,3 78.5 7,9 73.4 17,2P472A 101.9 12,6 117.6 3,3 133,0 33,1 76.9 0,9 86.2 62,9N473A 78.1 0,1 84.4 4,2 92.7 3,4 65.5 24,6 54.4 0,9C474A 17.3 0,7 21.9 10,7 25.1 6,9 19.1 33,3 3.9 0,0T475A 71.9 7,0 36.8 53,3 90.1 20,6 63.1 24,8 83,0 18,4E476A 78,0 0,1 24.6 30,4 90.3 23,4 40.3 9,9 73.2 0,5E477A 85.9 8,7 46.2 74,3 101.1 7,0 78.6 10,8 73.8 25,6I478A 9.2 4,5 16.9 9,5 17.3 2,0 20.2 6,7 20,0 13,8T479A 88.3 17,5 43.5 66,5 79.1 4,6 42.6 18,3 95.8 10,4E480A 99.2 11 ,5 46.5 87,2 108.3 18,7 65.3 11 ,3 91.5 42,2G481A 68.6 9,6 61.9 8,0 72.3 18,7 21.6 41 ,1 62.1 0,5V482A 52.3 4,4 55.5 20,4 59.3 8,4 25.1 7,0 36.8 15,3W483A 106.7 10,0 51.4 80,2 123.7 33,1 157.3 11 ,2 113.8 21 ,6N484A 109,0 3,3 45.3 78,1 106,0 4,9 65.7 4,1 86,0 10,5R485A 107.4 4,9 62,1 7,2 140.9 58,8 34.5 24,1 92.8 85,3A487S 108.7 1 ,5 48.5 88,3 113.2 39,9 162,6 34,3 100.9 41 ,6N488A 68,5 12,6 44.6 73,7 100.6 5,6 10.3 6,9 74.8 35,9R489A 118,1 22,0 11 1.6 2,9 111.2 13,9 13.5 28,3 104.9 20,9K490A 112,0 11 ,6 102.6 34,9 100.7 27,0 119.1 22,3 86.5 24,4V491A 119.9 1 ,5 128,0 16,7 122.8 14,2 52.7 7,0 115.5 34,8F492A 11 1 ,4 22,1 127.5 7,9 169.8 38,9 33.7 0,5 128,1 21 ,7G493A 83.5 19,0 86.5 39,4 103.9 1 ,0 41.8 15,2 98.3 0,5Q494A 90.8 3,4 98,4 2,5 94,7 40,4 70.9 2,9 104.3 8,6W495A 89.2 8,3 67.9 15,5 91.2 5,3 23.7 15,1 81 ,0 28,6V496A 96.3 6,9 112,0 54,9 137.5 29,0 76.1 33,6 122,0 2,3S497A 83.9 5,3 63,7 28,3 89.1 21 ,9 26.8 9,9 66,0 27,4S498A 117.1 28,5 103.6 23,8 128.6 0,3 139,2 12,8 98.5 2,3S499A 12.9 5,7 14,0 2,2 13.6 13,6 4,7 11 ,0 11.9 1 ,9T500A 78.8 11 ,0 66.3 1 ,0 87.6 4,3 56.6 5,6 76.2 18,9L501A 6.8 0,0 21.6 6,0 22.3 5,0 20.9 8,9 9.7 0,2N502A 64.6 12,9 75.3 31 ,4 84.6 9,4 26.1 8,6 94.3 11 ,1M503A 97.5 11 ,8 99.2 4,7 142.2 57,6 51.3 11 ,5 100,0 37,4S504A 29.9 11 ,3 35.1 12,3 42.5 6,7 39.9 18,2 42.7 4,0E505A 68.3 5,8 108.2 28,0 110.9 29,2 76.9 1 ,0 90.5 50,9A506S 120,7 22,9 115,0 1 ,2 115.3 13,6 114,4 19,6 104.9 2,5I507A 90.4 10,7 30.1 60,5 96.6 11 ,6 45.5 7,7 71 ,0 18,9K508A 63.1 4,4 79,3 18,2 113,8 0,7 80.1 12,2 87.9 32,0G509A 41.4 1 ,3 41.2 12,5 88.6 40,8 18.7 0,1 19.5 7,5F510A 94.4 4,0 104,7 0,1 151.3 36,0 75.3 25,6 129.7 23,0L511A 120,2 22,0 88.9 7,1 109.3 21 ,1 135.3 25,5 119.8 3,6V512A 27,3 0,9 20.6 12,3 35.3 2,8 22.1 10,7 43.7 0,9K513A 91.6 10,2 55.7 79,5 107.1 7,7 49.6 2,2 110.8 8,2C514A 5.1 1 ,4 13.9 9,7 20.9 4,2 31.8 14,5 18.8 6,8C515A 5,5 0,6 20.7 4,0 23.1 8,2 20.2 3,3 25.9 21 ,0A516S 10,0 1 ,6 26.3 6,4 24,0 8,1 22.2 3,8 13.3 3,2N518A 5.4 1 ,9 18.9 18,3 20.9 5,0 26.1 5,4 12.7 9,9L520A 108.9 7,0 70,0 1 ,3 124,0 14,9 98.7 10,7 77.2 18,8G521A 36.1 3,0 41 ,1 8,0 46.1 1 ,0 20,6 2,0 15,0 5,4T522A 94.4 3,2 74.7 1 ,4 121.6 9,2 74.5 47,4 113.2 6,7S523A 100.5 4,9 11 1.3 40,6 137.3 38,5 76.2 21 ,5 121.8 61 ,0C524A 6.7 2,0 15.3 11 ,0 15.7 11 ,5 9.2 6,5 15.8 9,1E525A 98.9 15,4 116,4 8,7 108.9 11 ,2 100.8 14,4 121 ,9 19,7T526A 97.9 6,9 58.5 20,5 94,0 8,6 80,0 0,6 89.8 4,8I527A 38,0 10,9 24.6 14,9 32,0 2,6 34,0 8,1 35.3 1 ,7L528A 109,0 5,1 91.3 11 ,8 109.1 6,3 108.8 52,4 101.5 37,2L529A 94,0 3,1 60.5 12,2 169.7 36,4 59.6 41 ,5 74.8 26,0N530A 107.6 1 ,2 90.6 2,0 120,0 17,2 66.7 27,1 88.8 19,0S531A 89.7 4,4 104,2 39,0 134.4 71 ,8 97,3 45,9 113.3 44,7P532A 122,0 29,5 75.6 6,4 92,5 11 ,4 58,6 10,4 60.5 4,9Table 4b:S51A 93.8 13,1 76.6 25,8 99.5 37,8 65.4 19,3 114,9 29,7S52A 103.5 9,1 81 ,4 35,2 100.5 21 ,0 70.5 1 ,3 135.1 0,6Y53A 100.1 28,6 111.9 38,1 102,0 15,8 114.1 13,0 112.4 2,3P54A 109.5 4,1 79.3 28,8 102.3 20,1 90.1 28,1 98.1 13,7M55A 92.5 13,9 116.6 7,3 110.7 14,7 91.5 11 ,3 101 ,0 12,8V56A 114.7 7,8 106.9 16,6 80.1 21 ,1 108.7 2,3 114.9 49,3S57A 92.8 24,5 97.3 1 ,0 99.7 2,8 114,0 14,9 144.9 1 ,5E58A 103.7 10,2 92.6 3,0 112.7 9,3 110.2 35,4 96.1 5,2S59A 103.6 46,0 134.7 38,0 140.7 13,6 106.8 22,5 145.4 54,8P60A 113.7 29,7 89.2 10,9 105.6 1 ,0 82,0 61 ,9 131.7 7,4E61A 85.5 22,7 77,0 0,6 125.4 2,6 90,3 20,1 100.7 27,3D62A 7.6 0,6 46.4 8,5 3.7 2,3 69,9 13,6 35.6 2,0L63A 15.1 31 ,9 4,7 15,1 57,0 10,0 49.1 10,5 26,5 15,7G64A 106.4 9,9 130.7 36,4 122.4 21 ,0 104,7 25,4 114.9 41 ,5C65A 0,1 0,1 5.6 1 ,1 -0,6 2,6 15.2 1 ,5 4.4 7,4A66S 96.1 12,5 79.3 5,3 101.3 24,9 124.4 42,0 98.4 9,6L67A 93.6 43,8 83.5 33,0 97.7 4,6 93.2 12,4 105.8 37,4R68A 77.9 8,0 55,0 18,3 108.4 2,5 82.5 40,0 114.9 23,3P69A 77.4 14,3 69.1 23,6 98,9 10,4 85.5 8,3 66,0 5,2Q70A 72.8 1 ,6 84.2 5,8 82.1 10,9 77.4 14,2 65.7 32,1S71A 115.5 32,0 74.2 15,8 67.8 0,6 68.5 18,1 100.1 14,9S72A 90.2 11 ,1 82.1 21 ,7 90.3 0,2 92.8 3,5 130,0 7,4G73A 102.5 48,6 85.5 17,5 67.2 7,9 90.3 3,3 112.4 6,9T74A 120.7 9,9 95.5 17,5 100.2 0,8 95.9 0,8 126.1 4,4V75A 81.6 45,3 80.5 7,2 69.2 8,4 88,0 25,3 137,0 30,7Y76A 17.7 1 ,7 13.1 4,4 29.4 8,7 48.6 9,8 55.4 1 ,9E77A 44.4 5,6 18,0 14,9 54.6 21 ,8 80.7 11 ,3 2,2 4,3A79S 23.9 8,6 44.7 21 ,0 72.2 0,1 61.2 11 ,3 66.5 25,0A80S 96.2 1 ,2 105.5 0,2 72.7 1 ,8 101.2 3,8 51.1 2,9V81A 41.5 6,7 59.3 16,7 74.4 11 ,3 99.4 6,8 72.3 10,9E82A 88.5 7,6 57.7 9,6 122.3 3,7 104,0 24,8 97.9 4,3V83A 81.7 20,0 58.2 17,9 81.4 19,5 65.8 2,8 91.3 8,3D84A 81.6 5,2 81.8 17,8 96.7 21 ,5 91 ,0 3,7 100.9 4,1V85A 83,0 16,8 105.2 2,9 83.5 4,8 119,5 0,6 124.4 17,0S86A 109,4 29,3 96,0 25,8 115,6 41 ,5 102.9 33,9 90.4 45,7A87S 102.9 32,1 99.9 2,1 109.4 19,3 75,7 48,2 140,2 74,7S88A 63,1 1 ,1 104,7 2,8 75.7 9,0 96.3 2,3 65.6 33,7I89A 90.9 24,1 69.9 1 ,6 106.5 13,8 84.4 35,2 96.9 7,0T90A 84.8 10,0 64,3 14,4 59.8 3,2 67.2 30,7 50.5 1 ,2L91A 8,0 2,0 7,4 4,8 -0,1 0,5 14.9 0,1 -2,8 1 ,2Q92A 79.9 22,1 89.8 52,2 77.9 32,6 91.4 21 ,6 72.3 33,3V93A 85.4 5,4 80.8 5,5 91.7 12,6 99.6 2,7 104.8 38,5L94A 56,0 10,4 101 ,3 2,6 88.1 5,6 105.9 13,4 80.6 14,1V95A 48.9 17,8 69.2 25,9 64,0 4,2 56.7 4,3 81.3 28,9D96A 91.7 3,6 123.1 14,4 70.8 2,9 99.5 23,5 107,0 12,3A97S 118.2 16,7 97.8 7,1 106.9 30,6 67.8 22,6 123.1 5,4G99A 95.2 39,0 68.9 28,0 94.2 38,3 72.3 4,2 94.6 22,21101 A 27,0 31 ,8 68.1 25,0 72,0 7,0 