Compositions and methods for minimizing protein loss at low protein concentrations

Abstract

The present invention relates to compositions and methods for minimizing protein loss (e.g., due to adsorption to solid surfaces) at low protein concentrations. The invention disclosed herein relates generally to the field of compositions comprising proteins, in particular pharmaceutical compositions comprising low protein concentrations of therapeutic proteins. The invention disclosed herein also relates to methods of administering the compositions to a subject in need thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 926,089, filed October 25, 2019, which is incorporated herein by reference in its entirety.

[0003] Submitting sequence lists as ASCII text files

[0004] The following content, submitted as an ASCII text file, is incorporated herein by reference in its entirety: Computer-readable form of a sequence list (CRF) (filename: A-2429-WO-PCT_ST25, created: October 23, 2020, size: 451,608 bytes). Technical Field

[0005] The invention disclosed herein generally relates to the field of compositions comprising proteins, and particularly pharmaceutical compositions comprising therapeutic proteins at low concentrations. The invention also relates to methods for administering the composition to a subject in need. Background Technology

[0006] Therapeutic proteins are an important class of therapies used to treat patients. Protein molecules are surface-active and can adsorb onto solid surfaces. Therapeutic proteins in pharmaceutical compositions can adsorb onto solid surfaces they come into contact with (e.g., the surface of a container holding the pharmaceutical composition), which can lead to protein loss during storage and use. Typically, these compositions contain high concentrations of therapeutic proteins (e.g., 1 mg / mL or higher) to ensure that protein adsorption onto solid surfaces does not result in an insufficient amount of medication available for administration to a patient. However, when the concentration of the protein in the composition is low (e.g., below 0.1 mg / mL, such as when the composition is diluted before administration to a patient), the risk of protein loss may be more pronounced, potentially leading to an insufficient amount of medication available for administration to a patient.

[0007] Surfactants are commonly used in pharmaceutical compositions containing therapeutic proteins, for example, to prevent protein aggregation and stabilize proteins. It is unclear whether surfactants can be used to effectively prevent protein loss due to surface adsorption when the protein is present in the pharmaceutical composition at low concentrations (e.g., 0.1 mg / mL or lower).

[0008] Protein compositions and methods that require minimizing protein loss due to adsorption onto solid surfaces are needed, particularly when the composition contains low concentrations of protein. Summary of the Invention

[0009] This document discloses compositions comprising low concentrations of protein and methods for administering these compositions to subjects in need. The compositions and methods disclosed herein have the advantage of minimizing or eliminating protein loss due to protein adsorption to solid surfaces and ensuring accurate administration of therapeutic proteins to patients.

[0010] In some embodiments, this document discloses an aqueous composition comprising a protein and a surfactant, wherein the protein is present in the composition at a concentration between about 0.001 μg / ml and about 100 μg / ml, and the surfactant is present in the composition at a concentration of at least about 0.25 times the critical micelle concentration (CMC) of the surfactant.

[0011] In some embodiments, the protein is a bispecific antibody construct comprising a first binding domain that binds to a target cell surface antigen, a second binding domain that binds to human CD3 on the surface of T cells, and optionally a third domain comprising a hinge-CH2 domain-CH3 domain-connector-hinge-CH2 domain-CH3 domain in an amino-to-carboxyl sequence. In some embodiments, the second binding domain comprises a polypeptide having the sequence SEQ ID NO:201. In some embodiments, the bispecific antibody construct is present at a concentration between about 0.001 μg / ml and about 50 μg / ml, or between about 0.01 μg / ml and about 50 μg / ml, or between 0.1 μg / ml and about 50 μg / ml, or between 0.1 μg / ml and about 10 μg / ml, or between 1 μg / ml and about 10 μg / ml.

[0012] In some embodiments, the surfactant is polysorbate, poloxamer, or Triton X-100. In some embodiments, the surfactant is polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, or Triton X-100. In some embodiments, the surfactant is poloxamer 188 or poloxamer 407. In some embodiments, the surfactant is present at a concentration between about 0.25 times and about 20 times the CMC of the surfactant, or between about 0.25 times and about 10 times the CMC.

[0013] In some embodiments, the composition further comprises a salt, an amino acid, a sugar or sugar derivative, or a combination thereof. In some embodiments, the salt is NaCl. In some embodiments, the sugar or sugar derivative is a monosaccharide, disaccharide, cyclic polysaccharide, or sugar alcohol. In some embodiments, the sugar is sucrose, trehalose, mannitol, or sorbitol. In some embodiments, the amino acid is lysine.

[0014] In some embodiments, the pH of the composition is between about 3.5 and about 7.5. In some embodiments, the pH of the composition is between about 4.2 and about 7.0.

[0015] In some embodiments, the composition further comprises a buffer or preservative. In some embodiments, the buffer is an acetate buffer, a glutamate buffer, a citrate buffer, a succinate buffer, a tartrate buffer, a fumarate buffer, a maleate buffer, a histidine buffer, or a phosphate buffer.

[0016] In some embodiments, each of the first and second binding domains of the bispecific antibody construct comprises a VH region and a VL region. In some embodiments, the bispecific antibody construct is a single-chain antibody construct. In some embodiments, the bispecific antibody construct comprises a polypeptide having an amino acid sequence selected from SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:176, SEQ ID NO:178, and SEQ ID NO:192. In some embodiments, the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:48, SEQ ID NO:67, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:178, or SEQ ID NO:192.

[0017] In some embodiments, the composition is contained in a plastic container such as an IV bag or IV tube. In some embodiments, the container is made of a material comprising polyolefin, polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), or polyurethane. In some embodiments, the container is made of a PVC-containing material, wherein the PVC is substantially free of di-2-ethylhexyl phthalate (DEHP) or tri-2-ethylhexyl trimellitate (TOTM).

[0018] In some embodiments, this document discloses a pharmaceutical formulation comprising an aqueous pharmaceutical composition contained within a container, wherein the aqueous pharmaceutical composition comprises: a bispecific antibody construct at a concentration between about 0.001 μg / ml and about 100 μg / ml, and a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant, wherein the surfactant has an HLB value of at least 20. In some embodiments, the surfactant is poloxamer 188 or poloxamer 407. In some embodiments, the aqueous pharmaceutical composition comprises a bispecific antibody construct at a concentration between about 0.001 μg / ml and about 50 μg / ml. In some embodiments, the aqueous pharmaceutical composition comprises a surfactant at a concentration between about 0.25 times and about 20 times the CMC of the surfactant, or between about 0.25 times and about 10 times the CMC of the surfactant.

[0019] In some embodiments, the aqueous pharmaceutical composition further comprises a salt, a buffer, an amino acid, a sugar or a sugar derivative, or a combination thereof. In some embodiments, the aqueous pharmaceutical composition has a pH between about 4.2 and about 7.0.

[0020] In some embodiments, the container is made of a material comprising polyolefin, PVC, EVA, or polyurethane (e.g., polyester and polyether).

[0021] In some embodiments, the bispecific antibody construct comprises a polypeptide having an amino acid sequence selected from SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:176, SEQ ID NO:178, and SEQ ID NO:192. In some embodiments, the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:48, SEQ ID NO:67, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:178, or SEQ ID NO:192.

[0022] This article also discloses a method for administering a bispecific antibody construct to a patient, the method comprising: preparing an aqueous pharmaceutical composition in a container, wherein the aqueous pharmaceutical composition comprises a bispecific antibody construct at a concentration between about 0.001 μg / ml and about 100 μg / ml and a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant; and administering the aqueous pharmaceutical composition to a patient, wherein the bispecific antibody construct comprises having a concentration selected from SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:76, SEQ ID NO:78, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:176, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:176, SEQ ID NO:19, SEQ ID NO:10 ...09, SEQ ID NO:109, SEQ ID NO:109, SEQ ID NO:109, SEQ ID NO:109, SEQ ID NO:109, SEQ ID NO:109, In some embodiments, the bispecific antibody construct comprises a polypeptide having the amino acid sequences of SEQ ID NO:178 and SEQ ID NO:192. In some embodiments, the bispecific antibody construct comprises a polypeptide having the amino acid sequences of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:48, SEQ ID NO:67, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:178, or SEQ ID NO:192. In some embodiments, the aqueous pharmaceutical composition comprises a bispecific antibody construct at a concentration between about 0.001 μg / ml and about 50 μg / ml.

[0023] In some embodiments, the aqueous pharmaceutical composition comprises a surfactant at a concentration between about 0.25 times and about 20 times the CMC of the surfactant, or between about 0.25 times and about 10 times the CMC. In some embodiments, the surfactant is polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, poloxamer 188, poloxamer 407, or triatomine X-100.

[0024] In some embodiments, the aqueous pharmaceutical composition further comprises one or more selected from salts, buffers, amino acids, sugars or sugar derivatives, and preservatives. In some embodiments, the aqueous pharmaceutical composition has a pH between about 4.2 and about 7.0.

[0025] In some embodiments, the container is made of a material comprising polyolefin, PVC, EVA, or polyurethane. In some embodiments, the surfactant is polysorbate 80, polysorbate 60, polysorbate 40, or polysorbate 20, and the container is made of a material comprising PVC that is substantially free of DEHP or TOTM.

[0026] In some embodiments, the aqueous pharmaceutical composition is prepared by diluting a first composition containing a bispecific antibody construct with a suitable aqueous solution. In some embodiments, the first composition is a liquid composition containing a bispecific antibody construct. In some embodiments, the first composition is a liquid composition reconstituted from a lyophilized composition containing a bispecific antibody construct. In some embodiments, the suitable solution contains a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant. In some embodiments, the aqueous pharmaceutical composition is prepared by adding a suitable aqueous solution to a container and then adding an appropriate amount of the first composition to the container.

[0027] In some embodiments, the patient is a cancer patient. In some embodiments, the administration is intravenous (IV). Attached Figure Description

[0028] Figure 1 A schematic diagram is shown for measuring proteins that bind to a solid surface.

[0029] Figure 2 This demonstrates the binding of a protein to a solid surface in the absence of a surfactant.

[0030] Figure 3 The study demonstrates how various surfactants can be added to prevent proteins from binding to solid surfaces.

[0031] Figure 4 This demonstrates that adding a surfactant to a solid surface before adding the protein is more effective in preventing the protein from binding to the surface.

[0032] Figure 5 The effects of different surfactants at the same concentration on the leaching of di-2-ethylhexyl phthalate (DEHP) from DEHP-containing PVC are shown.

[0033] Figure 6 The effect of different surfactants at the same CMC multiple on the leaching of DEHP from DEHP-containing PVC is shown. Detailed Implementation

[0034] The invention disclosed herein is based on the surprising discovery that when surfactants are used at concentrations below their critical micelle concentration, low concentrations of protein in liquid compositions can be stabilized and protein loss due to adsorption onto solid surfaces can be effectively prevented.

[0035] In some embodiments, this document discloses an aqueous composition comprising a protein and a surfactant, wherein the protein is present in the composition at a concentration between about 0.001 μg / ml and about 100 μg / ml, and the surfactant is present in the composition at a concentration of at least about 0.25 times the critical micelle concentration (CMC) of the surfactant.

[0036] The surfactant that can be used in the composition can be any surfactant commonly used in pharmaceutical compositions. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant is a polysorbate, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, or polysorbate 85. In some embodiments, the surfactant is polysorbate 20; in other embodiments, the surfactant is polysorbate 80. In some embodiments, the surfactant is poloxamer, such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407. In some embodiments, the surfactant is Triton X-100. Various surfactants are commercially available (e.g., Tween 20, Tween 80, Pluronic F68, and Pluronic F127, etc.).

[0037] The surfactant may be present in the composition at a concentration of at least about 0.25 times (0.25x) of the surfactant's critical micelle concentration (CMC). In some embodiments, the surfactant is present in the composition at a concentration between about 0.25 times and about 20 times the surfactant's CMC. In some embodiments, the surfactant is present in the composition at a concentration between about 0.25 times and about 15 times, or between about 0.25 times and about 10 times, or between about 0.25 times and about 8 times, or between about 0.25 times and about 6 times, or between about 0.25 times and about 4 times, or between about 0.25 times and about 2 times, or between about 0.25 times and about 1 times the surfactant's CMC.

[0038] In some embodiments, the surfactant is present in the composition at a concentration between about 0.5 times and about 20 times the CMC of the surfactant. In some embodiments, the surfactant is present in the composition at a concentration between about 0.5 times and about 15 times, or between about 0.5 times and about 10 times, or between about 0.5 times and about 8 times, or between about 0.5 times and about 6 times, or between about 0.5 times and about 4 times, or between about 0.5 times and about 2 times, or between about 0.5 times and about 1 time.

[0039] In some embodiments, the surfactant is present in the composition at a concentration of about 0.25 times, about 0.5 times, about 1 time, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 12 times, about 14 times, about 16 times, about 18 times, or about 20 times the CMC of the surfactant. In some embodiments, the surfactant is present in the composition at a concentration of about 1.25 times, about 2.5 times, about 3.5 times, about 4.5 times, about 5.5 times, about 6.5 times, about 7.5 times, about 8.5 times, or about 9.5 times the CMC of the surfactant.

[0040] As used herein, the term “about” when used to modify a particular value or range should be understood to mean that variations may exist within a given value or range, including up to 20% of the specified value or range (e.g., up to 10%, 5%, 4%, 3%, 2%, or 1%).

[0041] Critical micelle concentration (CMC) refers to the concentration of a surfactant above which micelles will form; it is a property of surfactants. The CMC value of a surfactant can be measured using experimental methods well-known in the art, such as fluorescence assays, surface tension and conductivity measurements, and dynamic light scattering. See, for example, Norman Scholz, Thomas Behnke, Ute Resch-Genger. Journal of Fluorescence 28:465-476 (2018) and... Topel, Acar Leyla Budama, Numan Hoda. Journal of Molecular Liquids, 177, 40-43 (2013). The CMC value of surfactants can also be obtained using, for example... Use a Sigma 700 or 701 device for automatic measurement.

[0042] In some embodiments, the CMC values ​​for each surfactant are listed in Table 1 below.

