Improved multivalent single-partite antibodies for dual-antigen restricted immunotherapy

Abstract

The present invention relates to antibody constructs and such constructs for use as a medicament and in immunotherapy to treat cancer, or mixed tumours, benign tumours, or allergic diseases, or infection diseases, or autoimmune diseases. Moreover, the present invention relates to nucleic acid molecule(s) encoding said antibody constructs. The present invention also relates to vectors comprising the nucleic acid molecule(s). Furthermore, the present invention relates to pharmaceutical compositions comprising said antibody constructs. Moreover, the present invention relates to diagnostic compositions in vivo comprising said antibody constructs. Furthermore, the present invention relates to a diagnostic kit in vitro. Moreover, the present invention relates to a kit comprising said antibody constructs. In particular, the present invention relates to antibody constructs wherein specific linkers and / or amino acid mutations are used. Furthermore, the invention relates to antibody constructs, as well as a method for producing the same, their uses, and nucleic acid molecules encoding the antibody constructs. The invention in particular provides antibody constructs that are capable of mediating target cell restricted activation of immune cells.

Description

Improved multivalent single-partite antibodies for dual-antigen restricted immunotherapy FIELD OF THE INVENTIONThe present invention relates to antibody constructs and such constructs for use as a medicament and in immunotherapy to treat cancer. Moreover, the present invention relates to nucleic acid molecule(s) encoding said antibody constructs. The present invention also relates to vectors comprising the nucleic acid molecule(s). Furthermore, the present invention relates to pharmaceutical compositions comprising said antibody constructs. Moreover, the present invention relates to a kit comprising said antibody constructs. In particular, the present invention relates to antibody constructs wherein specific linkers and / or amino acid mutations are used. Furthermore, the invention relates to antibody constructs, as well as a method for producing the same, their uses, and nucleic acid molecules encoding the antibody constructs. The invention in particular provides antibody constructs that are capable of mediating target cell restricted activation of immune cells.BACKGROUNDCompetitive dual and / or multi antigen restricted ImmunotherapiesThere is a large diversity of different dual- or multi-antigen targeting antibodies, antibody fragments, polypeptides, and genetically engineered immune cells (1, 2, 6, 7, 8, 67, 68). The large majority of them are not restricted to a combination of two or more target antigens. Therefore, to gain on specificity, different dual- or multi-antigen restricted T cell-engaging formats are under development.(i) For the CAR T cell format, a dual-promotor technique is claiming to be dual antigen specific (9). This format is using two different plasmid reporters to activate the CAR T cells, putting the promotor for the CAR receptor under the control of a synthetic Notch receptor. Once this dual targeting CAR T cell is activated, in a sequel of binding to two different antigens and promotor activation, it can bind and kill also cells expressing only one of the target antigens, not really discriminating between dual and double antigen positive cells.(ii) Another multi targeting technology is combining a modular protein system with different antigen specific binders, using artificial latching orthogonal cage-key proteins (LOCKR), in combination with CAR T cells or antibody formats, for restricted multi target binding (10).(iii) Using an antibody format, the hemibody technology is the most advanced dual antigen restricted immunotherapy (11, 12, 13). Two hemibody constructs bind and reconstitute a tri-specific antibody complex on the surface of a dual antigen positive target cell. Each hemibody is composed of an antigen binding single-chain variable fragment (scFvl or scFv2) fused to either the variable heavy (VH) or the variable light chain (VL) domain of a T cell-activating anti-CD3 antibody. When a complementary pair of hemibodies binds the respective antigens on the surface of a target cell, the VH and VL domains become aligned, re-associate and reconstitute the original CD3-binding site. This way, CD3-positive T lymphocytes become activated and retargeted for target cell destruction. In the patent application WO 94 / 09131 are different antibody formats reported, targeting two different antigens, but also using two separate antibody fragments similar to the hemibodies.(iv) An alternative antibody format is the Prodrug-Activating Chain Exchange (PACE) (54). This technique is using the antibody-domain exchange reaction, to redirect two inactive antibodies against two different target antigens. When the two antibodies are close together, the non-functional anti-CD3 Fvs fused to lgG-CH3 domains drive CH3 chain-exchange reaction between them, forming now an active anti-CD3 binding site to recruit T cells for target cell destruction. The drawback of this PACE format is, after the lgG-CH3 chain-exchange, the active antibody dimercomplex is in the tissue and bloodstream, with the ability to bind to single antigen positive cells causing significant toxicity.(v) The antibody format of the Demibodies is using at least two molecules, each specific for a different antigen on a target cell. Each Demibody has a dimerization domain like a leucine zipper, receptor-ligand (like cytokine and cytokine receptor), actin and an actin-binding protein or DNA aptamer. The binding to the target antigens at the cell surface and the dimerization is required in order to form an active complex (73). The drawbacks are, at high enough concentration the dimerization can happen without binding to target antigens, and after the active Demibody dimercomplex is formed, it can bind to single antigen positive cells causing serious side effects.(vi) The Precision Guided Antibody Tumor Engager (PrecisionGATE™) platform (Revitope Oncology, Inc.) is similar to the hemibody technology, using two antibodies directed against two different antigens with a split anti-CD3 effector domain (55). In the Revitope format, each construct with a split anti-CD3 VH or VL domain is connected via a linker, containing a specific protease cutting site, to a blocking peptide and therefore cannot activate T cells by themselves. Once the blocking peptide is removed by proteases, the two PrecisionGATE constructs function in the same way as the hemibodies do, recruiting effector T cells against dual antigen positive target cells (56).(vii) There are several more antibody formats using conditional T cell activation by proteolytic cleavage to extend the therapeutic window for targeting antigens also expressed on healthy vital tissues (57, 58, 59). These formats are using single constructs, or two and more separate constructs directed against single, double or multi target antigens. All constructs are able to bind to target antigens, but the T cell recruiting domain is inactive. In the tumor micro-environment, with high protease activity, the inhibitory or blocking anti-CD3 domains are removed, allowing now the constructs to bind and activate T cells.Drawbacks of all current dual- or multi antigen restricted immunotherapiesFor all current dual and / or multi-antigen restricted immunotherapies there are several major drawbacks.All formats, which are using an irreversible activation step, like antibody-domain exchange reactions, protease cleaving of a blocking peptide, or dimerization domains can bind after activation to single antigen positive cells, causing "on-target off tumor” site effects.For formats using two or more GMP ("Good Manufacturing Practice") certified constructs, this will increase production cost, environmental resources and carbon food print (14). For clinical testing, each of the constructs must be tested and validating separate and in combination. This will increase the cost for the clinical trials, the time and regulatory requirements (15, 16). If there are negative side effects in the patient under therapy, it will be difficultto clearly distinguish what construct caused the negative effect, compromising the combinatorial nature of the formats.The open and exposed hydrophobic amino acid residues within the hemibody split effector variable heavy (VH) and the variable light chain (VL) domains are likely in contact with the surrounding aqueous solvent and are thus potentially contributing to protein aggregation. This in turn is recognized by the production host and leads to intracellular degradation of aggregates thereby lowering recombinant GMP production yields. Also, due to unfavorable charge patches in the hemibodies and LOCKR proteins, the binding and transport properties of these constructs in vivo is negatively affected and that can cause a short plasma half-life (17). Also, the non-natural surface of the hemibody split and exposed VH I VL interface, or the LOCKR protein helices, might be recognized by the patient immune system as foreign or dangerous entities. There is a possible presence of T cell epitopes in the hemibody and LOCKR protein format. This could cause a drug immune response, via neutralizing antibodies, jeopardizing the therapeutic effect (18).All current antigen restricted formats, the hemibodies and the LOCKR CAR T cells, are only targeting a dual-antigen signature.The large field of cancer immunotherapy has flourished over the last decades, transforming the practice of oncology and providing long-term clinical benefit to some patients