65.3 29,3 77.1 11 ,3C103A 2.4 1 ,8 5.1 1 ,8 15.1 16,8 33.2 0,8 11.8 3,2L104A 88.5 3,8 104.9 12,6 87.2 2,7 95.4 15,6 144.5 20,2W105A 89.8 22,6 89,7 28,3 82.5 13,9 76.2 17,4 94.5 25,4V106A 87,0 5,4 104.6 6,7 116.4 2,3 107.4 10,7 99.7 24,1F107A 44.5 0,6 50.1 3,4 44.1 4,2 61.7 9,3 44,0 6,6K108A 91.6 31 ,1 94.3 21 ,1 95.6 29,7 50.2 2,1 108.9 15,2H109A 119.7 5,5 110.5 2,9 113.4 4,7 114.9 70,0 128.7 54,3S111A 96.4 23,9 85.3 24,5 90.9 39,5 100.2 25,7 128.6 6,2L1 12A 114.1 5,5 74.6 1 ,0 90.9 28,7 85.8 3,7 122.1 16,1N113A 114.7 29,5 84.3 3,1 83,0 13,0 80.4 28,5 88.9 11 ,6C114A 6,0 15,1 7,0 4,6 12.3 4,0 21 ,0 7,0 7,1 11 ,0Q1 15A 69.4 11 ,7 65.1 8,1 64.4 11 ,6 75,0 8,1 97.2 12,6P116A 44.7 6,4 58.2 5,7 51.9 4,7 55.7 2,0 47.5 31 ,3H117A 107.2 26,6 91.3 11 ,6 104.1 13,6 106.2 1 ,9 127.7 19,7F1 18A 90.1 38,1 74.3 1 ,0 87.9 33,2 55.3 1 ,9 101.2 10,6D1 19A 80.1 3,2 70.1 24,6 65.7 9,7 66.3 6,6 77.2 7,9L120A 116.6 47,7 110.1 10,3 127.5 34,1 90.4 14,8 132.1 11 ,4Q121A 101.9 28,6 89,2 10,0 96.7 24,8 74.2 3,8 133.5 18,0N122A 101.9 22,0 89.7 9,0 105.3 31 ,9 95.8 4,8 121.2 7,0R123A 49.9 8,3 33.9 12,1 48.6 12,3 40.8 9,7 53,1 10,0G124A 114.8 1 ,8 110.1 4,9 97.8 22,3 95.3 0,4 97.7 28,3V125A 61.8 11 ,4 62.7 12,5 76,2 12,7 66.7 12,0 99.4 20,3V126A 70.1 11 ,0 82.8 1 ,7 78.9 3,6 59.9 6,4 126.8 18,1S127A 80.7 21 ,4 83.1 2,8 106,8 7,5 59.3 22,2 100.5 70,6M128A 39.6 7,3 47.6 4,9 36.7 8,4 39,0 0,6 53.5 12,1V129A 127.2 13,0 95.5 18,9 97.9 11 ,8 95.3 6,2 99.9 21 ,2I130A 50.8 27,1 49.7 5,7 40.5 11 ,9 58.8 17,4 44.5 26,5L131A 116.6 17,9 91.9 37,7 114.3 47,8 113,2 17,3 121.9 52,0K132A 100.2 3,8 102,8 13,7 96.7 5,3 56.6 2,3 122.2 29,1M133A 123,0 16,8 86.5 12,7 103.4 11 ,9 106.9 10,5 143.8 54,2T134A 103.5 30,5 108,7 2,0 11 1.5 27,4 74.1 8,3 132.9 5,5E135A 106,7 13,0 99.8 1 ,4 113.8 30,9 97,4 52,5 117.7 18,2T136A 134.4 41 ,0 115.1 7,5 142,1 2,3 108.7 46,7 131.3 24,4Q137A 93,9 15,1 102.2 0,5 86.2 9,6 107,2 2,4 11 1 ,2 13,0A138S 84.8 8,8 107,6 9,2 102.4 22,8 81.9 41 ,1 131.4 8,2G139A 9.8 11 ,7 4.5 1 ,7 3.2 0,1 16.7 0,1 6,8 2,6E140A 83.9 30,0 73.5 6,4 74.8 27,2 75.6 54,2 142,0 9,1Y141A 28.2 40,9 12.5 0,8 1 ,6 2,3 19.3 10,7 5,2 1 ,4L142A 118.6 25,1 93.9 7,2 72,0 33,9 91.6 19,7 86.5 7,7L143A 128.6 24,4 109,0 60,1 85.5 12,2 58.4 13,3 118.1 17,5F144A 100.7 37,9 92.8 2,9 64.6 1 ,6 79.3 5,7 129.1 3,6I145A 29.6 11 ,4 36.2 0,2 34.5 0,2 51 ,0 4,9 19.7 20,2Q146A 72.6 0,3 74.2 29,8 108.6 6,9 68.7 32,6 107,0 0,7S147A 107.2 14,0 82.5 10,5 83,7 11 ,0 86.5 48,1 101.9 7,6A149S 124.2 12,3 98.5 3,0 103.2 0,8 90.1 29,5 119.7 51 ,0N151A 92.9 18,8 87.3 14,3 92.5 8,4 75.1 13,5 11 1.7 40,3Y152A 93.1 39,2 91.6 17,7 98.4 7,1 90.7 40,5 113.5 17,3T153A 51.4 47,7 64.6 10,4 65,0 16,3 54.9 14,1 71.6 18,9I154A 42.8 2,0 38,0 12,8 60.4 15,8 55.5 9,2 61 ,0 8,4L155A 96.4 1 ,5 93.9 25,3 69.2 28,5 108.5 1 ,1 109.4 12,0F156A 20.5 24,0 -2,8 6,0 5,0 8,5 19.2 7,1 8,4 9,2T157A 68.4 23,7 71.6 2,1 88.6 36,0 77.1 13,1 106.7 61 ,4V158A 38.1 31 ,4 43.8 8,4 32,1 3,2 36.1 7,6 30.6 1 ,5S159A 123.3 3,4 106,0 0,9 108.8 19,5 98.8 44,0 143.6 17,9I160A 76.7 21 ,1 102.2 18,5 86.8 15,6 80,0 27,3 113.4 11 ,7R161A 71.1 38,5 81.6 20,0 83.8 4,0 80.5 64,8 11 1.4 20,2N162A 96.4 16,5 99.2 9,6 112.5 9,3 95.8 2,9 100,0 18,9T163A 102.9 12,9 103.8 6,5 110.4 15,7 88.4 33,9 145.1 13,8L164A 127.1 9,3 96.3 0,9 115,9 28,8 84.7 1 ,7 132.8 9,1L165A 11 1.5 3,3 114,0 52,1 133.8 34,2 91.8 14,3 11 1.1 6,9Y166A 132.8 44,7 77.7 36,1 100.4 46,5 93.6 8,2 131.2 11 ,4T167A 98.9 12,4 84,0 19,1 96.5 13,0 86.2 5,9 130.7 0,5L168A 67.9 25,7 67.1 4,5 59.6 2,9 57.2 33,3 80.1 35,8R170A 100.3 19,2 92.5 33,5 110,3 20,7 105.2 0,1 100.2 10,9P171A 14.9 12,1 27,9 0,5 20.4 0,1 8.2 1 ,7 32.1 2,1Y172A 62.3 1 ,9 70,0 0,0 55.8 16,7 63,0 2,4 15.7 1 ,7F173A 9,1 2,3 3,4 1 ,7 1.8 3,7 -1 ,1 7,6 10.2 5,9 174A 101.7 13,7 81.6 24,8 109,0 10,6 104.8 11 ,1 108,6 9,1K175A 58.9 4,5 70.2 4,7 61.6 1 ,1 49.2 6,7 22.9 0,1G280A 94,6 8,2 135.3 44,2 134.6 13,9 124.5 52,2 137.8 27,9G282A 117.9 5,0 119.6 13,1 107.7 24,3 103,0 32,9 128.8 15,1L283A 7,0 1 ,5 16.4 0,5 7,5 0,3 2,6 0,8 -3,9 0,3T284A 104.3 21 ,0 103.1 1 ,7 84.7 26,2 105.8 31 ,9 97,6 4,4W285A 51.1 11 ,6 81.9 11 ,0 55,6 13,7 72.5 20,5 47.3 5,0E288A 93.2 21 ,3 81.8 8,2 92.3 9,6 66,0 18,3 70.3 57,6K290A 69.9 27,4 102.9 0,9 86.8 1 ,6 92.7 35,4 105,0 16,4A291 S 123.5 47,0 120.6 14,8 126.1 0,0 90.5 25,7 95.4 19,2L292A 79.9 39,5 80.6 12,5 90.9 1 ,8 67.6 37,6 88.3 11 ,0E293A 120.9 10,1 90.8 2,3 119.5 1 ,5 119.9 22,3 119.8 34,2E294A 105.4 1 ,0 107.1 21 ,5 109.6 10,5 90.1 36,4 127.7 8,8G295A 104.6 23,8 108.3 18,4 97.3 8,2 100.1 11 ,4 107,0 26,3N296A 84.4 20,2 86.7 11 ,8 88.1 18,0 83.8 7,8 89.7 24,7Y297A 117.9 23,5 106.8 22,9 97.1 6,5 87.7 20,1 104.3 9,8F298A 27.9 5,4 51.3 12,4 37.8 3,4 29.3 5,3 51 ,2 14,3S301A 91.8 48,6 108,0 7,8 113.3 26,3 85,5 12,0 128.3 20,7T302A 114.1 32,4 97.6 9,3 128,0 28,0 104.3 39,4 127.5 35,0Y303A 70.5 5,5 100.6 4,1 88.8 3,3 108.7 14,0 90.8 5,0S304A 101.6 13,6 89.2 3,6 113.9 32,4 83.4 2,0 110.1 18,9T305A 11 1.6 8,6 103,0 12,1 101 ,2 24,6 94.1 16,8 104,0 9,1N306A 65.6 16,1 81.6 5,4 68.7 9,2 45.7 6,0 85.5 5,3R307A 117.1 4,2 106,8 17,2 98.1 6,8 85.5 1 ,2 130.1 15,2T308A 69.4 2,4 77,0 22,3 96.8 3,0 94,0 10,9 94,0 5,7M309A 81.5 20,5 108.7 9,0 105.8 4,6 117.8 21 ,6 104.2 20,2131 OA 79.1 23,7 104,0 1 ,1 102.8 26,4 80.2 6,7 153,0 17,7R311A 56.9 1 ,7 53.5 6,7 65,0 6,1 51.6 6,2 16.8 1 ,1F314A 35,0 12,7 52,0 6,7 45.2 10,8 24.7 5,6 40.2 7,3A315S 46,4 29,8 52,9 14,0 49.7 0,2 42,0 8,9 71.1 4,4F316A 93.9 31 ,5 74.3 17,4 100.4 43,6 90,9 1 ,0 119.1 17,4V317A 71.3 14,0 68.1 1 ,0 92.5 21 ,0 81.5 17,7 114.7 13,8S318A 98.9 25,2 91.4 29,6 103.4 2,4 96.2 13,2 155.6 44,9S319A 115,2 31 ,8 122.4 23,2 117.7 37,3 99.2 2,1 109.1 24,3V320A 94.1 11 ,5 112.7 3,0 109.7 14,8 128.5 2,8 90.1 9,5A321 S 134,7 20,2 118.6 23,0 11 1 ,1 21 ,2 113.7 28,5 136.8 18,7R322A 99.4 47,0 107,2 21 ,1 11 1.4 4,4 92.4 46,4 