[0043] Table 1. CMC of commonly used surfactants

[0044] Polysorbate 20 0.007 Polysorbate 80 0.002 Polosham 188 0.4 Polosham 407 0.004 Qulaton X-100 0.014

[0045] *For the CMC values ​​listed in the table, see, for example, le Maire M, Champey P, Moller JV. 2000. Interaction of membrane proteins and lipids with solubilizing detergents. Biochim Biophys Acta 1508:86-111; Suksiriworapong J, Rungvimolsin T, A-gomol A, Junyaparasert VB, Chantasart D. Development and characterization of lyophilized diazepam-loaded polymeric micelles. 2014. AAPS PharmSciTech [AAPS Pharmaceutical Technology]. 15(1):52-64; https: / / www.sigmaaldrich.com / content / dam / sigma-aldrich / docs / Sigma / Product_Information_Sheet / 1 / t8532pis.pdf

[0046] The protein may be present in the composition at a concentration between about 0.001 μg / ml and about 100 μg / ml. In some embodiments, the protein is present at a concentration between about 0.001 μg / ml and about 90 μg / ml, or between about 0.001 μg / ml and about 80 μg / ml, or between about 0.001 μg / ml and about 70 μg / ml, or between about 0.001 μg / ml and about 60 μg / ml, or between about 0.001 μg / ml and about 50 μg / ml, or between about 0.001 μg / ml and about 40 μg / ml. The concentration is present in the composition between about 0.001 μg / ml and about 30 μg / ml, or between about 0.001 μg / ml and about 20 μg / ml, or between about 0.001 μg / ml and about 10 μg / ml, or between about 0.001 μg / ml and about 5 μg / ml, or between about 0.001 μg / ml and about 1 μg / ml, or between about 0.001 μg / ml and about 0.01 μg / ml.

[0047] In some embodiments, the protein concentration is between about 0.01 μg / ml and about 100 μg / ml, or between about 0.01 μg / ml and about 80 μg / ml, or between about 0.01 μg / ml and about 70 μg / ml, or between about 0.01 μg / ml and about 60 μg / ml, or between about 0.01 μg / ml and about 50 μg / ml, or between about 0.01 μg / ml and about 40 μg / ml, or between about 0.01 μg / ml and... The concentration is present in the composition in the range of about 30 μg / ml, or between about 0.01 μg / ml and about 20 μg / ml, or between about 0.01 μg / ml and about 10 μg / ml, or between about 0.01 μg / ml and about 5 μg / ml, or between about 0.01 μg / ml and about 1 μg / ml, or between about 0.01 μg / ml and about 0.1 μg / ml, or between about 0.1 μg / ml and about 1 μg / ml, or between about 0.1 μg / ml and about 51 μg / ml.

[0048] In some embodiments, the protein is present in the composition at concentrations of about 0.001 μg / ml, about 0.005 μg / ml, about 0.01 μg / ml, about 0.05 μg / ml, about 0.1 μg / ml, about 1 μg / ml, about 4 μg / ml, about 8 μg / ml, about 10 μg / ml, about 15 μg / ml, about 20 μg / ml, about 25 μg / ml, about 30 μg / ml, about 35 μg / ml, about 40 μg / ml, about 45 μg / ml, about 50 μg / ml, about 55 μg / ml, about 60 μg / ml, about 65 μg / ml, about 70 μg / ml, about 75 μg / ml, about 80 μg / ml, about 85 μg / ml, about 90 μg / ml, about 95 μg / ml, or about 100 μg / ml.

[0049] In the compositions disclosed herein, any concentration or range of protein may be combined with any concentration or range of surfactant.

[0050] Any protein can be a protein in the composition. In some embodiments, the protein in the composition is a therapeutic protein, such as an antigen-binding protein or a fusion protein.

[0051] As used herein, the term "antigen-binding protein" refers to a protein that specifically binds to one or more target antigens. Antigen-binding proteins include, but are not limited to, antibodies (e.g., monoclonal antibodies). Antigen-binding proteins typically comprise an antigen-binding fragment that specifically binds to an antigen, and optionally include a scaffold or framework portion that causes the antigen-binding fragment to present a conformation that facilitates the binding of the antigen-binding protein to the antigen. An "antigen-binding fragment" refers to a portion of an antibody that lacks at least some of the amino acids present in the full-length heavy chain and / or light chain but is still capable of specifically binding to an antigen. Antigen-binding fragments include, but are not limited to, single-chain variable fragments (scFv), nanobodies (e.g., the VH domain of a camelid heavy chain antibody; VHH fragment, see Cortez-Retamozo et al., Cancer Research, Vol. 64: 2853-57, 2004), Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, Fd fragments, and complementarity-determining regions (CDR) fragments, and may be derived from any mammalian source, such as human, mouse, rat, rabbit, or camelid. Antigen-binding fragments can compete with intact antibodies for binding to target antigens, and these fragments can be generated by modifying intact antibodies (e.g., enzymatic or chemical cleavage) or by de novo synthesis using recombinant DNA techniques or peptide synthesis known in the art.

[0052] In some embodiments, the protein is a bispecific antigen-binding protein. As used herein, the term "bispecific" refers to an antigen-binding protein capable of specifically binding to two different antigens or targets or epitopes. As used herein, "epitope" refers to any determinant cluster capable of being specifically bound by an antigen-binding protein such as an antibody or a fragment thereof. In some embodiments, the bispecific antigen-binding protein comprises a first domain that specifically binds to one antigen or target and a second domain that specifically binds to another antigen or target. In some embodiments, the first domain of the bispecific antigen-binding protein specifically binds to a target cell surface antigen, and the second binding domain of the bispecific antigen-binding protein specifically binds to human CD3 (a subunit of the T cell receptor complex on T cells). In some preferred embodiments, the bispecific antigen-binding protein is a bispecific T cell connective as described, for example, in WO 2008119567 and WO2017134140. Antibody constructs.

[0053] As used herein, the term "antibody construct" refers to a molecule whose structure and / or function are based on the structure and / or function of an antibody (e.g., a full-length or intact immunoglobulin molecule) and / or extracted from the variable heavy chain (VH) and / or variable light chain (VL) domains of an antibody or a fragment thereof. Thus, antibody constructs are capable of binding to their specific targets or antigens. Antibody constructs also include modified antibody fragments such as scFv, discFv or bis(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, biantibodies, single-chain biantibodies, tandem biantibodies (Tandab), tandem discFv, tandem triscFv, "multi-antibodies" (such as tri- or tetra-antibodies), and single-domain antibodies (such as nanobodies or single-variable-domain antibodies containing only one variable domain (which may be a VHH, VH, or VL that binds to an antigen or epitope independently of other V regions or domains).

[0054] In some embodiments, the bispecific antibody construct comprises a first binding domain and a second binding domain, wherein the first binding domain specifically binds to a first cell surface antigen, and the second binding domain specifically binds to human CD3. In some embodiments, the first and second domains of the bispecific antibody construct are “bispecific single-chain antibody constructs,” more preferably bispecific “single-chain Fv” (scFv). In scFv, the VL and VH regions of the antibody are linked, for example, by a synthetic linker, to form a single protein chain in which the VL and VH regions pair to form a monovalent molecule; see, for example, Huston et al. (1988) Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America] 85:5879-5883. The linker may be a short peptide of about 10 to about 25 amino acids, preferably about 15 to 20 amino acids. The linker is typically enriched with glycine for flexibility and serine or threonine for solubility, and may link the N-terminus of VH to the C-terminus of VL, and vice versa. Despite the removal of the constant region and the introduction of a linker, scFv retains the specificity of the original immunoglobulin. The VH and VL regions are arranged in a VH-VL or VL-VH order. Preferably, the VH region is located at the N-terminus of the linker sequence, and the VL region is located at the C-terminus of the linker sequence. In some embodiments, the first and second domains of the bispecific antibody construct are oligomers selected from (scFv)2, scFv single-domain mAbs, biantibodies, and any of these forms.

[0055] In some embodiments, the bispecific antibody construct further comprises a third domain. In some embodiments, the third domain is a single-chain Fc (scFc) domain. In some embodiments, the scFc domain is a scFc half-life extension (HLE) domain. In some preferred embodiments, the third domain of the bispecific antibody construct is an HLE domain with the following amino-to-carboxyl sequence: hinge-CH2-CH3-linker-hinge-CH2-CH3.

[0056] In some embodiments, the first binding domain of the bispecific antibody construct binds to a first cell surface antigen. In some embodiments, the first cell surface antigen is CD70. CD70 (also known as CD27L or TNFSF7) is a type II integrated membrane protein whose normal expression is limited to subsets of activated T cells and B cells, mature dendritic cells, and thymic medullary epithelial cells.

[0057] In some embodiments, the first cell surface antigen is a tumor antigen. As used herein, the term "tumor antigen" should be understood to refer to those antigens presented on tumor cells. These antigens can be presented on the cell surface having an extracellular portion that typically binds to both the transmembrane and cytoplasmic portions of a molecule. Sometimes these antigens can only be presented by tumor cells and not by normal cells. Tumor antigens may be expressed only on tumor cells or may represent tumor-specific mutations compared to normal cells. In such cases, they are referred to as tumor-specific antigens. More commonly, antigens are presented by both tumor cells and normal cells, and these are referred to as tumor-associated antigens. These tumor-associated antigens may be overexpressed compared to normal cells, or may be accessible to antibody binding in tumor cells due to the less compact structure of tumor tissue compared to normal tissue. In some embodiments, the first binding domain binds to a tumor antigen selected from the group consisting of: CD19, CD33, epidermal growth factor receptor variant III (EGFRvIII), mesothelin (MSLN), cadherin 19 (CDH19), FMS-like tyrosine kinase 3 (FLT3), delta-like ligand 3 (DLL3), placental cadherin (CDH3), B-cell maturation antigen (BCMA), prostate-specific membrane antigen (PSMA), human mucin 17 (MUC17), and claudin-18 isotype 2 (CLDN18.2). In some embodiments, the tumor antigen is a human tumor antigen.

[0058] In some preferred embodiments, the bispecific antibody construct comprises a first domain, a second domain, and an optional third domain, wherein the first domain binds to CD70, the second domain binds to human CD3, and the third domain (if present) is an HLE domain with the amino-to-carboxyl sequence as follows: hinge-CH2-CH3-linker-hinge-CH2-CH3. In other preferred embodiments, the bispecific antibody construct comprises a first domain, a second domain, and an optional third domain, wherein the first domain binds to a tumor antigen selected from the group consisting of CD19, CD33, EGFRvIII, MSLN, CDH19, FLT3, DLL3, CDH3, BCMA, PSMA, MUC17, and C:DN18.2, the second domain binds to human CD3, and the third domain (if present) is an HLE domain with the amino-to-carboxyl sequence as follows: hinge-CH2-CH3-linker-hinge-CH2-CH3. In a preferred embodiment, the first and second domains are linked together via a peptide linker and connected to a third domain (if present) via a peptide linker. Preferred peptide linkers have been described above and are characterized by having the amino acid sequence Gly-Gly-Gly-Gly-Ser (i.e., Gly4Ser) or a polymer thereof (i.e., (Gly4Ser)x), where x is an integer of 1 or greater (e.g., 2, 3, 4, 5, 6, or 7). In some preferred embodiments, the second binding domain comprises a polypeptide having the amino acid sequence SEQ ID NO: 201.

[0059] In some embodiments, the first binding domain specifically binds to CD33. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 1-15.

[0060] In some embodiments, the first binding domain specifically binds to EGFRvIII. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 16-26.

[0061] In some embodiments, the first binding domain specifically binds to the MSLN. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 27-38 and 165.

[0062] In some embodiments, the first binding domain specifically binds to CDH19. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO:39-56.

[0063] In some embodiments, the first binding domain specifically binds to DLL3. In some embodiments, the first binding domain comprises a polypeptide having the amino acid sequence SEQ ID NO: 68-78.

[0064] In some embodiments, the first binding domain specifically binds to CD19. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO:79-88.

[0065] In some embodiments, the first binding domain specifically binds to FLT3. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 57-67.

[0066] In some embodiments, the first binding domain specifically binds to CDH3. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 89-99.

[0067] In some embodiments, the first binding domain specifically binds to BCMA. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 100-110.

[0068] In some embodiments, the first binding domain specifically binds to PSMA. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 111-155, 166, and 167.

[0069] In some embodiments, the first binding domain specifically binds to CD70. In some embodiments, the first binding domain comprises a polypeptide having an amino acid sequence having any one of SEQ ID NO: 156-164.

[0070] In some embodiments, the second binding domain of the bispecific antibody construct specifically binds to human CD3ε on the surface of T cells. In some embodiments, the second domain of the bispecific antibody construct specifically binds to an extracellular exosite of the human CD3ε chain. In some embodiments, the second domain of the bispecific antibody construct specifically binding to human CD3 includes a VL region and a VH region, wherein the VL region includes CDR-L1 having the amino acid sequence of SEQ ID NO:193, CDR-L2 having the amino acid sequence of SEQ ID NO:194, and CDR-L3 having the amino acid sequence of SEQ ID NO:195, and the VH region includes CDR-H1 having the amino acid sequence of SEQ ID NO:196, CDR-H2 having the amino acid sequence of SEQ ID NO:197, and CDR-H3 having the amino acid sequence of SEQ ID NO:198.

[0071] In some embodiments, the second domain of the bispecific antibody construct comprises VH having the amino acid sequence of SEQ ID NO:199 and VL having the amino acid sequence of SEQ ID NO:200. In some embodiments, the second domain of the bispecific antibody construct comprises a polypeptide having the amino acid sequence of SEQ ID NO:201.

[0072] In some embodiments, the protein is a CD70xCD3 bispecific antibody construct comprising a first domain that specifically binds to CD70 and a second domain that specifically binds to CD3. In one embodiment, the first domain specifically binds to CD70 and comprises a CDR as shown in SEQ ID NO:156-161, and the second domain specifically binds to CD3 and comprises a CDR as shown in SEQ ID NO:193-198. In some embodiments, the bispecific antibody construct further comprises an HLE domain (third domain). In one embodiment, the bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:162, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:163. In one embodiment, the CD70xCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:164.