127.5 19,1D324A 118.9 10,1 82.1 11 ,6 93.6 15,3 82.2 9,7 151.7 14,5G326A 56.1 23,1 89.6 13,0 84,5 25,5 49.5 0,8 87.4 31 ,5Y327A 101.4 5,4 95.7 16,5 83,0 12,1 85.1 8,8 120.5 9,2T329A 49,0 18,3 65.2 22,4 33,0 21 ,0 39.2 2,1 65.4 26,6C330A 22,0 24,8 23.7 4,9 17.1 6,8 -4,8 4,6 24.6 6,5S331A 90.5 10,1 104.5 5,7 114.1 11 ,4 120,0 10,4 11 1.8 3,3S332A 15,0 1 ,8 24.3 13,6 12,0 1 ,0 9,2 3,9 19.8 6,6S333A 80.6 13,6 64.5 0,6 65.3 2,1 52.4 31 ,9 79.7 8,5S333A 21 ,8 31 ,6 89.8 0,6 75.3 13,5 73.6 6,4 88.3 0,0K334A 68.5 8,0 115.3 47,0 106,4 21 ,7 115,0 9,0 115,0 35,5H335A 21.7 7,5 31.4 23,5 31.7 2,0 18,9 4,3 34.8 1 ,6P336A 84,0 0,7 105.8 13,2 99.7 3,0 95.8 1 ,1 125.9 16,1S337A 85.6 1 ,5 96.6 11 ,8 90.8 6,2 78.5 12,9 127.2 9,6S339A 75.5 6,5 90.9 23,6 83.1 27,4 72,0 51 ,3 117,6 54,1A340S 52.1 8,8 48.4 12,6 53,0 10,0 37,0 5,5 65.4 24,1L341A 104.5 14,7 87.4 32,1 91.3 36,3 57.5 18,6 90.5 6,5V342A 28.2 8,4 34,0 5,7 39.4 18,7 20.6 3,4 42.7 24,3T343A 41 ,6 16,6 41.9 9,0 56.6 12,2 27.1 9,5 67.2 3,3I344A 40.3 12,6 44,0 1 ,3 54.5 1 ,4 34.2 3,5 26.4 8,4V345A 37.5 13,6 60.8 4,5 44.3 1 ,8 35.2 16,1 56.2 15,9E346A 50.1 5,6 75.7 8,1 73.7 21 ,5 56.1 20,5 63.1 10,1G348A 26.2 12,3 42.8 22,8 29.4 3,5 9.1 3,8 41.1 29,9F349A 12.8 9,6 22.3 5,3 21.4 1 ,3 1.3 4,7 18.8 1 ,7I350A 23.2 21 ,9 24.4 1 ,5 16.3 3,3 3.4 2,3 37,7 16,1N351A 114.7 2,5 98,0 20,9 92.5 4,6 70.2 46,2 11 1 ,0 56,7A352S 63.2 7,8 68.3 23,1 69.7 37,0 60.8 37,5 97.6 8,7T353A 74.4 34,5 93.2 7,1 119.3 12,3 85.6 42,9 126.9 0,9N354A 101.9 15,8 112.3 15,6 110,2 1 ,8 128,0 0,0 137.9 36,3S355A 88.9 27,4 95.2 32,1 91.9 24,4 62.3 20,0 116.3 33,4S356A 89.6 9,2 82.3 26,6 102.1 1 ,5 91.4 1 ,1 120.3 0,6E357A 97.4 0,6 110.1 24,1 85,0 12,2 86.2 29,2 125.8 17,8D358A 110.8 16,0 113,4 10,5 118.2 17,9 79.3 2,6 147.3 24,0Y359A 61.5 30,9 69.9 1 ,0 65.8 0,3 16,0 0,8 104.3 5,6E360A 82.1 17,0 85.1 9,9 108.2 20,7 45.9 2,7 126.9 6,11361 A 41.1 13,9 50.7 2,0 47.7 5,6 31.9 4,0 41.4 0,5D362A 57.7 10,7 75.3 9,7 71.3 0,4 54.6 4,6 73.7 12,3Q363A 71.9 3,1 107.9 18,2 128,6 5,6 98.3 2,4 123,0 4,0Y364A 94,0 22,2 116.9 1 ,3 92.8 12,4 62.2 6,2 134.9 37,7E365A 73.1 11 ,8 87.7 19,0 86.3 49,3 71.7 5,1 119.1 21 ,1E366A 77.4 6,2 91.2 8,7 81.8 18,1 100.7 6,5 101.3 1 ,9F367A 35.4 1 ,6 67.9 22,9 47.2 4,7 32.3 30,6 60,2 1 ,5C368A 8.4 5,1 17,6 1 ,3 8,7 2,9 6.6 0,7 -0,9 10,0F369A 9.5 3,3 16,1 1 ,1 10.9 5,8 4.3 1 ,0 -1 ,0 3,4Q412A 76,9 10,1 90,6 16,3 91.4 24,0 61.3 27,4 91.7 18,6P413A 89.4 2,8 94.5 24,7 86.7 19,2 82,9 31 ,5 93.1 31 ,6G414A 13.8 10,3 17.4 5,4 16.5 1 ,5 -4,1 1 ,1 21.9 7,9E415A 84.5 11 ,9 99,8 3,1 91 ,0 14,8 100.3 6,1 83.2 31 ,0Y416A 56,0 19,5 65,0 9,8 70.7 14,1 46.8 20,4 67.7 18,31417A 82.7 33,8 69.2 0,6 79.4 12,0 60.5 13,3 101.6 14,2F418A 11 ,3 13,2 13.6 5,9 15.7 3,1 0,6 14,1 22,5 0,0A420S 40.9 31 ,8 36.6 10,7 28.2 6,4 14.5 4,4 34.9 13,5E421A 105.5 26,2 81.2 5,5 95.7 27,9 63.8 13,5 96.2 1 ,7N422A 29.9 6,4 38,0 12,7 24.1 3,4 4.8 5,7 36.1 9,6D423A 83.8 0,9 87,0 13,8 110.9 24,9 86.1 27,8 120.6 7,0D424A 61.6 39,3 76,0 10,4 49,0 9,6 33.6 15,2 76.4 10,1Q426A 112.4 32,0 90,0 5,1 77.5 7,7 57.1 20,2 106.2 12,6F427A 17.4 15,9 35.2 1 ,7 17.5 11 ,0 1.7 2,0 26,0 0,0T428A 50,0 16,7 60.7 20,6 59.9 0,8 57,4 40,4 81.7 30,8K429A 56.9 0,7 78.5 2,9 69.3 7,9 12.7 24,6 125.8 18,3M430A 94.8 38,4 117.1 8,8 106.8 24,9 109.5 18,0 115.1 22,4F431A 6.6 14,8 17.4 0,8 23.2 15,6 -0,6 6,3 26.8 15,7T432A 56.5 36,3 52.2 16,9 70.1 19,4 53.5 16,3 68.5 30,3L433A 28.8 5,3 28.5 12,9 22.3 4,2 3.9 7,6 34.4 7,4N434A 98.1 30,9 89.2 11 ,2 91 ,0 9,0 83.6 2,2 112.9 15,5I435A 22.9 4,0 25.8 5,1 28.9 2,4 11.9 8,3 33.3 3,3R436A 25.4 5,3 35.4 7,1 30.6 3,9 15,0 15,2 56.9 5,6R437A 90,0 10,9 88.6 4,4 64.1 13,0 83.9 31 ,4 73.5 4,9K438A 93.5 21 ,3 97.4 11 ,5 120.3 7,7 102,4 37,4 110.3 28,8P439A 31.4 22,5 26,0 20,0 22.4 13,5 26.8 25,3 26.5 18,7V441A 40.2 14,0 44.6 3,6 29.5 7,5 31.2 13,2 35,6L442A 110.7 14,9 84.3 26,5 91.5 15,8 97.9 14,5 110.5 31 ,9A443S 86,1 49,7 101.4 1 ,6 89.8 3,4 59.5 15,6 107.7 19,9E444A 59.6 28,3 74.1 13,6 93.7 1 ,1 70.5 13,3 99.1 12,8A445S 97.5 2,7 114.4 37,4 110.5 20,9 90.5 44,0 109.7 51 ,3S446A 74.9 7,2 89.1 2,3 97,0 17,3 68.3 21 ,5 114.1 20,3A447S 105.7 32,9 110.4 9,2 107,2 29,3 99.7 58,1 11 1.8 18,2S448A 91 ,4 17,8 98.8 15,6 76.5 10,9 76,0 29,2 116.6 21 ,8Q449A 104.7 8,8 121.4 14,5 112,6 23,5 88.7 89,0 142.4 36,2A450S 26.7 4,4 56.6 8,6 78.8 23,8 61.5 21 ,9 60,7 13,8S451A 102.9 33,3 86,0 27,4 106.5 1 ,4 85,0 31 ,8 107.2 64,2C452A 11.9 0,4 15,5 1 ,3 12,0 1 ,6 9,4 2,8 2,8 4,8F453A 83.6 21 ,2 83.2 3,9 87,7 12,2 90,0 44,6 104.6 33,4Table 4c:S52A 78.8 3,3 97.2 29,9 102,0 16,3 156.9 36,7 120,7 30,5Y53A 102,5 24,5 97.3 4,1 105.8 11 ,2 154.9 39,4 103.6 12,3P54A 90.6 17,0 68.4 34,2 96.3 9,4 115,2 5,0 118,0 10,6M55A 85.6 19,1 93,0 1 ,3 106.8 11 ,3 128.6 0,5 100.5 6,8V56A 79.6 0,4 108.9 0,9 88.5 8,7 141.9 44,7 94.1 14,7S57A 119.2 12,9 104.5 8,1 190.3 4,2 111.4 7,1 127.1 22,8E58A 92,4 27,3 77.7 11 ,3 84.4 4,0 131.9 13,3 103.1 10,6S59A 91.3 7,4 101 ,0 0,4 102,0 21 ,1 143.1 10,5 90.8 21 ,9P60A 55.6 8,9 90.1 15,4 85.9 16,8 162.6 39,4 94.6 14,1E61A 58.2 35,8 86.5 8,2 86.6 21 ,9 120.2 30,9 94,6 1 ,1D62A -3,1 0,7 9.7 0,2 128.1 21 ,1 -4,5 0,2 92,0 5,8L63A 29.2 8,9 5.4 2,5 34.8 4,9 51 ,3 4,2 85.5 6,5G64A 86.8 47,8 113.5 11 ,6 108.6 9,5 132.2 30,1 90.5 6,8C65A -3,1 2,5 -3,3 8,1 3,7 1 ,5 -0,7 9,2 5.3 2,4A66S 56.4 20,6 93.4 4,0 84.6 7,2 118.1 33,1 94.6 13,4L67A 64.1 26,8 83.7 3,1 90.7 12,1 166,0 62,6 85.3 1 ,4R68A 69.9 16,4 80.7 9,5 78.5 10,8 123,0 50,4 94.8 9,0P69A 19.5 3,6 53.6 13,5 106,0 5,6 123.9 37,6 110.5 15,3Q70A 58.7 36,0 94.4 18,0 214.1 13,3 82.8 17,1 100.7 30,5S71A 74.8 38,5 87.2 24,2 103.8 8,0 149.9 54,5 115,9 9,5S72A 78.4 2,0 136.9 5,0 169.9 2,6 122.1 7,3 91.1 12,7G73A 69.6 3,4 96.3 5,7 91.1 5,3 133.3 29,4 108.3 4,6T74A 82.8 22,0 81 ,0 11 ,7 100,6 6,9 156.7 75,0 110.3 14,3V75A 90.9 3,3 70.6 15,1 67.1 16,4 111.5 12,7 97.7 22,7Y76A 