[0073] In some embodiments, the protein is a BCMAxCD3 bispecific antibody construct comprising a first domain that specifically binds to BCMA and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to BCMA and has a CDR as shown in SEQ ID NO:100-105, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the BCMAxCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:106, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:107. In one embodiment, the BCMAxCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:108. In one embodiment, the BCMAxCD3 bispecific antibody construct comprises a polypeptide containing the amino acid sequence of SEQ ID NO:109 or substantially consisting of that amino acid sequence. In another embodiment, the BCMAxCD3 bispecific antibody construct comprises a polypeptide containing the amino acid sequence of SEQ ID NO:110 or substantially consisting of that amino acid sequence.

[0074] In some embodiments, the bispecific antibody is a CD33xCD3 bispecific antibody construct comprising a first domain that specifically binds to CD33 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody construct further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to CD33 and has a CDR as shown in SEQ ID NO:3-5 and 8-10, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the CD33xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:1 or 2, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:6 or 7. In another embodiment, the CD33xCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of any one of SEQ ID NO:11 or 12. In another embodiment, the BCMAxCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:13 or 15, or a polypeptide consisting substantially of or composed of that amino acid sequence.

[0075] In some embodiments, the protein is an EGFRvIIIxCD3 bispecific antibody construct comprising a first domain that specifically binds to EGFRvIII and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to EGFRvIII and has a CDR as shown in SEQ ID NO:16-21, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the EGFRvIIIxCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:22, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:23. In one embodiment, the EGFRvIIIxCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:24 or 25. In one embodiment, the EGFRvIIIxCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:24 or 26, or a polypeptide consisting substantially of or composed of that amino acid sequence.

[0076] In some embodiments, the protein is an MSLNxCD3 bispecific antibody construct comprising a first domain that specifically binds to MSLN and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody construct further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to MSLN and has a CDR as shown in SEQ ID NO:27-32, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the MSLNxCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:33, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:34. In one embodiment, the MSLNxCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of any one of SEQ ID NO:35-38. In one embodiment, the MSLNxCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:165 or consisting substantially of that amino acid sequence or a polypeptide consisting of that amino acid sequence.

[0077] In some embodiments, the protein is a CDH19xCD3 bispecific antibody construct comprising a first domain that specifically binds to CDH19 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to CDH19 and has a CDR as shown in SEQ ID NO:39-44, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the CDH19xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:45 or 51, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:46 or 52. In one embodiment, the CDH19xCD3 bispecific antibody construct comprises an amino acid sequence containing any one of SEQ ID NO:47, 48-50, and 53-56, or a polypeptide consisting substantially of such amino acid sequences. In another embodiment, the CDH19xCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:48, or a polypeptide consisting substantially of such amino acid sequences.

[0078] In some embodiments, the protein is a DLL3xCD3 bispecific antibody comprising a first domain that specifically binds to DLL3 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to DLL3 and has a CDR as shown in SEQ ID NO:68-73, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the DLL3xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:74, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:75. In one embodiment, the DLL3xCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:76-78. In one embodiment, the DLL3xCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:78 or a polypeptide consisting substantially of or composed of that amino acid sequence.

[0079] In some embodiments, the protein is an FLT3xCD3 bispecific antibody construct comprising a first domain that specifically binds to FLT3 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to FLT3 and has a CDR as shown in SEQ ID NO:57-62, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the FLT3xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:63, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:64. In one embodiment, the FLT3xCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequences of any one of SEQ ID NO:65-67. In one embodiment, the FTL3xCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:67 or a polypeptide consisting substantially of or composed of that amino acid sequence.

[0080] In some embodiments, the protein is a CDH3xCD3 bispecific antibody construct comprising a first domain that specifically binds to CDH3 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody construct further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to CDH3 and has a CDR as shown in SEQ ID NO:89-94, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the CDH3xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:95, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:96. In one embodiment, the CDH3xCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of any one of SEQ ID NO:97-99. In one embodiment, the CDH3xCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:99 or a polypeptide consisting substantially of or composed of that amino acid sequence.

[0081] In some embodiments, the protein is a PSMAxCD3 bispecific antibody construct comprising a first domain that specifically binds to PSMA and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody construct further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to PSMA and has a CDR as shown in any one of SEQ ID NO: 111-116, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO: 193-198. In one embodiment, the first domain binds to PSMA and has a CDR as shown in any one of SEQ ID NO: 126-131 and 141-146, and the second domain binds to CD3 and has a CDR as shown in SEQ ID NO: 193-198. In one embodiment, the PSMAxCD3 bispecific antibody comprises VH and VL, wherein the VH comprises an amino acid sequence containing or substantially composed of the amino acid sequence of SEQ ID NO: 117, 132, or 147, and the VL comprises an amino acid sequence containing or substantially composed of the amino acid sequence of SEQ ID NO: 118, 133, or 148. In one embodiment, the PSMAxCD3 bispecific antibody construct comprises an amino acid sequence containing or substantially composed of the amino acid sequence of any one of SEQ ID NO: 119-125, 134-140, and 149-155. In one embodiment, the PSMAxCD3 bispecific antibody construct comprises an amino acid sequence containing or substantially composed of the amino acid sequence of any one of SEQ ID NO: 121, 122, 124, 125, 136, 137, 139, 140, 151, 152, 154, and 155. In one embodiment, the PSMAxCD3 bispecific antibody construct comprises an amino acid sequence containing SEQ ID NO:166 or 167, or a polypeptide consisting substantially of or composed of that amino acid sequence.

[0082] In some embodiments, the protein is a Cldn18.2xCD3 bispecific antibody construct comprising a first domain that specifically binds to Cldn18.2 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to Cldn18.2 and has a CDR as shown in SEQ ID NO:168-173, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the Cldn18.2xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:174, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:175. In one embodiment, the Cldn18.2xCD3 bispecific antibody construct comprises a polypeptide containing or substantially consisting of the amino acid sequence SEQ ID NO: 176 or 178. In another embodiment, the Cldn18.2xCD3 bispecific antibody construct comprises a polypeptide containing or substantially consisting of the amino acid sequence SEQ ID NO: 178.

[0083] In some embodiments, the protein is a MUC17xCD3 bispecific antibody construct comprising a first domain that specifically binds to MUC17 and a second domain that specifically binds to CD3. In some embodiments, the bispecific antibody further comprises an HLE domain (a third domain). In one embodiment, the first domain specifically binds to MUC17 and has a CDR as shown in SEQ ID NO:184-189, and the second domain specifically binds to CD3 and has a CDR as shown in SEQ ID NO:193-198. In one embodiment, the MUC17xCD3 bispecific antibody construct comprises VH and VL, wherein the VH comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:190, and the VL comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:191. In one embodiment, the MUC17xCD3 bispecific antibody construct comprises a polypeptide containing or substantially composed of the amino acid sequence of SEQ ID NO:192.

[0084] In some embodiments, the bispecific antibody construct comprises an amino acid sequence containing or substantially consisting of the amino acid sequence of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:48, SEQ ID NO:67, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:178, or SEQ ID NO:192.

[0085] The bispecific antibodies disclosed herein can be prepared using methods known in the art. For example, bispecific antibodies can be prepared using the methods disclosed in WO 2008 / 119657 and WO 2017 / 134140.

[0086] Additional excipients that can be used in compositions

[0087] In some embodiments, the composition further comprises one or more excipients suitable for pharmaceutical compositions. In some embodiments, the composition further comprises a salt, a buffer, a sugar or sugar derivative, an amino acid, or a preservative, or a combination of two or more of the foregoing substances. In some embodiments, the composition further comprises a salt, a sugar or sugar derivative, an amino acid, and optionally a preservative. In some embodiments, the composition further comprises a salt, a buffer, a sugar or sugar derivative, and an amino acid. In some embodiments, the composition further comprises a salt, a buffer, a sugar or sugar derivative, an amino acid, and a preservative.

[0088] Exemplary salts that can be used in the composition include salts suitable for use in pharmaceutical compositions (e.g., NaCl). Exemplary buffers that can be used in the composition include acetate buffers, glutamate buffers, citrate buffers, succinate buffers, tartrate buffers, fumarate buffers, maleate buffers, histidine buffers, and phosphate buffers. Exemplary sugars or sugar derivatives include monosaccharides, disaccharides, cyclic polysaccharides, and sugar alcohols, such as sugars (e.g., sucrose and trehalose) and sugar alcohols (e.g., mannitol or sorbitol). Exemplary amino acids include lysine, histidine, arginine, glycine, methionine, and alanine. Exemplary preservatives include benzoates (e.g., benzyl alcohol and sodium benzoate) and sorbates (e.g., potassium sorbate).

[0089] The pH of the composition can be in the range of about 3.5 to 7.5. In some embodiments, the composition has a pH of about 4.0 to about 7.0. In some embodiments, the composition has a pH of about 4.2 to about 7.0, or about 5.0 to about 7.0, or about 5.5 to about 7.0, or about 6.0 to about 7.0, or about 6.5 to about 7.0, or about 4.2 to about 6.5, or about 4.2 to about 6.0, or about 4.2 to about 5.5, or about 4.2 to about 5.0, or about 5.0 to about 6.0, or about 5.0 to about 6.5, or about 5.0 to about 5.5, or about 5.5 to about 6.0, or about 5.5 to about 6.5, or about 5.5 to about 6.0, or about 6.0 to about 6.5. In some embodiments, the pH of the composition is about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, or about 7.5.

[0090] The pH of the composition can be achieved by using one or more buffers listed above. In some embodiments, the composition comprises a buffer selected from acetate buffers, glutamate buffers, citrate buffers, succinate buffers, tartrate buffers, fumarate buffers, maleate buffers, histidine buffers, and phosphate buffers. In some embodiments, the composition comprises a combination of two buffers selected from the above list (e.g., glutamate buffers and citrate buffers).

[0091] In some embodiments, the composition substantially does not contain additional buffering agents. As used herein, the phrase “substantially does not contain additional buffering agents” means that the composition does not contain any buffering agents added to adjust and / or maintain the pH of the composition. For example, a saline solution (0.9% NaCl solution) contains no additional buffering agents and has a pH of about 5.5. The pH of a saline solution is believed to be achieved and maintained in part by atmospheric CO2 dissolved in the water. See, for example, Reddi, B.AJ Int.J.Med.Sci [International Journal of Medical Sciences]. 10:747-750 (2013). Such compositions may contain residual buffering agents that do not contribute to the buffering capacity of the composition.

[0092] In some embodiments, the composition comprises any concentration of protein disclosed above, any concentration of surfactant disclosed above, and further comprises a salt (e.g., NaCl), a sugar (e.g., sucrose), an amino acid (e.g., lysine), and optionally a preservative (e.g., benzyl alcohol). In some embodiments, the composition comprises any concentration of protein disclosed above, any concentration of surfactant disclosed above, and further comprises a salt (e.g., NaCl), a sugar (e.g., sucrose), an amino acid (e.g., lysine), a buffer (e.g., glutamate and / or citrate buffer), and optionally a preservative (e.g., benzyl alcohol). The pH of the composition can be any pH value disclosed above. In some embodiments, the pH of the composition is about 5.5.

[0093] In some embodiments, the compositions disclosed herein are pharmaceutical compositions. As used herein, the term "pharmaceutical composition" should be understood to mean a formulation comprising a protein (e.g., a bispecific antibody construct) suitable for injection and / or administration to a patient (e.g., a human) in need. More specifically, the pharmaceutical composition is substantially sterile and does not contain any agents that are excessively toxic or infectious to the recipient.

[0094] Container for the composition

[0095] In some embodiments, the compositions disclosed herein are contained in a container. Containers that may be used herein include those suitable for pharmaceutical use, such as containers made of non-toxic materials that maintain physical integrity. In some embodiments, the container is a component for intravenous (IV) administration. As used herein, the phrase “component for IV administration” should be understood to mean a portion of a container or system that is accessible to the composition during IV administration. In some embodiments, the container is an IV bag or IV tube.

[0096] Materials that can be used to manufacture containers include those commonly used in the manufacture of pharmaceutical containers, such as glass and plastic.

[0097] In some embodiments, the container is a plastic container. In some embodiments, the container is made of a material comprising polyolefins (e.g., polypropylene (PP) and polyethylene (PE)), polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), or polyurethanes (e.g., polyesters and polyethers). In some embodiments, the container is made of a material comprising PVC. In some embodiments, the PVC is substantially free of di-2-ethylhexyl phthalate (DEHP) or tri-2-ethylhexyl trimellitate (TOTM). As used herein, the term "substantially free" should be understood to mean that DEHP or TOTM is not used and / or not detected in the PVC. DEHP and TOTM are plasticizers that can be used to make PVC softer so that it can be made into different shapes. In some embodiments, the container is made of a material that does not contain PVC.

[0098] In some embodiments, the container is made of a material comprising polyolefin, EVA, or polyurethane (e.g., polyester and polyether). In some embodiments, the container is made of a material comprising PP and / or PE.

[0099] Under certain conditions, DEHP or TOTM contained in certain types of PVC plastics can leach out of the plastic in the presence of certain surfactants (e.g., polysorbates, see Example 3) at certain concentrations. Without wishing to be bound by any particular theory, it is believed that the higher the lipophilicity of the surfactant, the easier it is for DEHP or TOTM to leach out in the presence of the surfactant. The hydrophilic-lipophilic balance (HLB) of a surfactant is a measure of its degree of hydrophilicity or lipophilicity and can be calculated using methods known in the art. See, for example, Griffin, William C. Calculation of HLB Values ​​of Non-Ionic Surfactants, Journal of the Society of Cosmetic Chemists, 5(4):249-56 (1954). HLB values ​​can be used to predict the properties of surfactants; for example, HLB > 10 indicates that the surfactant is more soluble in water (insoluble in lipids), while HLB < 10 indicates that the surfactant is more soluble in lipids (insoluble in water). Exemplary surfactants that may be used in the compositions disclosed herein include HLB values ​​of 17 (polysorbate 20) and 15 (polysorbate 80). https: / / pharmlabs.unc.edu / labs / emulsions / hlb.htm ) and 29 (Polosham 188)( http: / / www.rumapel.com.ar / cosmetica_ miscelaneos / ficha_tecnica / Pluracare%20L-%20F%20Grades.pdf In embodiments where the container is made of PVC plastic containing DEHP or TOTM, the surfactant in the composition preferably has an HLB value of at least 20 (e.g., poloxamer, see Example 3), more preferably an HLB value between 20 and 30.