17.2 11 ,2 29.5 5,7 36.2 7,7 48.2 26,6 76.8 2,2E77A 3,0 1 ,6 23.4 0,9 92.7 18,4 126.5 10,6 120.2 12,9A79S 28.4 8,6 28,3 3,7 58.2 0,1 47.2 0,1 74.4 12,9A80S 83.8 23,2 111.8 1 ,2 182,4 35,3 107.4 5,6 126,0 13,0V81A 55.7 6,1 64.8 0,9 79.9 6,7 93.2 14,5 92,6 6,9E82A 63.9 9,2 74,2 12,1 100.8 11 ,2 151.2 61 ,9 103.7 8,3V83A 53.5 6,7 63.1 6,5 79.9 2,8 87.8 15,7 101 ,0 23,6D84A 56.5 3,0 71.6 0,6 89.5 3,6 105,0 26,8 105.5 23,7V85A 91 ,0 18,8 126.6 28,1 181 ,0 1 ,1 99.5 31 ,9 103.4 3,4S86A 69.8 23,5 71.7 0,3 101.8 9,1 104.2 8,9 102.5 0,0A87S 99.3 41 ,1 56.8 26,1 92.2 5,6 142.4 38,8 105.8 0,1S88A 71.4 4,1 99,0 12,0 66,0 1 ,7 87.6 10,2 109.8 0,6I89A 55,0 14,4 87.7 2,2 81.6 17,2 133.7 5,5 99.2 0,8T90A 47,0 13,9 88.7 22,0 104,1 37,6 60.2 10,2 81 ,7 1 ,2L91A -1 ,3 0,9 2.1 5,1 26.6 4,9 3.2 2,0 1 ,3 0,7Q92A 49,6 2,8 103,0 15,6 98.7 18,4 86,0 14,1 96.5 12,8V93A 92.3 31 ,7 97.7 3,4 156.7 7,5 94.5 1 ,3 103.5 33,4L94A 65.5 0,4 114.7 1 ,1 133.7 20,4 86.7 35,1 102.3 5,8V95A 66.5 18,2 53,9 47,9 45,6 8,0 75.7 11 ,8 77.8 2,5D96A 57.4 37,7 119.8 17,4 204,0 16,5 101.6 11 ,3 126.8 6,4A97S 94,0 43,1 90.8 64,9 104,2 13,9 159,0 4,7 93.3 5,2G99A 55.6 14,1 79.5 16,8 66.3 12,7 82.3 26,9 97,0 3,41101 A 57.1 9,9 67.5 0,3 73.3 7,3 78,0 16,8 76.1 8,1C103A 10.5 2,9 6,4 3,9 -0,2 0,6 3.5 30,3 51 ,6 5,4L104A 90.2 4,5 132.1 0,3 1.7 1 ,3 124,0 1 ,7 133.1 21 ,2W105A 66.2 7,0 72.3 5,5 13,5 5,5 121.7 37,4 97.5 11 ,9V106A 75.1 18,8 71.6 14,7 76.4 8,0 142.1 78,1 97.6 2,2F107A 32.9 4,1 45.7 8,3 62.7 0,9 31.8 6,2 94.2 0,7K108A 74.7 8,6 90.4 3,3 82.8 7,2 93.2 11 ,2 90.3 0,8H109A 78.4 41 ,0 88.4 16,5 92.7 6,3 168.8 9,6 97.1 15,4S111A 103.6 2,3 92.1 0,0 2,2 0,8 133.7 62,2 108.3 0,2L1 12A 101.6 10,6 71.5 2,3 88.4 9,1 118,0 20,7 98.8 7,5N113A 92.4 11 ,7 101 ,6 11 ,7 95,0 21 ,6 154.1 6,4 96,0 4,1C114A 1 ,6 1 ,9 3,6 2,4 0,5 0,8 15,0 12,9 44.5 6,2Q115A 55.3 30,4 78,4 13,5 70.8 7,6 91.7 24,2 71 ,0 13,2P116A 30.1 10,1 57.1 5,9 98.5 29,9 24.6 12,3 59,0 7,9H1 17A 93.5 30,1 86.3 4,2 104,4 12,3 161.6 68,4 113.3 5,3F118A 72.9 10,1 76.2 20,7 79.3 0,1 96.6 8,5 84.6 2,6D119A 49.3 4,9 62.4 2,7 59.5 14,9 72.2 25,5 78.3 1 ,8L120A 85.5 4,2 103.4 6,4 102.3 17,0 150.3 68,4 95.2 12,5Q121A 86.3 8,9 89.5 14,9 96.5 5,2 157,8 56,9 109.4 13,1N122A 89.6 11 ,0 31.5 67,7 90,0 3,3 107.5 10,3 117.2 3,9R123A 30.9 5,9 55,0 2,0 52.4 2,0 46.5 18,3 77.5 17,2G124A 73.2 19,9 82.6 0,5 99.8 12,7 171 ,6 40,2 111.8 6,5V125A 71.6 20,8 37.9 66,8 77,0 11 ,9 54.2 60,1 70.3 7,2V126A 95,0 4,9 51 ,0 36,0 83.3 21 ,7 61.9 20,8 84.3 1 ,6S127A 91 ,5 22,2 62.9 47,3 72.5 7,5 82.4 0,2 82.6 14,4M128A 24.8 19,6 45.7 4,5 40.9 0,3 49.2 18,4 79.7 4,1V129A 70.9 22,7 102.4 2,5 94.4 14,3 143.5 41 ,4 125,1 5,4I130A 26.9 1 ,2 38.5 6,5 35.9 3,4 40,7 14,8 70,0 11 ,3L131A 83.3 7,6 94.3 4,5 97.4 6,5 179.9 65,8 111.4 4,9K132A 86.3 17,2 109.7 3,8 94,0 11 ,2 123.4 19,9 97.3 2,2M133A 106.1 28,4 91.6 14,3 91 ,1 13,2 162.2 45,0 122,6 4,2T134A 82.1 31 ,0 96,1 10,6 88.9 14,1 133.3 10,0 89.8 10,0E135A 93.7 25,0 90,0 4,0 95.6 5,5 126,3 14,9 110.4 0,5T136A 116,9 11 ,9 106.9 21 ,2 107,4 7,1 195,9 56,2 121.1 12,4Q137A 116,2 3,2 72.5 11 ,8 231.1 7,4 123.2 20,0 133.1 5,0A138S 89.3 9,1 104.5 15,8 84.2 3,4 149.8 28,3 96.4 15,2G139A 0,6 11 ,7 3,7 2,6 1.4 0,7 -1 ,0 8,8 40.6 8,2E140A 90.1 36,3 94,4 9,0 98.6 18,7 121.9 24,6 71.2 8,7Y141A 12.4 13,5 1 ,5 1 ,7 0,0 0,1 6.3 13,8 35.5 2,6L142A 78.3 21 ,4 90.1 9,2 2,0 0,5 140.2 2,1 106.3 1 ,3L143A 11 1.3 35,9 102.5 17,4 87,5 5,6 154.6 88,4 90,9 23,1F144A 104,0 3,1 90,0 2,0 2,0 2,6 140.1 1 ,5 89.4 2,4I145A 24.7 0,4 31.9 20,8 114,0 1 ,9 27.3 2,0 60,0 10,7Q146A 76.5 14,6 93.3 14,4 68.7 0,7 115.7 21 ,7 100.5 8,0S147A 94.4 19,9 96.6 12,2 99.9 7,3 136,0 48,4 106.8 5,6A149S 123.7 36,3 51.6 104,5 105,8 22,1 144.1 4,5 110.3 8,8N151A 95.8 23,2 87.4 0,3 75.4 3,7 121.3 7,4 97.2 2,6Y152A 84.5 14,7 90.7 3,5 96.9 2,1 123.4 11 ,7 97.5 5,9T153A 49.4 4,2 50.8 0,3 76.7 9,8 65.4 20,8 67.1 11 ,1I154A 40.1 18,1 41.1 4,5 50.2 8,0 47.5 2,2 65.8 8,3L155A 79.2 31 ,7 80.8 10,4 72.8 3,5 131.6 22,9 108.6 10,8F156A 3.2 0,6 7.4 6,0 1.6 1 ,9 2,8 14,2 39.8 14,2T157A 63.4 21 ,1 82.2 18,7 92.2 8,8 105.9 41 ,2 82.5 13,2V158A 26.1 25,5 32.3 2,7 31.7 1 ,0 32,0 12,5 53,0 3,1S159A 137.5 8,1 102.4 6,3 109.9 7,6 142.8 15,3 111.1 0,8I160A 79.4 6,6 80,5 15,5 89.7 21 ,1 144.4 22,2 98.5 6,9R161A 70.5 5,4 94.4 5,0 94.6 9,0 131.1 7,7 96.7 2,9N162A 94.8 11 ,5 80.7 13,8 90.9 7,3 148.2 55,3 109,0 26,0T163A 114.5 2,4 73.4 15,7 91.7 0,0 185,0 87,2 107.3 15,9L164A 95.1 49,1 95.2 2,9 100.1 16,9 179.8 24,4 103.1 2,8L165A 98.2 10,3 118.2 7,6 89.8 6,3 168.6 33,2 113.7 25,3Y166A 88.5 12,3 84.2 17,4 102,5 18,9 155.3 56,3 105,0 1 ,5T167A 84.4 10,3 83,1 24,1 85,0 9,1 128,2 28,8 94.6 9,7L168A 55,0 11 ,2 58,0 7,6 62.7 9,7 9,2 4,2 67.6 2,9R170A 97.1 18,4 90.5 7,2 89.4 10,6 157.7 52,5 126.2 18,5P171A 18.8 0,1 17.6 3,3 13.9 3,4 -4,4 2,4 40.5 4,6Y172A 41.5 14,7 100,4 5,5 117.1 162,0 66.7 7,5 92.7 35,2F173A 0,0 0,0 8.9 3,3 2,1 1 ,4 0,0 11 ,3 22.2 0,0R174A 83,4 6,1 87.6 8,2 84.3 17,2 114.5 61 ,6 111.7 2,9K175A 43.2 9,3 61.8 12,8 153.2 7,1 59.3 14,2 91.6 6,1M176A 104.7 4,0 90.6 2,8 102.3 11 ,2 161.5 29,7 101 ,9 13,7N178A 78.6 12,1 79.6 2,2 174.1 35,4 108.8 9,3 111.2 1 ,9D180A 92.5 5,1 92.6 10,0 79,7 2,7 104.7 38,5 103.3 4,7A181 S 61.7 0,5 87.5 13,5 100.3 25,8 73.7 9,2 98.6 1 ,8V183A 78.7 14,2 97.6 8,5 104,0 2,9 135.9 43,3 110.3 2,9C184A 15.7 9,5 15,9 0,7 9,8 0,8 0,1 4,8 24.8 1 ,8I185A 95,2 29,6 116,2 7,9 105.4 4,9 127.7 21 ,6 102.6 2,1S186A 52.1 1 ,6 67.7 5,1 68.3 3,6 18.2 14,0 88.5 1 ,4E187A 80.6 14,0 37.8 83,1 74,0 24,6 34,0 19,8 94.2 8,7S188A 64.4 1 ,7 98.7 2,5 90.4 6,8 43.4 8,2 91.8 6,3V189A 70.7 16,4 67.8 12,8 86,0 17,6 66,0 26,3 103.5 29,9P190A 19.1 8,8 18.1 1 ,5 4.6 2,2 1.8 20,2 39.6 8,8E191A 84,0 3,9 76,0 0,5 93.6 12,6 20.8 35,8 91.8 28,4P192A 86.1 19,1 86,0 4,1 93.3 0,5 53.5 5,0 103.6 0,2I193A 76.2 9,5 103.8 12,2 97.7 0,4 2.7 10,7 114.5 