[0100] Containers made from the materials listed above, such as IV components (e.g., IV bags and tubes for IV administration), are commercially available. Suitable containers are available, for example, from manufacturers such as Baxter Healthcare Corporation and B. Braun Medical Inc.

[0101] pharmaceutical preparations

[0102] This document also discloses pharmaceutical formulations comprising the aqueous composition disclosed above. As used herein, the term "pharmaceutical formulation" should be understood to mean a formulation containing the aqueous composition disclosed herein in a suitable pharmaceutical container prior to administration to a patient (e.g., a person). In some embodiments, this document discloses a pharmaceutical formulation containing an aqueous pharmaceutical composition in a container, wherein the aqueous pharmaceutical composition comprises: a) a protein at a concentration between about 0.001 μg / ml and about 100 μg / ml, and b) a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant, and wherein the protein is not blinatumomab.

[0103] In some embodiments, the surfactant included in the composition is a polysorbate. In some embodiments, the surfactant is a polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85. In some embodiments, the surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the surfactant is poloxamer. In some embodiments, the surfactant is poloxamer 188 or poloxamer 407. In some embodiments, the surfactant is Triton X-100.

[0104] In some embodiments, this document discloses a pharmaceutical formulation comprising an aqueous pharmaceutical composition in a container, wherein the aqueous pharmaceutical composition comprises: a) a bispecific antibody construct at a concentration between about 0.001 μg / ml and about 100 μg / ml, and b) a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant, wherein the surfactant is poloxamer. In some embodiments, the poloxamer is poloxamer 188 or poloxamer 407.

[0105] In some embodiments, the surfactant is present in the composition at a concentration between about 0.25 times and about 20 times the CMC of the surfactant. In some embodiments, the surfactant is present in the composition at a concentration between about 0.25 times and about 10 times the CMC of the surfactant. In some embodiments, the surfactant is present in the composition at a concentration within any of the concentration ranges disclosed above. In some embodiments, the surfactant is present in the composition at a concentration that is any of the concentrations disclosed above. The CMC value of the surfactant can be determined by the methods disclosed above. In some embodiments, the CMC values ​​of certain commonly used surfactants are listed in Table 1.

[0106] In some embodiments, the aqueous pharmaceutical composition comprises a protein at a concentration between about 0.001 μg / ml and about 50 μg / ml. In some embodiments, the composition comprises a protein (e.g., a bispecific antibody construct) at a concentration within any range disclosed above. In some embodiments, the protein (e.g., a bispecific antibody construct) is present in the composition at any concentration disclosed above. Any concentration or concentration range of the protein disclosed above may be combined with any concentration or concentration range of the surfactant disclosed above.

[0107] As disclosed above, the protein can be a therapeutic protein, such as an antigen-binding protein and a fusion protein. In some embodiments, the protein is a bispecific antigen-binding protein. In some embodiments, the protein is a bispecific antibody construct disclosed above. In some embodiments, the protein is a CD70xCD3 bispecific antibody construct. In some embodiments, the protein is a BCMAxCD3 bispecific antibody construct. In some embodiments, the protein is a CD33xCD3 bispecific antibody construct. In some embodiments, the protein is an EGFRvIIIxCD3 bispecific antibody construct. In some embodiments, the protein is an MSLNxCD3 bispecific antibody construct. In some embodiments, the protein is a CDH19xCD3 bispecific antibody construct. In some embodiments, the protein is a DLL3xCD3 bispecific antibody construct. In some embodiments, the protein is an FLT3xCD3 bispecific antibody construct. In some embodiments, the protein is a CDH3xCD3 bispecific antibody construct. In some embodiments, the protein is a PSMAxCD3 bispecific antibody construct. In some embodiments, the protein is a Cldn18.2xCD3 bispecific antibody construct. In some embodiments, the protein is a MUC17xCD3 bispecific antibody construct. Each of these bispecific antibody constructs is disclosed above. In some embodiments, the protein comprises, is substantially composed of, or consists of, the amino acid sequences of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:48, SEQ ID NO:67, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:178, or SEQ ID NO:192.

[0108] The pH of the composition can be within any pH range disclosed above. In some embodiments, the pH of the composition can be any pH disclosed above.

[0109] In some embodiments, the aqueous pharmaceutical composition further comprises one or more excipients suitable for use in the pharmaceutical composition. In some embodiments, the aqueous pharmaceutical composition further comprises a salt, a buffer, an amino acid, a sugar or a sugar derivative, a preservative, or a combination thereof. In some embodiments, the aqueous pharmaceutical composition further comprises a salt, an amino acid, a sugar or a sugar derivative, a preservative, or a combination thereof. Exemplary salts, buffers, amino acids, sugars or their derivatives, and preservatives that can be used in the composition are disclosed above.

[0110] In some embodiments, the container is a plastic container. In some embodiments, the container is made of a material comprising polyolefins (e.g., PP and PE), PVC, EVA, or polyurethanes (e.g., polyesters and polyethers). In some embodiments, the container is made of a material comprising PVC. In some embodiments, the PVC is substantially free of DEHP or TOTM. In some embodiments, the container is made of a material that does not contain PVC.

[0111] In some embodiments, the surfactant included in the composition is poloxamer, and the container may be made of a material comprising polyolefins, PVC, EVA, or polyurethane (e.g., polyesters and polyethers). In some embodiments, the surfactant included in the composition is polysorbate or Triton X-100, and the container may be made of a material comprising polyolefins, PVC, EVA, or polyurethane (e.g., polyesters and polyethers) that is substantially free of DEHP or TOTM.

[0112] In some embodiments, the container is a component for intravenous (IV) administration. In some embodiments, the container is an IV bag or IV tube.

[0113] In some embodiments, the pharmaceutical formulation comprises an aqueous pharmaceutical composition in a container, wherein the aqueous pharmaceutical composition comprises a bispecific antibody construct (e.g., any bispecific antibody construct disclosed herein), a surfactant (e.g., any surfactant disclosed herein), and further comprises a salt (e.g., NaCl), an amino acid (e.g., lysine), a sugar or sugar derivative (e.g., sucrose or mannitol), an optional preservative (e.g., benzyl alcohol), and wherein the container is made of a material comprising polyolefin, PVC, EVA, or polyurethane (e.g., polyester and polyether). In some embodiments, the pharmaceutical formulation comprises an aqueous pharmaceutical composition in a container, wherein the aqueous pharmaceutical composition comprises a bispecific antibody construct (e.g., any bispecific antibody construct disclosed herein), a surfactant (e.g., any surfactant disclosed herein), and further comprises a salt (e.g., NaCl), a buffer (e.g., a glutamate buffer and / or a citrate buffer), an amino acid (e.g., lysine), a sugar or sugar derivative (e.g., sucrose or mannitol), an optional preservative (e.g., benzyl alcohol), and wherein the container is made of a material comprising a polyolefin, PVC, EVA, or polyurethane (e.g., polyester and polyether). The concentration of the bispecific antibody construct may be any concentration disclosed above for proteins. The concentration of the surfactant may be any concentration disclosed above. The pH of the composition is in the range of about 3.5 to about 7.0. In some embodiments, the pH of the composition is about 5.5. In some embodiments, the container is an IV bag.

[0114] Method of applying the composition

[0115] This document also discloses methods for administering the compositions disclosed herein to a patient. In some embodiments, this document discloses a method for administering a protein to a patient, the method comprising a) preparing an aqueous pharmaceutical composition in a container, wherein the aqueous pharmaceutical composition comprises a protein (e.g., a bispecific antibody construct disclosed herein) at a concentration between about 0.001 μg / ml and about 100 μg / ml and a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant, and b) administering the aqueous pharmaceutical composition to a patient, wherein the protein is not bonnetumab.

[0116] In some embodiments, the aqueous pharmaceutical composition is prepared by diluting a first composition containing a protein (e.g., a bispecific antibody construct) with a suitable aqueous solution. In some embodiments, the aqueous pharmaceutical composition is prepared by diluting the first composition containing the protein by adding a suitable solution to a container and then adding an appropriate amount of the first composition to the container.

[0117] In some embodiments, the first composition is a liquid composition comprising proteins. In some embodiments, the first composition is a liquid composition reconstituted from a lyophilized composition comprising proteins. In some embodiments, the first composition is a liquid composition reconstituted from a lyophilized composition comprising proteins using sterile water.

[0118] In some embodiments, a suitable aqueous solution for diluting the first composition comprises a surfactant at a concentration of at least about 0.25 times the CMC of the surfactant. In some embodiments, a suitable aqueous solution for diluting the first composition comprises a surfactant at a concentration between about 0.25 times and 20 times the CMC of the surfactant, or between about 0.25 times and about 10 times the CMC of the surfactant. In some embodiments, a suitable aqueous solution for diluting the first composition comprises a surfactant at a concentration of 0.25 times, about 0.5 times, about 1 time, about 2 times, about 3 times, about 4 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 15 times, or about 20 times the CMC of the surfactant. In some embodiments, a suitable aqueous solution for diluting the first composition further comprises NaCl. In some embodiments, a suitable aqueous solution for diluting the first composition has a pH between about 3.5 and about 7.0, or between about 4.0 and about 6.5. In some embodiments, a suitable aqueous solution for diluting the first composition has a pH of about 5.5. In some embodiments, the method further includes rinsing the container with a suitable aqueous solution for diluting the first composition prior to the preparation step.

[0119] In some embodiments, the surfactant in the aqueous pharmaceutical composition is a polysorbate. In some embodiments, the surfactant is a polysorbate selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85. In some embodiments, the surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the surfactant is poloxamer. In some embodiments, the surfactant is poloxamer 188 or poloxamer 407. In some embodiments, the surfactant is Triton X-100.

[0120] In some embodiments, the surfactant in the aqueous pharmaceutical composition is present in the composition at a concentration between about 0.25 times and about 20 times the CMC of the surfactant. In some embodiments, the surfactant is present in the aqueous pharmaceutical composition at a concentration between about 0.25 times and about 10 times the CMC of the surfactant. In some embodiments, the surfactant is present in the aqueous pharmaceutical composition at a concentration within any of the concentration ranges disclosed above. In some embodiments, the surfactant is present in the aqueous pharmaceutical composition at a concentration that is any of the concentrations disclosed above. The CMC value of the surfactant can be determined by the methods disclosed above. In some embodiments, the CMC values ​​of certain commonly used surfactants are listed in Table 1.

[0121] In some embodiments, the aqueous pharmaceutical composition comprises a protein at a concentration between about 0.001 μg / ml and about 50 μg / ml. In some embodiments, the aqueous pharmaceutical composition comprises a protein at a concentration within any range disclosed above. In some embodiments, the protein is present in the composition at any concentration disclosed above.

[0122] As disclosed above, the protein may be a therapeutic protein, such as an antigen-binding protein, mAb, or fusion protein. In some embodiments, the protein is a bispecific antigen-binding protein. In some embodiments, the protein is a bispecific antibody construct disclosed above. In some embodiments, the protein is a CD70xCD3 bispecific antibody construct. In some embodiments, the protein is a BCMAxCD3 bispecific antibody construct. In some embodiments, the protein is a CD33xCD3 bispecific antibody construct. In some embodiments, the protein is an EGFRvIIIxCD3 bispecific antibody construct. In some embodiments, the protein is an MSLNxCD3 bispecific antibody construct. In some embodiments, the protein is a CDH19xCD3 bispecific antibody construct. In some embodiments, the protein is a DLL3xCD3 bispecific antibody construct. In some embodiments, the protein is an FLT3xCD3 bispecific antibody construct. In some embodiments, the protein is a CDH3xCD3 bispecific antibody construct. In some embodiments, the protein is a PSMAxCD3 bispecific antibody construct. In some embodiments, the protein is a Cldn18.2xCD3 bispecific antibody construct. In some embodiments, the protein is a MUC17xCD3 bispecific antibody construct. Each of these bispecific antibody constructs is disclosed above. In some embodiments, the protein comprises, is substantially composed of, or consists of, the amino acid sequences of SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:25, SEQ ID NO:48, SEQ ID NO:67, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:165, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:178, or SEQ ID NO:192.

[0123] The pH of the composition can be within any pH range disclosed above. In some embodiments, the pH of the composition can be any pH disclosed above.

[0124] In some embodiments, the aqueous pharmaceutical composition further comprises one or more excipients suitable for use in the pharmaceutical composition. In some embodiments, the aqueous pharmaceutical composition further comprises a salt, a buffer, an amino acid, a sugar or sugar derivative, an optional preservative, or a combination of two or more of the foregoing substances. Exemplary salts, buffers, amino acids, sugars or their derivatives, and preservatives that can be used in the composition are disclosed above.

[0125] In some embodiments, the container is a plastic container or component. In some embodiments, the container is made of a material comprising polyolefins (e.g., PP and PE), PVC, EVA, or polyurethanes (e.g., polyesters and polyethers). In some embodiments, the container is made of a material comprising PVC. In some embodiments, the PVC is substantially free of DEHP or TOTM. In some embodiments, the container is made of a material that does not contain PVC. In some embodiments, the container is an IV bag or IV tube.

[0126] In some embodiments, the aqueous pharmaceutical composition is administered to a patient via intravenous (IV) administration. In some embodiments, the patient is a cancer patient. In some embodiments, the patient is a person.

[0127] Methods for binding proteins to solid surfaces

[0128] This document also discloses a method for binding a protein to a solid surface. In some embodiments, this document discloses a method for binding a protein to a solid surface, the method comprising: a) incubating an aqueous solution containing the protein with the solid surface, wherein the protein is labeled with a fluorophore; b) removing the aqueous solution from the solid surface and rinsing the surface; and c) imaging the solid surface using a confocal microscope.

[0129] Table 2 below lists the sequences disclosed in this paper.

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182] The invention will be more fully understood by referring to the following examples. However, these examples should not be construed as limiting the scope of the invention.

[0183] Example

[0184] Example 1. Methods for measuring protein binding to solid surfaces

[0185] The bispecific antibody constructs were of internal origin. They were labeled with fluorophores and purified after the labeling process.

[0186] Each measurement chamber contains a plastic cover. To measure protein binding to a solid surface, the measurement chamber with the plastic cover at the bottom is first incubated with a solution containing a fluorophore-protein (e.g., a fluorophore-labeled antibody construct). The sample solution is then aspirated, the cover is rinsed, and filled with buffer for later imaging on a confocal microscope. Fluorescence intensity measured by confocal microscopy indicates the binding of the bispecific antibody construct to the cover. Figure 1 A diagram of the experimental setup is shown.

[0187] Figure 2The titration of two fluorophore-labeled antibody constructs bound to a solid surface (e.g., a coverslip) in the absence of a surfactant is illustrated. The fluorescence intensity of the bound fluorophore-labeled antibody constructs was measured by confocal xy-scanning of the surface.

[0188] Example 2. Treating solid surfaces with surfactants to prevent proteins from binding to the surface.

[0189] Several surfactants were used at different folds of their respective CMCs to determine the effectiveness of each surfactant in preventing the binding of bispecific antibody constructs to solid surfaces. In this study, the surface was first incubated with a solution containing the surfactant, followed by the addition of a fluorophore-labeled antibody construct and incubation. Afterward, the solution was aspirated, the surface was rinsed, and buffered for imaging using a confocal microscope. The results were presented in... Figure 3 The figure is shown below. In this figure, the first group of bars represents the bispecific antibodies that bound to the surface without any surfactant. These were used as a baseline, and all the following data groups were compared to these. From the second group to the last group, they represent the relative percentages of proteins that bound to surfaces pretreated with different surfactants at different folds of different CMCs. The inset is a magnified view of the lower region of the figure. PS 80, PS20, P188, P407, and Triton X-100 were investigated.

[0190] The order in which surfactants and antibodies were added to the surface was tested. For bispecific antibodies 1 and 2, two orders were tested: in the first order, the surfactant-containing solution was added to the surface before the antibody was added; the other order was the reverse. Results were... Figure 4 The figures are shown below (antibody 1 on the left, antibody 2 on the right). For both graphs, the first set of bars represents the bispecific antibodies that bound to the surface without any surfactant. These are used as a baseline, and all the following data sets are compared to these. From the second to the last set are the relative percentages of antibodies that bound to the surface pretreated with PS 80 at different folds of their CMC. Surfactants effectively prevent proteins from binding to the surface.

[0191] Example 3. Incompatibility of certain surfactants with plasticizers used in plastic IV parts

[0192] Baxter Viaflex PVC-DEHP IV bags pre-filled with saline diluent were used in this study. Surfactants polysorbate 80 (PS80), polysorbate 20 (PS20), poloxamer 188 (P188), poloxamer 407 (P407), and Triton X-100 were used. Different amounts of the different surfactants were incubated with the bags at 25°C for 24 or 48 hours. The bags were then sampled and analyzed by reversed-phase ultra-high-performance liquid chromatography (RP-UHPLC) with a UV detector. Mobile phases A and B were 0.1% trifluoroacetic acid (TFA) in DI aqueous solution and 0.1% TFA in acetonitrile solution, respectively. The gradients are listed in Table 3 below. The flow rate was 0.6 mL / min. For quantification, a standard curve for DEHP was established under the same conditions.

[0193] Table 3. RP-UPLC gradient

[0194]

[0195] Compare PS80, PS20, and P188 in a 0.3% (w / w) saline solution in a PVC-DEHP IV bag at 25°C for 24 and 48 hours. Results are shown in... Figure 5 As shown in the diagram, PS80 and PS20 caused significant leaching of DEHP from the PVC-DEHP IV bag, while P188 did not cause any leaching. Figure 5 Use saline solution only as a control.