13,7V194A 39.1 15,8 47.2 2,1 38.6 3,4 9.2 15,0 54,1 6,0E195A 46.4 16,8 67.1 25,2 68.8 2,3 -9,7 6,3 75.9 17,6W196A 28.7 15,8 15.6 31 ,5 14.8 3,5 -6,7 10,0 41.8 10,8V197A 69.4 25,1 86.8 3,8 88.6 13,8 47.3 14,1 90.6 0,4L198A 68.3 6,9 92,4 1 ,7 85.1 18,1 26.7 4,7 81.3 7,2D200A 76.4 8,6 98.3 46,9 79,0 5,3 86.8 6,9 81 ,3 3,9S201A 85.7 2,7 80.9 3,3 83.3 7,6 148.3 80,1 107.5 2,7E204A 88,9 23,9 102,0 2,0 99.3 7,9 138.7 12,6 114.5 9,0S205A 102.1 11 ,2 96.8 12,0 98.2 0,4 176.8 37,1 111.6 2,5C206A 68,0 21 ,0 81.7 5,1 96,0 5,5 85.1 9,5 81.3 4,7E208A 88.8 32,5 96.4 13,2 99.2 8,2 107.1 4,2 89.4 6,1E209A 90.1 3,9 76,3 7,1 85.2 7,9 134.1 56,9 116.2 5,1S210A 3.5 1 ,8 7.7 1 ,3 -0,5 0,1 5,9 13,0 26.2 4,3P21 1A 88.2 2,3 76.3 20,4 106.3 6,3 130.2 57,1 118.7 0,9A212S 95.2 45,6 52.8 71 ,9 101.6 23,6 167,0 39,2 111.4 8,2V214A 91.2 5,0 75.2 5,0 93,0 16,9 126.9 12,3 115.3 10,3K216A 58.5 5,5 75.8 5,7 74.8 5,8 32.5 19,4 86.8 0,2E217A 72.2 1 ,8 72.4 2,6 61.6 8,0 21.2 11 ,0 83.4 0,2E218A 82.8 19,6 104,0 22,7 103.3 18,9 118,0 1 ,0 93.8 5,5K219A 93,0 0,5 113.1 40,1 103.7 17,1 93.7 10,7 106.3 4,2L224A 65.6 13,1 73.1 0,4 74,4 21 ,1 23.8 3,3 84.4 0,4G226A 94.5 39,2 97.7 9,6 86.2 9,8 177.3 7,8 94.7 21 ,6T227A 80,1 9,7 88,6 9,7 222.3 21 ,7 103.3 1 ,8 109.3 11 ,5D228A 88.6 27,1 78.5 2,3 63.7 8,9 48.5 27,0 79.2 3,6I229A 43.9 15,1 49,0 5,9 40.3 5,9 5.5 11 ,9 52.2 2,8R230A 91.2 9,3 103.5 5,6 104,8 12,5 146,0 54,1 110,0 2,6C231A 2.2 2,7 9.4 11 ,8 34,9 1 ,5 4,7 1 ,1 -2,5 0,9C232A 2,8 4,6 7,3 0,2 9.1 1 ,8 8.5 12,1 0,5 0,3A233S 71.2 4,2 82,8 15,3 74.3 5,4 23.8 14,8 75.8 1 ,7R234A 89.4 21 ,6 99,0 16,2 103.1 11 ,2 1 ,1 6,0 97.2 3,0L237A 86.3 19,9 126.6 10,4 182,7 10,6 135.3 6,4 112,5 25,0R239A 95.9 19,3 80.1 6,8 88.4 1 ,4 154.4 40,3 92.8 3,1E240A 116.4 21 ,4 97.7 1 ,0 190.4 1 ,3 107.2 28,9 151.2 18,8C241A 13,6 13,1 12.7 5,9 6.2 0,2 7.9 6,0 24.7 8,1T242A 73,0 4,8 85.5 2,7 88.1 16,0 69,3 43,5 86,3 0,6R243A 72.1 10,6 83,0 19,6 89.5 18,8 112,1 3,5 89.9 15,2L244A 21.9 17,9 30.6 9,1 19.4 0,8 6.8 4,5 49.7 0,5F245A 72.5 35,1 89.8 24,4 86.6 10,7 98.2 33,2 86,0 2,3T246A 18.3 18,5 27,0 1 ,2 17.3 0,9 2.2 15,0 32,0 3,9 1247 A 10.6 5,2 10.4 5,9 14.3 0,7 -9,7 11 ,6 34.7 4,8D248A 26.3 16,8 20.5 3,6 18.6 3,2 8.6 15,8 39.9 1 ,3L249A 9.3 11 ,9 6.5 8,0 7.5 0,4 -3,9 15,8 23,0 4,7N250A 38.2 2,7 61.9 0,7 57.7 2,5 41.9 9,5 58.2 6,7Q251A 85.4 15,7 86.6 12,5 87.8 14,1 115.9 26,2 115,4 20,9T252A 141 ,8 17,8 93.1 15,5 78.2 19,4 132.4 12,9 84.8 1 ,8T255A 77.1 7,9 131.3 9,7 170.3 47,8 104.6 19,6 108,0 9,3Q259A 68,0 35,4 65,0 9,8 55.5 3,2 66.6 23,6 77.9 0,6F261A 29.9 10,0 39,0 7,2 28.8 7,4 18,0 19,0 47.8 2,0L262A 94.3 13,7 79.8 20,7 91.2 14,4 127.9 29,0 94.2 1 ,4K263A 46.3 8,0 60,4 8,9 42.6 0,9 81.2 71 ,5 64.6 4,7V264A 59.6 4,8 101.7 4,7 11 1 ,1 35,5 90.8 22,1 77.3 9,1P267A 70.7 2,0 60.1 19,6 78.3 16,0 67.3 18,7 79.9 21 ,3L268A 28.3 11 ,2 38.3 9,3 34.6 6,4 6.4 9,9 51.7 1 ,3W269A 96.3 34,3 93.7 1 ,9 80.3 6,8 84,0 2,8 82.4 12,6I270A 21.5 4,7 34.2 2,0 31 ,0 11 ,0 15.2 5,6 51.4 3,3R271A 60.6 13,6 89.3 12,4 89.3 5,9 27.8 43,5 72.6 2,0C272A 4,5 8,2 1.8 8,3 4.8 1 ,2 -1 ,9 6,5 22.9 1 ,7K273A 27.8 5,6 23,0 2,0 31.6 4,8 7.8 10,2 47.9 1 ,3A274S 31.4 8,0 16.4 0,5 24.7 1 ,7 14.4 3,6 53,2 8,2H276A 91.2 23,8 99.2 20,4 97,9 19,7 152.2 59,3 38.1 1 ,9V277A 108,3 29,4 111 ,0 11 ,8 100.3 2,1 193.6 51 ,0 93.6 2,1N278A 107.8 14,3 98.4 0,4 91.8 5,5 107.4 13,4 28.8 1 ,0H279A 84.7 24,6 98.5 4,4 98.3 4,0 153,0 0,2 44.1 1 ,0G280A 99.4 65,7 88.2 18,2 107.4 12,2 171.7 49,7 80.9 1 ,6G282A 81.4 38,6 100,5 4,6 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85,0 33,3 108,0 40,3 85,7 4,4 84.1 13,8A447S 104.5 14,2 91.6 0,8 113.4 39,3 119.6 0,3 97.3 15,1S448A 100.8 0,0 83.4 25,3 114.7 26,9 11 1 ,0 2,0 98.1 26,8Q449A 104,3 30,1 105,5 10,5 106.3 40,9 128.4 40,0 91.4 2,0A450S 48.1 1 ,5 49.8 0,1 52.4 22,9 45.4 10,8 60.6 10,4S451A 80,9 17,5 91 ,6 26,6 124.9 45,1 103.4 22,8 97.6 15,6C452A 6,4 1 ,8 3.8 0,2 -7,3 9,8 39.3 10,9 4,5 0,0F453A 44,0 86,3 75,2 20,2 75.3 37,2 70.4 33,5 82.2 7,3S454A 113.8 26,1 92,1 30,3 140,5 23,9 125.1 64,8 113.6 1 ,8D455A 103.9 11 ,9 86,0 33,2 58.6 32,9 70.5 45,9 52.3 107,7G456A 85,0 33,3 80,9 13,9 113.4 25,8 86,3 46,7 110.8 6,7Y457A 39.3 31 ,3 19.7 0,9 13.5 12,2 12,0 7,0 41.6 2,3P458A 1.3 0,2 1.1 0,8 2,3 2,2 13.6 13,7 0,7 1 ,1L459A 122,7 11 ,7 120.3 0,6 141.5 9,4 105.2 28,4 96.6 6,4P460A 77.8 3,4 74.5 18,8 73.7 14,2 57.1 7,9 81.4 27,5S461A 104.5 3,5 95.3 23,6 109.3 22,4 104.2 4,3 103,8 26,3W462A 24.6 45,4 1 ,6 1 ,4 4,9 7,7 43,9 60,0 1.8 2,1T463A 83.7 9,0 92,0 24,7 80.1 2,0 89,0 5,1 92,9 24,3W464A 2,0 0,7 1.9 0,5 3.7 8,7 5.3 1 ,4 1 ,7 1 ,0K465A 119,1 2,5 129.4 1 ,3 80.3 15,3 62.1 17,6 92.6 6,5K466A 106.5 2,8 96.1 16,7 62.1 12,1 91.8 33,0 89,0 8,2C467A 28,0 1 ,1 19.5 0,9 0,9 9,5 73.8 24,2 25.1 0,9S468A 105.4 22,2 95.9 9,2 117.9 11 ,9 114.8 21 ,1 100.2 8,5D469A 96.2 5,2 90.9 15,6 105,0 8,4 90.6 0,5 104.2 4,0K470A 108,0 0,1 93.1 15,6 102.3 7,9 89.8 22,7 85,0 13,7S471A 104.2 16,3 82.4 27,1 97.1 53,5 91.3 3,8 93.7 9,6P472A 135.8 3,7 99.7 3,2 105.6 25,5 83.7 11 ,4 95.4 0,3N473A 91.6 1 ,9 102.5 0,1 30,5 21 ,0 105,9 87.4 5,8C474A 21.6 3,1 20.4 1 ,5 31.4 2,7 129.5 10,6 31.5 5,5T475A 73.1 1 ,5 81.3 8,7 72.5 8,6 67.6 21 ,6 85.6 15,0E476A 67.1 4,1 73.3 18,6 71.4 38,0 79.8 14,2 80.7 8,0E477A 81.5 0,9 92.5 5,7 86.9 15,7 89,0 9,4 89.3 10,5I478A 4.7 1 ,1 4.5 1 ,1 15.8 0,3 39.5 62,0 6.7 1 ,8T479A 76,9 3,1 87,6 27,9 103.2 22,8 69.4 7,8 77.4 17,5E480A 86.4 6,4 106,0 25,2 93.6 20,4 77.2 2,5 95.8 44,5G481A 92.1 1 ,6 77.2 2,3 65.8 1 ,4 69.4 0,7 76.4 4,7V482A 59.7 0,7 82,0 4,5 42.2 14,1 97.4 9,1 61.7 11 ,5W483A 91.1 8,8 108.3 11 ,5 126.4 2,3 113.5 16,9 98.3 15,3N484A 97.8 6,3 89.2 11 ,2 104.1 41 ,7 76.2 33,5 93.7 6,6R485A 134.2 6,5 92.5 14,2 102.8 5,7 96.3 3,8 94.5 0,2A487S 92.4 9,9 90.6 23,0 121.4 0,5 11 1.9 17,2 103.8 7,9N488A 70.9 3,4 66.8 19,3 73.8 28,5 50.3 0,2 54,0 6,4R489A 117.2 27,8 95.8 20,7 130.1 37,4 151 ,0 4,9 83.6 11 ,9K490A 101 ,7 4,5 95.7 42,3 136.9 45,7 90,0 42,5 84.7 30,8V491A 141.4 0,6 128,1 11 ,1 119.4 21 ,9 125.4 9,1 143.1 4,5F492A 120.1 8,0 104.3 42,2 184.5 35,0 196.9 7,1 125.2 9,2G493A 87,3 2,5 87.7 34,9 127,0 18,0 97.7 1 ,4 86.4 2,7Q494A 100.5 4,2 85,5 30,7 99.6 30,9 107,0 29,3 87.7 22,6W495A 75,8 5,5 75.7 6,4 94.6 9,1 81 ,1 23,2 82,0 9,3V496A 117,0 11 ,9 75.3 47,5 151.9 25,0 159,0 9,7 98,1 48,6S497A 82,6 2,5 88,0 40,8 109.4 57,2 75.3 1 ,5 97.3 4,4S498A 103.7 1 ,6 85.7 14,0 151 ,8 27,1 11 1.8 26,1 86.7 15,3S499A 14,2 0,8 5,0 12,1 3.8 3,2 15.1 2,2 24.4 4,0T500A 77.1 11 ,3 76.9 10,9 73.5 9,7 71.4 0,7 95,0 3,2L501A 2.3 0,3 2.6 1 ,1 4.8 5,5 12,3 13,2 2.8 0,8N502A 62.3 7,1 68.6 15,5 72.3 32,5 60.1 31 ,1 51.1 4,1M503A 11 1.9 1 ,6 100.6 1 ,3 57,9 21 ,5 98,0 29,1 86.5 0,2S504A 41.5 4,1 47.6 13,8 66.8 2,2 120.1 18,4 46.3 7,8E505A 98.9 0,3 106,5 6,2 106,2 24,1 133.6 22,1 101.6 1 ,8A506S 97.7 13,8 87.9 3,5 134.4 38,1 116.4 15,3 98.2 30,7I507A 74,0 1 ,4 74.8 12,4 82.4 6,4 61.6 1 ,1 89.1 4,9K508A 93.6 0,2 92.9 0,6 85,0 16,1 160.5 19,0 87.3 26,7G509A 73.9 3,3 77.1 3,1 40.9 5,9 108.6 1 ,2 69.3 5,3F510A 105,0 7,6 103.8 20,7 97.7 20,5 97.6 14,3 70.5 1 ,7L511A 119,5 9,2 94.9 15,1 100.1 22,0 128.8 17,2 103.9 11 ,2V512A 25.3 2,5 26.1 0,3 23.3 10,4 30.1 3,9 45.4 0,4K513A 93,0 16,1 81 ,4 8,6 92.6 15,6 87.5 10,1 99.3 7,4C514A 1.2 0,8 1.5 0,0 14.4 1 ,6 10.7 2,4 1.7 1 ,6C515A 2.2 2,8 1.3 0,4 11.6 11 ,1 11.2 1 ,0 1 ,4 2,8A516S 20.6 4,5 17.3 2,3 19.1 48,8 69.5 10,9 33,0 1 ,9N518A 2,5 0,6 2.4 0,2 9.6 10,9 7.7 7,5 2.1 0,9L520A 101.6 8,1 87,0 2,1 65.7 8,1 62.8 7,8 115.7 34,4G521A 48.8 1 ,8 39.5 3,3 16.9 5,2 14.8 8,3 42.3 5,9T522A 79.6 3,4 98.1 13,7 48,6 86.9 9,3 87.1 1 ,4S523A 80.6 19,4 97.6 3,7 86.7 8,7 109.4 8,7 72.5 22,5C524A 7.9 2,1 6.5 3,1 7.4 2,2 8.4 2,4 47.1 82,3E525A 11 1.4 J,1 98.3 5,6 115.5 4,4 107.2 56,4 86.9 42,5T526A 86.3 10,0 89.3 7,3 120.8 36,0 81.9 9,2 94.8 18,2I527A 36.4 9,3 33.3 4,0 32.4 0,8 65,1 54,4 59.3 6,1L528A 70.4 0,7 11 1 ,5 0,7 109.6 5,4 76.7 5,9 97.8 22,3L529A 79.6 29,0 85.9 11 ,8 83,0 30,2 194.9 23,1 78.7 25,4N530A 108.7 0,1 116,0 16,4 79.5 31 ,2 78.6 46,2 99.2 4,6S531A 95.1 0,9 133.1 11 ,3 68.5 18,4 171.9 10,2 123.4 18,1P532A 11 1.2 4,3 128.3 1 ,3 124.9 11 ,4 116.5 19,0 104,0 8,2G533A 90.7 19,0 91.8 6,0 99,8 3,5 102.6 2,3 113.7 8,7P534A 96.8 8,3 90.2 42,0 107.4 15,3 85.9 28,8 115.5 5,9F535A 2,7 1 ,0 3,7 2,4 19,0 1 ,8 61.4 28,4 2,6 4,3P536A 103.5 4,1 98.3 17,2 113.5 17,4 64.6 20,0 106,1 15,2F537A 116.2 5,0 103.9 7,2 93.1 3,6 154,7 5,6 96.3 8,5Based on these data the following key amino acids within the epitopes and following domains of the antibodies tested were identified:Example 4: Design and generation of biparatopic anti-FLT3 antibodiesUsing the controlled fab arm exchange method, biparatopic antibodies were generated based on the monoparatopic antibodies described herein above and in Labrijn, et al.; Nature Protocols 9: 2450-2463, 2014. Altogether 185 biparatopic antibodies were generated, i.e. all possible combinations, except for antibody Bracco / / which could not be produced in sufficient amounts to generate all combinations. As epitope binning data was available for the monoparatopic antibodies, one candidate for each non-competing bin was selected to form biparatopic antibodies with Broccoli. Thereby it could still be assessed whether a certain combination of bins shows a superior functional activity.Example 5: Biparatopic anti-FLT3 antibodies have an increased affinity and avidity compared to monoparatopic anti-FLT3 antibodies.Affinity experiments with biparatopic anti-FLT3 antibodies were performed by BLI [as described in Example 2] and Surface Plasmon Resonance (SPR), comparing them directly with the corresponding monoparatopic antibodies. The SPR-based binding method involves immobilization of a ligand (antibody) on the surface of a sensor chip. The binding partner of interest or an analyte (FLT3 ECD) flow through the flow channel. Different concentrations of an analyte flow over the ligand and the interactions of ligand-analyte can be characterised. The SPR signal originates from changes in the refractive index of the light source at the surface of the sensor chip. The increase in mass associated with a binding event causes a proportional increase in the refractive index, which is observed as a change in response-resonance signal.Results for the monoparatopic antibodies are shown in Table 5, results for the biparatopic antibodies in Table 6.Table 5:Table 6:Figure 2 visually depicts results obtained for the monoparatopic antibodies and the biparatopic antibodies. As can be seen, essentially all biparatopic antibodies shown a strongly increasedaffinity / avidity to FLT3 compared to the monoparatopic antibodies. This binding data confirms that both arms are capable of interacting with the target at the same time.Example 6: Biparatopic anti-FLT3 antibodies have an increased internalization capacity compared to monoparatopic anti-FLT3 antibodiesIn this experiment the internalization capacity of biparatopic anti-FLT3 antibodies was compared to the internalization capacity of corresponding monoparatopic antibodies in two cell lines - MOLM13, a human AML cancer cell line (DMSZ, ACC554), and Ba / F3 cells (Riken, RCB0805) engineered to overexpress human FLT3.An internalization assay was developed by conjugating a polyclonal Fab fragment anti-human IgG, Fc specific (Jackson research, 109-007-008) to a pH sensitive dye, pH rodo deep red (Thermofischer Scientific, P35355). For pH rodo deep red, the lower the pH, the brighter the fluorescence in the deep red spectrum (655 nm) when excited by a red laser (647 nm). Therefore, when bound to the Fc portion of a target antibody, upon antibody-antigen complex internalization, the Fab-pH rodo