[0196] PS 80, PS 20, P188, P407, and Triton X-100 were compared by incubating in brine in PVC-DEHP IV bags at 25°C for 24 hours. The amount of DEHP leached was... Figure 6 The graph is plotted based on the multiples of CMC. Clearly, polysorbate extracted a certain amount of DEHP, while poloxamer did not. The amount of DEHP extracted is related to the amount of surfactant used. sequence list <110> Amgen <120> Compositions and methods for minimizing protein loss at low protein concentrations <130> A-2429-WO-PCT <150> 62 / 926,089 <151> 2019-10-25 <160> 201 <170> PatentIn version 3.5 <210> 1 <211> 122 <212> PRT <213> Artificial sequence <220> <223> CD33 ccVH E11 <400> 1 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 2 <211> 122 <​​​​​<223> CD33 VH E11 <400> 2 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 3 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> CD33 HCDR1 E11 <400> 3 Asn Tyr Gly Met Asn 1 5 <210> 4 <211> 17 <212> PRT <213> Artificial sequence <220> <223> CD33 HCDR2 E11 <400> 4 Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe Gln 1 5 10 15 Gly <210> 5 <211> 13 <212> PRT <213> Artificial sequence <220> <223> CD33 HCDR3 E11 <400> 5 Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr 1 5 10 <210> 6 <211> 113 <212> PRT <213> Artificial sequence <220> <223> CD33 CC VL E11 <400> 6 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly 1 5 10 15 Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser 20 25 30 Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Ala His Phe Pro Ile Thr Phe Gly Cys Gly Thr Arg Leu Glu Ile 100 105 110 Lys <210> 7 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> CD33 VL E11 <400> 7 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly 1 5 10 15 Glu Arg Thr Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser 20 25 30 Ser Thr Asn Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Asp Ser Pro Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln 85 90 95 Ser Ala His Phe Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile 100 105 110 Lys <210> 8 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> CD33 LCDR1 E11 <400> 8 Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu 1 5 10 15 Ala <210> 9 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> CD33 LCDR2 E11 <400> 9 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 10 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> CD33 LCDR3 E11 <400> 10 Gln Gln Ser Ala His Phe Pro Ile Thr 1 5 <210> 11 <211> 250 <212> PRT <213> Artificial sequence <220> <223> CD33 HL CC E11 <400> 11 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser 130 135 140 Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys 145 150 155 160 Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu 165 170 175 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser 180 185 190 Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu 210 215 220 Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr 225 230 235 240 Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys 245 250 <210> 12 <211> 250 <212> PRT <213> Artificial Sequence <220> <223> CD33 HL E11 <400> 12 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser 130 135 140 Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys 145 150 155 160 Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu 165 170 175 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser 180 185 190 Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu 210 215 220 Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr 225 230 235 240 Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 245 250 <210> 13 <211> 505 <212> PRT <213> Artificial sequence <220> <223> CD33 CC E11 HL x I2C HL bispecific molecule <400> 13 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser 130 135 140 Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys 145 150 155 160 Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu 165 170 175 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser 180 185 190 Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu 210 215 220 Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr 225 230 235 240 Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 260 265 270 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr 275 280 285 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 290 295 300 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 305 310 315 320 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 325 330 335 Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 340 345 350 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp 355 360 365 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 370 375 380 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val 385 390 395 400 Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 405 410 415 Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn 420 425 430 Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly 435 440 445 Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu 450 455 460 Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp 465 470 475 480 Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe 485 490 495 Gly Gly Gly Thr Lys Leu Thr Val Leu 500 505 <210> 14 <211> 530 <212> PRT <213> Artificial Sequence <220> <223> CD33 E11 HL x I2C HL <400> 14 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30 Pro Gly Glu Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu 50 55 60 Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala 65 70 75 80 Asp Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser 85 90 95 Thr Ala Tyr Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly 130 135 140 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met 145 150 155 160 Thr Gln Ser Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr 165 170 175 Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys 180 185 190 Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu 195 200 205 Leu Leu Ser Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe 210 215 220 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro 225 230 235 240 Gln Pro Glu Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe 245 250 255 Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly 260 265 270 Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 275 280 285 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 290 295 300 Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 305 310 315 320 Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr 325 330 335 Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser 340 345 350 Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr 355 360 365 Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile 370 375 380 Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 385 390 395 400 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln 405 410 415 Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr 420 425 430 Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn 435 440 445 Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu 450 455 460 Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser 465 470 475 480 Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln 485 490 495 Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg 500 505 510 Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His 515 520 525 His His 530 <210> 15 <211> 993 <212> PRT <213> Artificial sequence <220> <223> CD33 CC x I2C-scFc bispecific HLE molecule <400> 15 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Ile Arg Asn Leu Gly Gly Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Ser Trp Ser Asp Gly Tyr Tyr Val Tyr Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser 130 135 140 Pro Asp Ser Leu Thr Val Ser Leu Gly Glu Arg Thr Thr Ile Asn Cys 145 150 155 160 Lys Ser Ser Gln Ser Val Leu Asp Ser Ser Thr Asn Lys Asn Ser Leu 165 170 175 Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Leu Ser 180 185 190 Trp Ala Ser Thr Arg Glu Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser 195 200 205 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asp Ser Pro Gln Pro Glu 210 215 220 Asp Ser Ala Thr Tyr Tyr Cys Gln Gln Ser Ala His Phe Pro Ile Thr 225 230 235 240 Phe Gly Cys Gly Thr Arg Leu Glu Ile Lys Ser Gly Gly Gly Gly Ser 245 250 255 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 260 265 270 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr 275 280 285 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 290 295 300 Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 305 310 315 320 Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 325 330 335 Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr 340 345 350 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp 355 360 365 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly 370 375 380 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val 385 390 395 400 Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu 405 410 415 Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn 420 425 430 Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly 435 440 445 Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu 450 455 460 Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp 465 470 475 480 Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe 485 490 495 Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr 500 505 510 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 515 520 525 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 530 535 540 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 545 550 555 560 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 565 570 575 Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val 580 585 590 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 595 600 605 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 610 615 620 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 625 630 635 640 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 645 650 655 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 660 665 670 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 675 680 685 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 690 695 700 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 705 710 715 720 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 725 730 735 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 740 745 750 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys 755 760 765 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 770 775 780 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 785 790 795 800 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 805 810 815 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 820 825 830 Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys 835 840 845 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 850 855 860 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 865 870 875 880 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 885 890 895 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 900 905 910 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 915 920 925 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 930 935 940 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 945 950 955 960 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 965 970 975 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 980 985 990 Lys <210> 16 <211> 5 <212> PRT <213> Artificial sequence <220> <223> EGFRvIIIxCD3-scFc VH CDR1 <400> 16 Asn Tyr Gly Met His 1 5 <210> 17 <211> 17 <212> PRT <213> Artificial sequence <220> <223> EGFRvIIIxCD3-scFc VH CDR2 <400> 17 Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val Arg 1 5 10 15 Gly <210> 18 <211> 15 <212> PRT <213> Artificial sequence <220> <223> EGFRvIIIxCD3-scFc VH CDR3 <400> 18 Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp Tyr 1 5 10 15 <210> 19 <211> 16 <212> PRT <213> Artificial sequence <220> <223> EGFRvIIIxCD3-scFc VL CDR1 <400> 19 Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu Ser 1 5 10 15 <210> 20 <211> 7 <212> PRT <213> Artificial sequence <220> <223> EGFRvIIIxCD3-scFc VL CDR2 <400> 20 Arg Ile Ser Arg Arg Phe Ser 1 5 <210> 21 <211> 9 <212> PRT <213> Artificial sequence <220> <223> EGFRvIIIxCD3-scFc VL CDR3 <400> 21 Met Gln Ser Thr His Val Pro Arg Thr 1 5 <210> 22 <211> 124 <212> PRT <213> Artificial sequence <220> <223> EGFRvIII_CCxCD3-scFc VH <400> 22 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 23 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> EGFRvIII_CCxCD3-scFc VL <400> 23 Asp Thr Val Met Thr Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly 1 5 10 15 Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser 20 25 30 Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro 35 40 45 Pro Arg Leu Leu Ile Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser 85 90 95 Thr His Val Pro Arg Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys 100 105 110 <210> 24 <211> 251 <212> PRT <213> Artificial Sequence <220> <223> EGFRvIII_CCxCD3-scFc scFv <400> 24 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr 130 135 140 Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile 145 150 155 160 Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 165 170 175 Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile 180 185 190 Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala 210 215 220 Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg 225 230 235 240 Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys 245 250 <210> 25 <211> 506 <212> PRT <213> Artificial Sequence <220> <223> EGFRvIII_CCxCD3-scFc Bispecific Molecule <400> 25 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr 130 135 140 Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile 145 150 155 160 Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 165 170 175 Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile 180 185 190 Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala 210 215 220 Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg 225 230 235 240 Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly 245 250 255 Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 260 265 270 Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys 275 280 285 Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 290 295 300 Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala 305 310 315 320 Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn 325 330 335 Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val 340 345 350 Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr 355 360 365 Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val 385 390 395 400 Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr 405 410 415 Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro 420 425 430 Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly 435 440 445 Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser 450 455 460 Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu 465 470 475 480 Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val 485 490 495 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 500 505 <210> 26 <211> 994 <212> PRT <213> Synthetic Sequence <220> <223> EGFRvIII_CCxCD3-scFc Bispecific HLE Molecule <400> 26 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ser Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Asn Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asp Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Asp Ile Leu Thr Gly Asn Pro Arg Asp Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Thr Val Met Thr 130 135 140 Gln Thr Pro Leu Ser Ser His Val Thr Leu Gly Gln Pro Ala Ser Ile 145 150 155 160 Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr 165 170 175 Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro Pro Arg Leu Leu Ile 180 185 190 Tyr Arg Ile Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ala Gly Thr Asp Phe Thr Leu Glu Ile Ser Arg Val Glu Ala 210 215 220 Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser Thr His Val Pro Arg 225 230 235 240 Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly 245 250 255 Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 260 265 270 Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys 275 280 285 Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 290 295 300 Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala 305 310 315 320 Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn 325 330 335 Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val 340 345 350 Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr 355 360 365 Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val 385 390 395 400 Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr 405 410 415 Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro 420 425 430 Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly 435 440 445 Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser 450 455 460 Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu 465 470 475 480 Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val 485 490 495 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys 500 505 510 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 515 520 525 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 530 535 540 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 545 550 555 560 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 565 570 575 Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys 580 585 590 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 595 600 605 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 610 615 620 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 625 630 635 640 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 645 650 655 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 660 665 670 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 675 680 685 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 690 695 700 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 705 710 715 720 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 725 730 735 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 755 760 765 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 785 790 795 800 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 805 810 815 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 820 825 830 Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 835 840 845 Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 850 855 860 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 865 870 875 880 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 885 890 895 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 900 905 910 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 915 920 925 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 945 950 955 960 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 965 970 975 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 980 985 990 Gly Lys <210> 27 <211> 5 <212> PRT <213> Artificial sequence <220> <223> MSLN_5 VH CDR1 <400> 27 Asp Tyr Tyr Met Thr 1 5 <210> 28 <211> 17 <212> PRT <213> Artificial sequence <220> <223> MSLN_5 VH CDR2 <400> 28 Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 29 <211> 16 <212> PRT <213> Artificial sequence <220> <223> MSLN_5 VH CDR3 <400> 29 Asp Arg Asn Ser His Phe Asp Tyr Asp Arg Asn Ser His Phe Asp Tyr 1 5 10 15 <210> 30 <211> 11 <212> PRT <213> Artificial sequence <220> <223> MSLN_5 VL CDR1 <400> 30 Arg Ala Ser Gln Gly Ile Asn Thr Trp Leu Ala 1 5 10 <210> 31 <211> 7 <212> PRT <213> artificial sequence <220> <223> MSLN_5 VL CDR2 <400> 31 Gly Ala Ser Gly Leu Gln Ser 1 5 <210> 32 <211> 9 <212> PRT <213> artificial sequence <220> <223> MSLN_5 VL CDR3 <400> 32 Gln Gln Ala Lys Ser Phe Pro Arg Thr 1 5 <210> 33 <211> 117 <212> PRT <213> artificial sequence <220> <223> MSLN _5 VH <400> 33 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 34 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> MSLN_5 VL <400> 34 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Thr Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Ser Phe Pro Arg 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 35 <211> 239 <212> PRT <213> Artificial Sequence <220> <223> MSLN_5 scFv <400> 35 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser 130 135 140 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly 145 150 155 160 Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys 210 215 220 Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 225 230 235 <210> 36 <211> 494 <212> PRT <213> Artificial Sequence <220> <223> MSLN_5xI2C0 Bispecific Molecule <400> 36 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser 130 135 140 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly 145 150 155 160 Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys 210 215 220 Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser 225 230 235 240 Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 245 250 255 Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe 260 265 270 Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys 275 280 285 Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala 290 295 300 Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser 340 345 350 Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 370 375 380 Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly 385 390 395 400 Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser 405 410 415 Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg 420 425 430 Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg 435 440 445 Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly 450 455 460 Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser 465 470 475 480 Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 <210> 37 <211> 982 <212> PRT <213> Artificial sequence <220> <223> MSLN_5xCD3-scFc bispecific HLE molecule <400> 37 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Asn Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser 130 135 140 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly 145 150 155 160 Ile Asn Thr Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 165 170 175 Lys Leu Leu Ile Tyr Gly Ala Ser Gly Leu Gln Ser Gly Val Pro Ser 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys 210 215 220 Ser Phe Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser 225 230 235 240 Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 245 250 255 Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe 260 265 270 Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys 275 280 285 Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala 290 295 300 Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser 340 345 350 Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 370 375 380 Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly 385 390 395 400 Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser 405 410 415 Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg 420 425 430 Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg 435 440 445 Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly 450 455 460 Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser 465 470 475 480 Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly 485 490 495 Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 500 505 510 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 515 520 525 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 530 535 540 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 545 550 555 560 Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser 565 570 575 Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 580 585 590 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 595 600 605 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 610 615 620 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 625 630 635 640 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 645 650 655 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 660 665 670 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 675 680 685 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 690 695 700 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 705 710 715 720 Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 755 760 765 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 770 775 780 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 785 790 795 800 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 805 810 815 Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly 820 825 830 Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp 835 840 845 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 850 855 860 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 865 870 875 880 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 885 890 895 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 900 905 910 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 915 920 925 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 930 935 940 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 945 950 955 960 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu[[ID=K18]] 965 970 975 Ser Leu Ser Pro Gly Lys 980 <210> 38 <211> 982 <212> PRT <213> Artificial Sequence <220> <223> MSLN_5_CCxCD3-scFc Bispecific HLE Molecule <400> 38 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Phe 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Gly Ile Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Val Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser 130 135 140 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp 145 150 155 160 Ile Ser Arg Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 165 170 175 Lys Leu Leu Ile Ser Ala Ala Ser Arg Leu Gln Ser Gly Val Pro Ser 180 185 190 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 195 200 205 Ser Leu Gln Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Ala Lys 210 215 220 Ser Phe Pro Arg Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys Ser 225 230 235 240 Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu 245 250 255 Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe 260 265 270 Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys 275 280 285 Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala 290 295 300 Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp 305 310 315 320 Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu 325 330 335 Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser 340 345 350 Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 355 360 365 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 370 375 380 Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly 385 390 395 400 Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser 405 410 415 Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg 420 425 430 Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg 435 440 445 Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly 450 455 460 Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser 465 470 475 480 Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly 485 490 495 Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 500 505 510 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 515 520 525 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 530 535 540 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 545 550 555 560 Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser 565 570 575 Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 580 585 590 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 595 600 605 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 610 615 620 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 625 630 635 640 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 645 650 655 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 660 665 670 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 675 680 685 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 690 695 700 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 705 710 715 720 Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 755 760 765 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 770 775 780 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 785 790 795 800 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 805 810 815 Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly 820 825 830 Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp 835 840 845 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 850 855 860 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 865 870 875 880 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 885 890 895 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 900 905 910 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 915 920 925 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 930 935 940 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 945 950 955 960 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 965 970 975 Ser Leu Ser Pro Gly Lys 980 <210> 39 <211> 5 <212> PRT <213> Artificial sequence <220> <223> CDR-H1 CDH19 65254.007 <400> 39 Ser Tyr Gly Met His 1 5 <210> 40 <211> 17 <212> PRT <213> Artificial sequence <220> <223> CDR-H2 CDH19 65254.007 <400> 40 Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys 1 5 10 15 Asp <210> 41 <211> 16 <212> PRT <213> Artificial sequence <220> <223> CDR-H3 CDH19 65254.007 <400> 41 Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 42 <211> 11 <212> PRT <213> Artificial sequence <220> <223> CDR-L1 CDH19 65254.007 <400> 42 Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser 1 5 10 <210> 43 <211> 7 <212> PRT <213> Artificial sequence <220> <223> CDR-L2 CDH19 65254.007 / / <400> 43 Gln Asp Thr Lys Arg Pro Ser 1 5 <210> 44 <211> 9 <212> PRT <213> Artificial sequence <220> <223> CDR-L3 CDH19 65254.007 <400> 44 Gln Ala Trp Glu Ser Ser Thr Val Val 1 5 <210> 45 <211> 125 <212> PRT <213> Artificial sequence <220> <223> VH CDH19 65254.007 <400> 45 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 46 <211> 107 <212> PRT <213> artificial sequence <220> <223> VL CDH19 65254.007 <400> 46 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr 20 25 30 Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr 35 40 45 Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Ser 100 105 <210> 47 <211> 247 <212> PRT <213> Artificial Sequence <220> <223> VH-VL CDH19 65254.007 <400> 47 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser 245 <210> 48 <211> 507 <212> PRT <213> Artificial Sequence <220> <223> CDH19 65254.007 x I2C <400> 48 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu His His His His His His 500 505 <210> 49<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 755 760 765 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 770 775 780 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 785 790 795 800 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 805 810 815 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 820 825 830 Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu 835 840 845 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 850 855 860 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 865 870 875 880 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 885 890 895 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 900 905 910 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 915 920 925 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 930 935 940 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 945 950 955 960 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 965 970 975 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 50 <211> 987 <212> PRT <213> Artificial Sequence <220> <223> CDH19 65254.007 x I2C -scFc_delGK bispecific HLE molecule <400> 50 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Gly Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 755 760 765 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 770 775 780 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 785 790 795 800 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 805 810 815 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys 820 825 830 Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val 835 840 845 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 850 855 860 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 865 870 875 880 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 885 890 895 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 900 905 910 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 915 920 925 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 930 935 940 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 945 950 955 960 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 965 970 975 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 51 <211> 125 <212> PRT <213> Artificial Sequence <220> <223> CDH19 65254.007_CC x I2C -scFc VH <400> 51 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 125 <210> 52 <211> 106 <212> PRT <213> artificial sequence <220> <223> CDH19 65254.007_CC x I2C -scFc VL <400> 52 Ser Tyr Glu Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr 20 25 30 Ser Trp Tyr Gln Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr 35 40 45 Gln Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Cys Gly Thr Lys Leu Thr Val Leu 100 105 <210> 53 <211> 246 <212> PRT <213> Artificial Sequence <220> <223> CDH19 65254.007_CC x I2C -scFc scFv <400> 53 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly 225 230 235 240 Thr Lys Leu Thr Val Leu 245 <210> 54 <211> 501 <212> PRT <213> Artificial Sequence <220> <223> CDH19 65254.007_CC x I2C - scFc Bispecific Molecule <400> 54 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu 500 <210> 55 <211> 989 <212> PRT <213> Artificial Sequence <220> <223> CDH19 65254.007_CC x I2C -scFc Bispecific HLE Molecule <400> 55 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 755 760 765 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 770 775 780 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 785 790 795 800 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 805 810 815 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 820 825 830 Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu 835 840 845 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 850 855 860 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 865 870 875 880 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 885 890 895 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 900 905 910 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 915 920 925 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 930 935 940 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 945 950 955 960 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 965 970 975 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 56 <211> 987 <212> PRT <213> Artificial sequence <220> <223> CDH19 65254.007_CC x I2C - scFc_delGK bispecific HLE molecule <400> 56 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Phe Ile Trp Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Arg Ala Gly Ile Ile Gly Thr Ile Gly Tyr Tyr Tyr Gly Met 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly 115 120 125 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Tyr Glu Leu 130 135 140 Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln Thr Ala Ser Ile 145 150 155 160 Thr Cys Ser Gly Asp Arg Leu Gly Glu Lys Tyr Thr Ser Trp Tyr Gln 165 170 175 Gln Arg Pro Gly Gln Ser Pro Leu Leu Val Ile Tyr Gln Asp Thr Lys 180 185 190 Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser Asn Ser Gly Asn 195 200 205 Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met Asp Glu Ala Asp 210 215 220 Tyr Tyr Cys Gln Ala Trp Glu Ser Ser Thr Val Val Phe Gly Cys Gly 225 230 235 240 Thr Lys Leu Thr Val Leu Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro 755 760 765 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 770 775 780 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 785 790 795 800 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 805 810 815 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys 820 825 830 Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val 835 840 845 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 850 855 860 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 865 870 875 880 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu 885 890 895 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 900 905 910 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 915 920 925 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 930 935 940 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 945 950 955 960 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 965 970 975 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 57 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> FLT3_7 A8xCD3-scFc VH CDR1 <400> 57 Asn Ala Arg Met Gly Val Ser 1 5 <210> 58 <211> 32 <212> PRT <213> Artificial Sequence <220> <223> FLT3_7 A8xCD3-scFc VH CDR2 <400> 58 His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Asn 1 5 10 15 His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser Leu Lys Asn 20 25 30 <210> 59 <211> 28 <212> PRT <213> Artificial sequence <220> <223> FLT3_7 A8xCD3-scFc VH CDR3 <400> 59 Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp Tyr Ile Val 1 5 10 15 Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp Tyr 20 25 <210> 60 <211> 11 <212> PRT <213> Artificial sequence <220> <223> FLT3_7 A8xCD3-scFc VL CDR1 <400> 60 Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly 1 5 10 <210> 61 <211> 7 <212> PRT <213> Artificial sequence <220> <223> FLT3_7 A8xCD3-scFc VL CDR2 <400> 61 Ala Ala Ser Thr Leu Gln Ser 1 5 <210> 62 <211> 9 <212> PRT <213> Artificial sequence <220> <223> FLT3_7 A8xCD3-scFc VL CDR3 <400> 62 Leu Gln His Asn Ser Tyr Pro Leu Thr 1 5 <210> 63 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> FLT3_7 A8xCD3-scFc VH <400> 63 Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60 Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 64 <211> 107 <212> PRT <213> Artificial sequence <220> <223> FLT3_A8 - scFc VL <400> 64 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp 20 25 30 Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Cys Gly Thr Lys Val Glu Ile Lys 100 105 <210> 65 <211> 246 <212> PRT <213> Artificial sequence <220> <223> FLT3_7 A8xCD3- scFv <400> 65 Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60 Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly 225 230 235 240 Thr Lys Val Glu Ile Lys 245 <210> 66 <211> 501 <212> PRT <213> Artificial Sequence <220> <223> FLT3_7 A8xCD3 Bispecific Molecule <400> 66 Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60 Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly 225 230 235 240 Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu 500 <210> 67 <211> 989 <212> PRT <213> Artificial sequence <220> <223> FLT3_7 A8xCD3-scFc bispecific HLE molecule <400> 67 Gln Val Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Glu 1 5 10 15 Thr Leu Thr Leu Thr Cys Thr Leu Ser Gly Phe Ser Leu Asn Asn Ala 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Ser Thr Ser 50 55 60 Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Ser Ser Lys Thr Gln Val 65 70 75 80 Val Leu Thr Met Thr Asn Val Asp Pro Val Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Val Gly Tyr Gly Ser Gly Trp Tyr Gly Phe Phe Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly 115 120 125 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr 130 135 140 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 145 150 155 160 Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly Trp Tyr Gln 165 170 175 Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr 180 185 190 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 195 200 205 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 210 215 220 Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Leu Thr Phe Gly Cys Gly 225 230 235 240 Thr Lys Val Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu 245 250 255 Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu 260 265 270 Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp 275 280 285 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg 290 295 300 Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp 305 310 315 320 Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln 325 330 335 Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg 340 345 350 His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly 355 360 365 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro 385 390 395 400 Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser 405 410 415 Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln 420 425 430 Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu 435 440 445 Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys 450 455 460 Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr 465 470 475 480 Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr 485 490 495 Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro 500 505 510 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 515 520 525 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 530 535 540 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 545 550 555 560 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 565 570 575 Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr 580 585 590 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 595 600 605 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 610 615 620 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 625 630 635 640 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 645 650 655 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 660 665 670 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 675 680 685 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 690 695 700 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 705 710 715 720 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys 755 760 765 Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 770 775 780 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 785 790 795 800 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 805 810 815 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 820 825 830 Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu 835 840 845 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 850 855 860 Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 865 870 875 880 