conjugate is also internalized and emits more fluorescence in endosomes (pH 6.5-5.5) and lysosomes (pH 4.5) compared to the non-internalised Fab-pH Rodo conjugate (pH 7). The principle of the assay is depicted in Figure 3.To measure internalization of FLT3 upon binding of different monoparatopic and biparatopic antibodies, 10,000 Ba / F3 overexpressing human FLT3 and MOLM13 cells were incubated in 96- well U-bottom plates with antibodies of interest at a concentration of 5 nM, in the presence of 2 molar ratios of Fab-pH Rodo deep red conjugate. Internalization was measured by flow cytometry after 48 hours (Figure 4B and 5B).Overall, a good correlation between the results obtained with the two cell lines was observed, indicating that the antibody behaviour is consistent across the cell lines tested. Results also clearly demonstrate that biparatopic anti-FLT3 antibodies have increased internalization capacity compared to monoparatopic anti-FLT3. Results for MOLM13 cells are shown in Figure 4A, results for Ba / F3 cells overexpressing human wild-type FLT3 in Figure 5A.Whilst all biparatopic antibodies showed an increased internalization capacity as compared to monoparatopic antibodies, this effect was particularly pronounced for biparatopic antibodies that bind to certain specific domains of FLT3, such as biparatopic antibodies binding to domain 1 (D1 ) and domain 3 (D3) of the extracellular portion of FLT3, as well as biparatopic antibodies binding to an epitope N-terminal of the D1 domain and domain 3 (D3) of the extracellular portionof FLT3. Respective analyses for MOLM13 cells are shown in Figure 6, results for Ba / F3 cells overexpressing human wild-type FLT3 in Figure 7.It was also observed, that internalization does not directly correlate to affinity, indicating that the mechanism of action of biparatopic antibodies does not solely depend on this parameter.The internalization capacity of the best biparatopic antibodies was also tested in additional AML cell lines, MV4-11 (DMSZ, ACC102) and NOMO-1 (DMSZ, ACC542), which confirmed the results with cell lines MOLM13 and Ba / F3 cells engineered to overexpress human FLT3. See Figures 8 and 9.Example 7: Proliferation dataIn this experiment biparatopic antibodies were tested to determine whether they could inhibit or stimulate proliferation of Ba / F3 cells overexpressing human wild-type FLT3. 5,000 cells were incubated with 100 pg / mL of biparatopic anti-FLT3 antibodies for 72 hours. At endpoint, cellular ATP, used as a substitute for cell number, was measured with Cell Titer Gio 2D (Promega) and signal was captured on an Envision plate reader (Perkin Elmer). As a control antibody an antibody specific for chicken lysozyme was included.Results are shown in Figure 10. Biparatopic antibodies did not show more than 25% inhibition of proliferation, nor did they show more than 25% increase in proliferation, suggesting that they do not have inhibitory or agonistic activity on Ba / F3 cells overexpressing human wild-type FLT3.Example 8: Biparatopic anti-FLT3 antibodies improve payload deliveryAn indirect ADC assay was developed to measure antibody internalization- and payload- mediated cytotoxicity in AML cell lines. The main component of the assay is commercially available from Moradec LLC (AH-202AF-50, AH-201 AF-50) and consists of a Fab Fragment AntiHuman IgG, that specifically binds to human IgG Fc, conjugated to a MMAF payload with an average DAR of 1.3-1 .5 via a cathepsin cleavable (ValCit-PAB or ValAla-PAB) or non-cleavable linker. AML cells including Ba / F3 overexpressing human wild-type FLT3, MOLM13, MV4-11 , NOMO-1 , OCIAML2 (DSMZ No. ACC99), OCIAML5 (DSMZ No. ACC247) and THP1 (ATCC No. TIB- 202) were plated at 2,000 or 4,000 cells per well in 96-well plates and incubated for 72 hours with an antibody of interest and the Fab-MMAF conjugate at a molar ratio of 1 to 6. At endpoint, cellviability was measured with Cell Titer Gio 2D (Promega) as above (see Example 6). The data were analysed by fitting a dose-response curve and exporting the concentration of antibody required to reach 30% or 50% growth inhibition (GI30 and GI50, respectively) compared to vehicle-control.Results are shown in Figures 11 (Ba / F3 hFTL3), 12 (MOLM13), 13 MV4-11 ), 14 (NOMO1 ), 15 (OCIAML2), 16 (OCIAML5) and 17 (THP1 ). Overall, biparatopic anti-FLT3 antibodies demonstrated superior cytotoxicity capacity compared to monoparatopic antibodies in all cell lines tested. Moreover a correlation between internalization capacity and cytotoxicity could be observed.Example 9: Biparatopic anti-FLT3 ADCs antibodies kill AML cellsTo evaluate the translatability of the indirect ADC assay (Example 8) and the potential of biparatopic ADCs in AML, antibody Broccoli / Tartufo was directly conjugated to Tesirine, consisting of a PBD warhead via a Vai-Ala cathepsin cleavable linker. AML cells including MOLM13 and NOMO1 were plated at 4,000 cells per well in 96-well plates and incubated for 72 hours with antibody Broccoli / Tartufo-ADC or the benchmark antibody Mylotarg (FarmaMondo, Art. No. 100021300U). To evaluate off-target toxicity cells were pre-incubated with 30 ug / mL of naked antibody Broccoli / Tartufo for 1 hour at 37C to saturate binding sites ahead of ADC binding. At endpoint, cell viability was measured with CellTiterGlo 2D (Promega). The data were analysed by fitting a dose-response curve.Results are shown in figure 18 (panel A for MOLM 13 and panel B for NOMO1 ). The BPA ADC has comparable efficacy compared to Mylotarg in MOLM13 cells, whilst it is superior to Mylotarg in NOMO1 cells. Biparatopic antibodies binding to an epitope N-terminal of D1 and an epitope on domain D3 therefore seem to be particularly useful for the treatment of diseases, such as AML.