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 885 890 895 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 900 905 910 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 915 920 925 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 930 935 940 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 945 950 955 960 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 965 970 975 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 68 <211> 5 <212> PRT <213> artificial sequence <220> <223> VH CDR1 DLL3_1_CC_delGK <400> 68 Watch Tyr Tyr Trp Watch 1 5 <210> 69 <211> 16 <212> PRT <213> artificial sequence <220> <223> VH CDR2 DLL3_1_CC_delGK <400> 69 Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 70 <211> 10 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 DLL3_1_CC_delGK <400> 70 Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr 1 5 10 <210> 71 <211> 12 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 DLL3_1_CC_delGK <400> 71 Arg Ala Ser Gln Arg Val Asn Asn Asn Tyr Leu Ala 1 5 10 <210> 72 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 DLL3_1_CC_delGK <400> 72 Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 73 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 DLL3_1_CC_delGK <400> 73 Gln Gln Tyr Asp Arg Ser Pro Leu Thr 1 5 <210> 74 <211> 118 <212> PRT <213> Artificial sequence <220> <223> VH DLL3_1_CC_delGK <400> 74 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 75 <211> 108 <212> PRT <213> artificial sequence <220> <223> VL DLL3_1_CC_delGK <400> 75 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Asn Asn Asn 20 25 30<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys <210> 77 <211> 496 <212> PRT <213> Artificial sequence <220> <223> DLL3_1_CCxCD3_delGK bispecific molecule <400> 77 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 <210> 78 <211> 982 <212> PRT <213> Artificial Sequence <220> <223> DLL3_1_CCxCD3-scFc_delGK Bispecific HLE Molecule <400> 78 Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Cys Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Tyr Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Ser Ile Ala Val Thr Gly Phe Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu 130 135 140 Ser Leu Ser Pro Gly Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln 145 150 155 160 Arg Val Asn Asn Asn Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln 165 170 175 Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 180 185 190 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 195 200 205 Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln 210 215 220 Tyr Asp Arg Ser Pro Leu Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile 225 230 235 240 Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly 245 250 255 Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser 260 265 270 Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro 275 280 285 Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn 290 295 300 Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser 305 310 315 320 Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys 325 330 335 Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly 340 345 350 Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val 355 360 365 Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 370 375 380 Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser 385 390 395 400 Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val 405 410 415 Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala 420 425 430 Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro 435 440 445 Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu 450 455 460 Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp 465 470 475 480 Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 485 490 495 Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 500 505 510 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 515 520 525 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 530 535 540 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 545 550 555 560 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr 565 570 575 Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp 580 585 590 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 595 600 605 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 610 615 620 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 625 630 635 640 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 645 650 655 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 660 665 670 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 675 680 685 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 690 695 700 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 705 710 715 720 Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 725 730 735 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 740 745 750 Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 755 760 765 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 770 775 780 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 785 790 795 800 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 805 810 815 Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly 820 825 830 Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp 835 840 845 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 850 855 860 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 865 870 875 880 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 885 890 895 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 900 905 910 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 915 920 925 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 930 935 940 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 945 950 955 960 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 965 970 975 Ser Leu Ser Pro Gly Lys 980 <210> 79 <211> 5 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 CD19 97-G1RE-C2 <400> 79 Ser Tyr Gly Met His 1 5 <210> 80 <211> 17 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 CD19 97-G1RE-C2 <400> 80 Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val Lys 1 5 10 15 Gly <210> 81 <211> 13 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 CD19 97-G1RE-C2 <400> 81 Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val 1 5 10 <210> 82 <211> 122 <212> PRT <213> Artificial sequence <220> <223> VH CD19 97-G1RE-C2 CC <400> 82 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr Tyr Ala Glu Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr Gly Leu Glu Val Trp 100 105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 83 <211> 16 <212> PRT <213> Synthetic Sequence <220> <223> VL CDR1 CD19 97-G1RE-C2 <400> 83 Arg Ser Ser Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp 1 5 10 15 <210> 84 <211> 7 <212> PRT <213> artificial sequence <220> <223> VL CDR2 CD19 97-G1RE-C2 <400> 84 Leu Gly Ser Asn Arg Ala Ser 1 5 <210> 85 <211> 9 <212> PRT <213> artificial sequence <220> <223> VL CDR3 CD19 97-G1RE-C2 <400> 85 Met Gln Ala Leu Gln Thr Pro Phe Thr 1 5 <210> 86 <211> 112 <212> PRT <213> artificial sequence <220> <223> VL CD19 97-G1RE-C2 CC <400> 86 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ile Ser Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Lys 20 25 30 Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly Thr Lys Val Asp Ile Lys 100 105 110 <210> 87 <211> 525 <212> PRT <213> Artificial Sequence <220> <223> CD19 97 - G1RE - C2 CC x I2C0 <400> 87 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser 20 25 30 Leu Pro Val Ile Ser Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn 65 70 75 80 Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 100 105 110 Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly 115 120 125 Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val 145 150 155 160 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 165 170 175 Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys 180 185 190 Cys Leu Glu Trp Val Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr 195 200 205 Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 210 215 220 Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr 225 230 235 240 Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr 245 250 255 Gly Leu Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly 260 265 270 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 275 280 285 Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr 290 295 300 Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly 305 310 315 320 Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr 325 330 335 Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp 340 345 350 Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp 355 360 365 Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr 370 375 380 Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 385 390 395 400 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 405 410 415 Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 420 425 430 Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly 435 440 445 Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 450 455 460 Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe 465 470 475 480 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 485 490 495 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn 500 505 510 Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 515 520 525 <210> 88 <211> 1013 <212> PRT <213> Artificial Sequence <220> <223> CD19 97 - G1RE - C2 CC x I2C0 - scFc <400> 88 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Val Met Thr Gln Ser Pro Leu Ser 20 25 30 Leu Pro Val Ile Ser Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser 35 40 45 Gln Ser Leu Leu His Lys Asn Ala Phe Asn Tyr Leu Asp Trp Tyr Leu 50 55 60 Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn 65 70 75 80 Arg Ala Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr 85 90 95 Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val 100 105 110 Tyr Tyr Cys Met Gln Ala Leu Gln Thr Pro Phe Thr Phe Gly Cys Gly 115 120 125 Thr Lys Val Asp Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 130 135 140 Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val 145 150 155 160 Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe 165 170 175 Thr Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys 180 185 190 Cys Leu Glu Trp Val Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Tyr 195 200 205 Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser 210 215 220 Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr 225 230 235 240 Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Thr Ile Phe Gly Asn Tyr 245 250 255 Gly Leu Glu Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly 260 265 270 Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val 275 280 285 Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr 290 295 300 Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly 305 310 315 320 Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr 325 330 335 Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp 340 345 350 Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp 355 360 365 Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr 370 375 380 Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 385 390 395 400 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 405 410 415 Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 420 425 430 Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly 435 440 445 Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly 450 455 460 Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe 465 470 475 480 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val 485 490 495 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn 500 505 510 Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly 515 520 525 Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 530 535 540 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 545 550 555 560 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 565 570 575 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 580 585 590 Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr 595 600 605 Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 610 615 620 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 625 630 635 640 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 645 650 655 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 660 665 670 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 675 680 685 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 690 695 700 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 705 710 715 720 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 725 730 735 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 740 745 750 Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 755 760 765 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 770 775 780 Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu 785 790 795 800 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 805 810 815 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 820 825 830 Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val 835 840 845 Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser 850 855 860 Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 865 870 875 880 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala 885 890 895 Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 900 905 910 Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln 915 920 925 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 930 935 940 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 945 950 955 960 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 965 970 975 Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser 980 985 990 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 995 1000 1005 Leu Ser Pro Gly Lys 1010 <210> 89 <211> 5 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 CDH3 G8A 6 - B12 <400> 89 Ser Tyr Pro Ile Asn 1 5 <210> 90 <211> 16 <212> PRT <213> Artificial sequence <220> <223> VH CDR2 CDH3 G8A 6 - B12 <400> 90 Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys Gly 1 5 10 15 <210> 91 <211> 15 <212> PRT <213> Artificial sequence <220> <223> VH CDR3 CDH3 G8A 6-B12 <400> 91 Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr 1 5 10 15 <210> 92 <211> 17 <212> PRT <213> Artificial sequence <220> <223> VL CDR1 CDH3 G8A 6-B12 <400> 92 Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Phe 1 5 10 15 Ala <210> 93 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VL CDR2 CDH3 G8A 6-B12 <400> 93 Trp Ala Ser Thr Arg Glu Ser 1 5 <210> 94 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL CDR3 CDH3 G8A 6-B12 <400> 94 Gln Gln Tyr Tyr Ser Tyr Pro Tyr Thr 1 5 <210> 95 <211> 123 <212> PRT <213> Artificial sequence <220> <223> VH CDH3 G8A 6-B12 <400> 95 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 96 <211> 113 <212> PRT <213> Artificial sequence <220> <223> VL CDH3 G8A 6-B12 <400> 96 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ser Asn Gln Lys Asn Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Light <210> 97 <211> 251 <212> PRT <213> artificial sequence <220> <223> CDH3 G8A 6-B12 scFv <400> 97 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln 130 135 140 Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn 145 150 155 160 Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr 165 170 175 Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 180 185 190 Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 210 215 220 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Tyr 225 230 235 240 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 245 250 <210> 98 <211> 506 <212> PRT <213> Artificial sequence <220> <223> CDH3 G8A 6 - B12 x I2C0 bispecific molecule <400> 98 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln 130 135 140 Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn 145 150 155 160 Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr 165 170 175 Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 180 185 190 Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 210 215 220 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Tyr 225 230 235 240 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ser Gly Gly Gly Gly 245 250 255 Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 260 265 270 Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys 275 280 285 Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 290 295 300 Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala 305 310 315 320 Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn 325 330 335 Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val 340 345 350 Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr 355 360 365 Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val 385 390 395 400 Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr 405 410 415 Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro 420 425 430 Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly 435 440 445 Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser 450 455 460 Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu 465 470 475 480 Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val 485 490 495 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 500 505 <210> 99 <211> 994 <212> PRT <213> Artificial Sequence <220> <223> CDH3 G8A 6 - B12 x I2C0 bispecific molecule HLE <400> 99 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20 25 30 Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Trp Thr Gly Gly Gly Thr Asn Tyr Ala Ser Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Ser Arg Gly Val Tyr Asp Phe Asp Gly Arg Gly Ala Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser 115 120 125 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln 130 135 140 Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn 145 150 155 160 Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr 165 170 175 Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 180 185 190 Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly 195 200 205 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 210 215 220 Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr Pro Tyr 225 230 235 240 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Ser Gly Gly Gly Gly 245 250 255 Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly 260 265 270 Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys 275 280 285 Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp 290 295 300 Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala 305 310 315 320 Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn 325 330 335 Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val 340 345 350 Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr 355 360 365 Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly 370 375 380 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val 385 390 395 400 Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr 405 410 415 Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro 420 425 430 Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly 435 440 445 Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser 450 455 460 Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu 465 470 475 480 Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val 485 490 495 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly Asp Lys 500 505 510 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 515 520 525 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 530 535 540 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 545 550 555 560 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 565 570 575 Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg Cys 580 585 590 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 595 600 605 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 610 615 620 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 625 630 635 640 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 645 650 655 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 660 665 670 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 675 680 685 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 690 695 700 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 705 710 715 720 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 725 730 735 Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp 755 760 765 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 770 775 780 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 785 790 795 800 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 805 810 815 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 820 825 830 Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln Tyr Gly Ser Thr Tyr Arg 835 840 845 Cys Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 850 855 860 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 865 870 875 880 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 885 890 895 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 900 905 910 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 915 920 925 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 930 935 940 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 945 950 955 960 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 965 970 975 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 980 985 990 Gly Lys <210> 100 <211> 5 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CDR1 VH <400> 100 Asn His Ile Ile His 1 5 <210> 101 <211> 17 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CDR2 VH <400> 101 Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe Gln 1 5 10 15 Gly <210> 102 <211> 12 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CDR3 VH <400> 102 Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr 1 5 10 <210> 103 <211> 11 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CDR1 VL <400> 103 Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 104 <211> 7 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CDR2 VL <400> 104 Tyr Thr Ser Arg Leu His Thr 1 5 <210> 105 <211> 9 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CDR3 VL <400> 105 Gln Gln Gly Asn Thr Leu Pro Trp Thr 1 5 <210> 106 <211> 121 <212> PRT <213> Artificial sequence <220> <223> BCMA A7 27-C4-G7 CC (44 / 100) VH <400> 106 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His 20 25 30 Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 107 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> BCMA A7 27-C4-G7 CC (44 / 100) VL <400> 107 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Pro[[ID=I8]] 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Asn Thr Leu Pro Trp 85 90 95 Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 100 105<00C4114><210> 108 <2!1> 243 <212> PRT <213> Artificial Sequence <220> <223> BCMA A7 27-C4-G7 CC (44 / 100) scFv <400> 108 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His 20 25 30 Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln 145 150 155 160 Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys <210> 109 <211> 498 <212> PRT <213> Artificial Sequence <220> <223> BCMA A7 27 - C4 - G7 CC (44 / `100) x I2C0 Bispecific Molecule <400> 109 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His 20 25 30 Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln 145 150 155 160 Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu <210> 110 <211> 986 <212> PRT <213> Artificial Sequence <220> <223> BCMA A7 27-C4-G7 CC (44 / 100) x I2C0-scFc Bispecific Molecule HLE <400> 110 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn His 20 25 30 Ile Ile His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Met 35 40 45 Gly Tyr Ile Asn Pro Tyr Pro Gly Tyr His Ala Tyr Asn Glu Lys Phe 50 55 60 Gln Gly Arg Ala Thr Met Thr Ser Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Tyr Tyr Arg Asp Thr Asp Val Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln 145 150 155 160 Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Lys Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Thr 180 185 190 Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 195 200 205 Phe Thr Ile Ser Ser Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Gly Asn Thr Leu Pro Trp Thr Phe Gly Cys Gly Thr Lys Val 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 740 745 750 Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 755 760 765 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 770 775 780 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 785 790 795 800 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 805 810 815 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu 820 825 830 Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu 835 840 845 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 850 855 860 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 865 870 875 880 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 885 890 895 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 900 905 910 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 915 920 925 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 930 935 940 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 945 950 955 960 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 965 970 975 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 111 <211> 5 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VH CDR1 <400> 111 Asp Tyr Tyr Met Tyr 1 5 <210> 112 <211> 17 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VH CDR2 <400> 112 Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Thr Tyr Tyr Ser Asp Ile Ile Lys 1 5 10 15 Gly <210> 113 <211> 12 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VH CDR3 <400> 113 Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 1 5 10 <210> 114 <211> 11 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VL CDR1 <400> 114 Lys Ala Ser Gln Asn Val Asp Ala Asn Val Ala 1 5 10 <210> 115 <211> 7 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VL CDR2 <400> 115 Ser Ala Ser Tyr Val Tyr Trp 1 5 <210> 116 <211> 9 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VL CDR3 <400> 116 Gln Gln Tyr Asp Gln Gln Leu Ile Thr 1 5 <210> 117 <211> 121 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.17 CC VH <400> 117 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 118 <211> 107 <212> PRT <213> artificial sequence <220> <223> PM 76-B10.17 CC VL <400> 118 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Asn 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile 85 90 95 Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 119 <211> 243 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.17 CC scFv <400> 119 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys <210> 120 <211> 498 <212> PRT <213> Synthetic sequence <220> <223> PM 76 - B10.17 CC x I2C0 bispecific molecule <400> 120 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu <210> 121 <211> 986 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.17 CC x I2C0 - scFc Bispecific HLE Molecule <400> 121 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 740 745 750 Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 755 760 765 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 770 775 780 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 785 790 795 800 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 805 810 815 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu 820 825 830 Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu 835 840 845 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 850 855 860 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 865 870 875 880 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 885 890 895 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 900 905 910 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 915 920 925 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 930 935 940 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 945 950 955 960 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 965 970 975 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 122 <211> 984 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.17 CC x I2C0 - scFc_delGK Bispecific HLE Molecule <400> 122 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <210> 123 <211> 498 <212> PRT <213> Synthetic Sequence <220> <223> PM 76 - B10.17 CC x I2C0 CC (103 / 43) - scFc Bispecific Molecule <400> 123 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu <210> 124 <211> 986 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.17 CC x I2C0 CC (103 / 43)-scFc Bispecific HLE Molecule <400> 124 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 740 745 750 Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 755 760 765 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 770 775 780 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 785 790 795 800 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 805 810 815 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu 820 825 830 Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu 835 840 845 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 850 855 860 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 865 870 875 880 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 885 890 895 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 900 905 910 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 915 920 925 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 930 935 940 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 945 950 955 960 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 965 970 975 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 125 <211> 984 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.17 CC x I2C0 CC (103 / 43)-scFc_delGK Bispecific HLE Molecule <400> 125 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Ala Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Ala Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <210> 126 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> PM 76-B10.11 CC VH CDR1 <400> 126 Asp Tyr Tyr Met Tyr 1 5 <210> 127 <211> 17 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC VH CDR2 <400> 127 Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Tyr Ser Asp Ile Ile Lys 1 5 10 15 Gly <210> 128 <211> 12 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC VH CDR3 <400> 128 Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 1 5 10 <210> 129 <211> 11 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC VL CDR1 <400> 129 Lys Ala Ser Gln Asn Val Asp Thr Asn Val Ala 1 5 10 <210> 130 <211> 7 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC VL CDR2 <400> 130 Ser Ala Ser Tyr Val Tyr Trp 1 5 <210> 131 <211> 9 <212> PRT <213> artificial sequence <220> <223> PM 76-B10.11 CC VL CDR3 <400> 131 Gln Gln Tyr Asp Gln Gln Leu Ile Thr 1 5 <210> 132 <211> 121 <212> PRT <213> artificial sequence <220> <223> PM 76-B10.11 CC VH <400> 132 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 133 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.11 CC VL <400> 13​​​​​​​​​​​​​​​​​​​​​​ 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 134 <211> 243 <212> PRT <213> Synthetic Sequence <220> <223> PM 76-B10.11 CC scFv <400> 134 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys <210> 135 <211> 498 <212> PRT <213> Artificial sequence <220> <223> PM 76 - B10.11 CC x I2C0 bispecific molecule <400> 135 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu <210> 136 <211> 986 <212> PRT <213> Artificial sequence <220> <223> PM 76 - B10.11 CC x I2C0 - scFc bispecific HLE molecule <400> 136 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 740 745 750 Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 755 760 765 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 770 775 780 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 785 790 795 800 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 805 810 815 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu 820 825 830 Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu 835 840 845 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 850 855 860 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 865 870 875 880 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 885 890 895 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 900 905 910 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 915 920 925 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 930 935 940 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 945 950 955 960 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 965 970 975 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 137 <211> 984 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.11 CC x I2C0 - scFc_delGK Bispecific HLE Molecule <400> 137 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <210> 138 <211> 498 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC x I2C0 CC (103 / 43)-scFc bispecific molecule <4​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu <210> 139 <211> 986 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.11 CC x I2C0 CC (103 / 43)-scFc Bispecific HLE Molecule <400> 139 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 740 745 750 Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 755 760 765 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 770 775 780 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 785 790 795 800 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 805 810 815 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu 820 825 830 Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu 835 840 845 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 850 855 860 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 865 870 875 880 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 885 890 895 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 900 905 910 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 915 920 925 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 930 935 940 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 945 950 955 960 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 965 970 975 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 140 <211> 984 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.11 CC x I2C0 CC (103 / 43)-scFc_delGK bispecific HLE Molecule <400> 140 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Gly Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Cys Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Cys Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <210> 141 <211> 5 <212> PRT <213> artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VH CDR1 <400> 141 Asp Tyr Tyr Met Tyr 1 5 <210> 142 <211> 17 <212> PRT <213> artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VH CDR2 <400> 142 Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile Lys 1 5 10 15 Gly <210> 143 <211> 12 <212> PRT <213> artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VH CDR3 <400> 143 Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr 1 5 10 <210> 144 <211> 11 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VL CDR1 <400> 144 Lys Ala Ser Gln Asn Val Asp Thr Asn Val Ala 1 5 10 <210> 145 <211> 7 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VL CDR2 <400> 145 Ser Ala Ser Tyr Val Tyr Trp 1 5 <210> 146 <211> 9 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VL CDR3 <400> 146 Gln Gln Tyr Asp Gln Gln Leu Ile Thr 1 5 <210> 147 <211> 121 <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VH <400> 147 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 148 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> PM 76-B10.11 CC x I2C0-scFc VL <400> 148 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Val Tyr Trp Asp Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Ala Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Val Gln Ser 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Gln Gln Leu Ile 85 90 95 Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 149 <211> 243 <212> PRT <213> Artificial sequence <220> <223> PM 76 - B10.11 CC x I2C0 - scFc scFv <400> 149 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys <210> 150 <211> 498 <212> PRT <213> Synthetic sequence <220> <223> PM 76 - B10.11 CC x I2C0 - scFc bispecific molecule <400> 150 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu <210> 151 <211> 986 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.11 CC x I2C0 - scFc Bispecific HLE Molecule <400> 151 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly 725 730 735 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 740 745 750 Gly Ser Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys 755 760 765 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 770 775 780 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 785 790 795 800 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 805 810 815 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu 820 825 830 Glu Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu 835 840 845 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 850 855 860 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 865 870 875 880 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 885 890 895 Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 900 905 910 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 915 920 925 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 930 935 940 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 945 950 955 960 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 965 970 975 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 980 985 <210> 152 <211> 984 <212> PRT <213> Artificial Sequence <220> <223> PM 76 - B10.11 CC x I2C0 - scFc_delGK Bispecific HLE Molecule <400> 152 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 [[ID=​​​​​​​​​​​​​​​Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala 260 265 270 Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln 275 280 285 Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr 290 295 300 Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr 305 310 315 320 Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn 325 330 335 Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn 340 345 350 Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr 355 360 365 Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 370 375 380 Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr 385 390 395 400 Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly 405 410 415 Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly 420 425 430 Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly 435 440 445 Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu 450 455 460 Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val 465 470 475 480 Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr 485 490 495 Val Leu Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro 500 505 510 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 515 520 525 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 530 535 540 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 545 550 555 560 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu 565 570 575 Gln Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His 580 585 590 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 595 600 605 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 610 615 620 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 625 630 635 640 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 645 650 655 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 660 665 670 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 675 680 685 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 690 695 700 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 705 710 715 720 Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Ser Gly Gly Gly Gly 725 730 735 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 740 745 750 Gly Gly Gly Gly Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 755 760 765 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 770 775 780 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 785 790 795 800 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 805 810 815 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Cys Glu Glu Gln 820 825 830 Tyr Gly Ser Thr Tyr Arg Cys Val Ser Val Leu Thr Val Leu His Gln 835 840 845 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 850 855 860 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 865 870 875 880 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 885 890 895 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 900 905 910 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 915 920 925 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 930 935 940 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 945 950 955 960 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 965 970 975 Ser Leu Ser Leu Ser Pro Gly Lys 980 <210> 153 <211> 49 eight <212> PRT <213> Artificial sequence <220> <223> PM 76-B10.11 CC x I2C0 CC (103 / 4 three)-scFc bispecific molecule <400> 153 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Glu 1 5 10 15 It should be noted that there seems to be an error in the original text where "498" in is likely "498" and in the translation, it is wrongly written as "49 eight". Also, in , "103 / 43" is likely "103 / 43" and wrongly written as "103 / 4 three" in the translation. Please check and correct the original text for a more accurate translation.Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu Trp Val 35 40 45 Ala Ile Ile Ser Asp Gly Gly Tyr Tyr Thr Tyr Tyr Ser Asp Ile Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Phe Pro Leu Leu Arg His Gly Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly 115 120 125 Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro 130 135 140 Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys 145 150 155 160 Ala Ser Gln Asn Val Asp Thr Asn Val Ala Trp Tyr Gln Gln Lys Pro 165 170 175 Gly Gln Ala Pro Lys Ser Leu Ile Tyr Ser Ala Ser Tyr Val Tyr Trp 180 185 190 Asp Val Pro Ser Arg Phe Ser Gly Ser Ala Ser Gly Thr Asp Phe Thr 195 200 205 Leu Thr Ile Ser Ser Val Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys 210 215 220 Gln Gln Tyr Asp Gln Gln Leu Ile Thr Phe Gly Cys Gly Thr Lys Leu 225 230 235 240 Glu Ile Lys Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser 245 250 255 Gly Gly Gly Leu Val Gln Pro Gly Gly Ser L...