Claims

Claims1 . A biparatopic antibody that specifically binds two epitopes of FLT3, wherein one of said two epitopes on FLT3 is located N-terminal of the D1 domain of FLT3 (SEQ ID No. 143) and the other one of said two epitopes on FLT3 is located on or includes a portion of domain D3 (SEQ ID No. 146).

2. The biparatopic antibody of claim 1 , wherein said biparatopic antibody is a soluble antibody.

3. The biparatopic antibody of claim 1 or 2, wherein said biparatopic antibody is not a cellular therapeutic.

4. The biparatopic antibody according to any one of the preceding claims, wherein said biparatopic antibody comprises a first antigen binding fragment comprising CDRs selected from a) an HCDR1 of SEQ ID No. 36, an HCDR2 of SEQ ID No. 37, an HCDR3 of SEQ ID No. 38, an LCDR1 of SEQ ID No. 39, an LCDR2 of SEQ ID No. 40, and an LCDR3 of SEQ ID No. 41 , b) an HCDR1 of SEQ ID No. 52, an HCDR2 of SEQ ID No. 53, an HCDR3 of SEQ ID No. 54, an LCDR1 of SEQ ID No. 7, an LCDR2 of SEQ ID No. 55, and an LCDR3 of SEQ ID No. 56, c) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75, d) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 78, an HCDR3 of SEQ ID No. 79, an LCDR1 of SEQ ID No. 31 , an LCDR2 of SEQ ID No. 32, and an LCDR3 of SEQ ID No. 80, e) an HCDR1 of SEQ ID No. 115, an HCDR2 of SEQ ID No. 116, an HCDR3 of SEQ ID No. 117, an LCDR1 of SEQ ID No. 118, an LCDR2 of SEQ ID No. 119, and an LCDR3 of SEQ ID No. 120, f) an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 123, an HCDR3 of SEQ ID No. 124, anLCDR1 of SEQ ID No. 125, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 126,g) an HCDR1 of SEQ ID No. 129, an HCDR2 of SEQ ID No. 130, an HCDR3 of SEQ ID No. 131 , an LCDR1 of SEQ ID No. 132, an LCDR2 of SEQ ID No. 133, and an LCDR3 of SEQ ID No.134, and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96.

5. The biparatopic antibody according to claim 4, wherein said biparatopic antibody comprises a first antigen binding fragment comprising an HCDR1 of SEQ ID No. 71 , an HCDR2 of SEQ ID No. 65, an HCDR3 of SEQ ID No. 72, an LCDR1 of SEQ ID No. 73, an LCDR2 of SEQ ID No. 74, and an LCDR3 of SEQ ID No. 75 and a second antigen binding fragment comprising an HCDR1 of SEQ ID No. 91 , an HCDR2 of SEQ ID No. 92, an HCDR3 of SEQ ID No. 93, an LCDR1 of SEQ ID No. 94, an LCDR2 of SEQ ID No. 95, and an LCDR3 of SEQ ID No. 96.

6. The biparatopic antibody according to any one of the preceding claims, wherein said biparatopic antibody comprise a first VH and VL pair selected from a) the variable heavy chain of SEQ ID No. 34 and the variable light chain of SEQ ID No. 35, b) the variable heavy chain of SEQ ID No. 50 and the variable light chain of SEQ ID No. 51 , c) the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70, d) the variable heavy chain of SEQ ID No. 76 and the variable light chain of SEQ ID No. 77, e) the variable heavy chain of SEQ ID No. 113 and the variable light chain of SEQ ID No. 1 14, f) the variable heavy chain of SEQ ID No. 121 and the variable light chain of SEQ ID No. 122, g) the variable heavy chain of SEQ ID No. 127 and the variable light chain of SEQ ID No. 128, and a second VH and VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90.

7. The biparatopic antibody according to claim 6, wherein said biparatopic antibody comprisesa first VH / VL pair comprising the variable heavy chain of SEQ ID No. 69 and the variable light chain of SEQ ID No. 70 and a second VH / VL pair comprising the variable heavy chain of SEQ ID No. 89 and the variable light chain of SEQ ID No. 90.

8. The biparatopic antibody according to claim 6 or 7, wherein said antigen binding fragments comprise VH and VL pairs having at least 85 percent, 90 percent, 93 percent, 95 percent, 98 percent or 99 percent sequence identity to the variable heavy chains sequences and the variable light chain sequences of claims 7 or 8.

9. A biparatopic antibody according, wherein said biparatopic antibody binds to the same epitopes as a biparatopic antibody comprising the CDRs of an antibody according to claim 4 or 5 or comprising the same VH and VL pairs of an antibody according to claims 6-8.

10. An antibody-drug conjugate comprising a biparatopic antibody according to anyone of claims 1 -9, and a payload.11 . A nucleic acid encoding a biparatopic antibody according to any one of claims 1 -9.

12. A vector comprising the nucleic acid according to claim 11 .

13. A host cell comprising the nucleic acid of claim 11 or the vector of claim 12.

14. The biparatopic antibody according to any one of claims 1 -9, the antibody-drug conjugate according to claim 10 for use in medicine, preferably wherein said use in medicine is the treatment of cancer, such as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

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