Claims

1. Use of poloxamer for preventing DEHP leaching from containers made of PVC containing DEHP, wherein the container comprises an aqueous composition comprising a bispecific antibody construct at a concentration between 0.001 μg / ml and 100 μg / ml and poloxamer at a concentration of 0.5 to 8 times the critical micelle concentration (CMC) of poloxamer, wherein the bispecific antibody construct comprises a first binding domain that binds to a target cell surface antigen, a second binding domain that binds to human CD3 on the surface of T cells, and optionally a third domain comprising a hinge-CH2 domain-CH3 domain-connector-hinge-CH2 domain-CH3 domain in an amino-to-carboxyl order, wherein the amino acid sequence of the second binding domain is as shown in SEQ ID NO:

201.

2. The use as described in claim 1, wherein the bispecific antibody construct is present at a concentration between 0.001 μg / ml and 50 μg / ml.

3. The use as described in claim 1 or 2, wherein the bispecific antibody construct is present at a concentration between 0.01 μg / ml and 50 μg / ml.

4. The use as described in claim 1 or 2, wherein the bispecific antibody construct is present at a concentration between 0.1 μg / ml and 50 μg / ml.

5. The use as described in claim 1 or 2, wherein the bispecific antibody construct is present at a concentration between 0.1 μg / ml and 10 μg / ml.

6. The use as described in claim 1 or 2, wherein the bispecific antibody construct is present at a concentration between 1 μg / ml and 10 μg / ml.

7. The use as claimed in any one of claims 1-6, wherein the poloxamer is poloxamer 188 or poloxamer 407.

8. The use as claimed in any one of claims 1-7, wherein the composition further comprises a salt, an amino acid, a sugar or a sugar alcohol, or a combination thereof.

9. The use as claimed in claim 8, wherein the composition further comprises a buffer or preservative.

10. The use as described in claim 8 or 9, wherein the pH of the composition is between 3.5 and 7.

5.

11. The use as described in claim 10, wherein the pH of the composition is between 4.2 and 7.

0.

12. The use as described in any one of claims 8-11, wherein the salt is NaCl.

13. The use as described in any one of claims 8-12, wherein the sugar is a monosaccharide, disaccharide, or cyclic polysaccharide.

14. The use as described in any one of claims 8-12, wherein the sugar or sugar alcohol is sucrose, trehalose, mannitol or sorbitol.

15. The use as described in any one of claims 8-14, wherein the amino acid is lysine.

16. The use as described in any one of claims 9-15, wherein the buffer is an acetate buffer, a glutamate buffer, a citrate buffer, a succinate buffer, a tartrate buffer, a fumarate buffer, a maleate buffer, a histidine buffer, or a phosphate buffer.

17. The use as described in any one of claims 1-16, wherein each of the first binding domain and the second binding domain of the bispecific antibody construct comprises a VH region and a VL region.

18. The use as described in any one of claims 1-17, wherein the bispecific antibody construct is a single-chain antibody construct.

19. The use according to any one of claims 1-18, wherein the bispecific antibody construct comprises a polypeptide having an amino acid sequence selected from SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 25, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 78, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO: 167, SEQ ID NO: 178 and SEQ ID NO:

192.

20. The use as described in any one of claims 1-19, wherein the composition is a pharmaceutical composition.

21. The use as described in any one of claims 1-20, wherein the composition is contained in a plastic container made of PVC containing DEHP.

22. The use as claimed in claim 21, wherein the plastic container is an IV bag or IV tube made of PVC containing DEHP.

23. A method for preventing DEHP from leaching from a PVC container containing DEHP into an aqueous composition contained in the container, wherein the aqueous composition is as described in any one of claims 1-22, and wherein the aqueous composition is prepared by diluting a first composition containing the bispecific antibody construct with a suitable aqueous solution, wherein the first composition is a liquid composition containing the bispecific antibody construct.

24. The method of claim 23, wherein the first composition is a liquid composition reconstructed from a lyophilized composition comprising the bispecific antibody construct.

25. The method of any one of claims 21-24, wherein the suitable aqueous solution comprises poloxamer at a concentration of 0.5 to 8 times the CMC of poloxamer.

26. The method of any one of claims 23-25, wherein the aqueous composition is prepared by adding the suitable aqueous solution to the container and then adding an appropriate amount of the first composition to the container.

27. The method of any one of claims 23-26, wherein the aqueous composition is suitable for intravenous use.

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