[0096] , Among the many hundreds of different therapeutic strategies listed today, a few stand out which focus on retargeting cytotoxic T lymphocytes at malignant cells. Of these, the most advanced are chimeric antigen receptors (CARs) transfected into T cells and bispecific T cellengaging antibodies (BiTEs), both using a monospecific paratope as targeting device. By and large, the target molecules addressed by these antibody derivatives are differentiation antigens present on malignant cells that can also be expressed on their non-transformed counterparts. If the antigen is expressed on vital tissue, the redirected cytotoxic T cells can cause severe side effects, like neurological toxicity following anti-MAGE-A3 TOR gene therapy

[0097] .Different bi- and tri-specific antibody and CAR formats have been developed, using two or more target-binding domains, not primarily to gain specificity, but to reduce the likelihood of therapy failure due to target antigen loss [98-100], The increased binding valency of these multimers results in high avidity (low off-rates), but most of these formats are nor truly restricted against a specific antigen combination. Instead they can also bind to single antigen positive cells, causing "on-target off tumor” site effects. The first clinically approved tri-functional antibody Removab®, for treatment of malignant ascites in patients with EpCAM-positive carcinomas, showed significant binding to Kupffer cells of the liver, causing exacerbated T-cell mediated off-target hepatotoxicity and thus has been withdrawn from clinical market

[0101] ,In tumor diagnostics, multi-parameter analyses are used to distinguish specific tumor types from their respective non-transformed tissues of origin, based on the expression of aberrant antigen signatures. Today, these findingsconstitute an integral part of the World Health Organization (WHO) classification system of hematopoietic neoplasms, and also hold true for cancer stem cells of different solid tissues.The modular structural and functional organisation of antibodies allows extensive manipulation by genetic engineering. Different immunoglobulin-like domains can be separated and / or joined without losing specific domain-associated functional features. Moreover, they can be combined and linked with heterologous protein domains. It is therefore possible to develop fusion constructs in a rational way devoid of the natural limitations of conventional antibodies.The antigen recognizing variable domains of the heavy (VH) and light chain (VL) of an antibody can be joined by a peptide linker via genetic engineering while preserving the antigen binding capability. Such antigen binding single chain variable fragments (scFvs) can be used as small antibody surrogates with high tissue penetrating capability and low serum retention time. Importantly, these scFv moieties can be easily employed as antigen specific modules in the development of novel recombinant therapeutics.In sum, current antibody scFv based T cell engaging strategies are effective therapeutic options for specific cancer types but there are also some limitations. Their addressed target antigens have to be highly expressed on tumor cells but rarely present in healthy tissue to prevent severe side effects. Therefore, there is still the need for a highly effective antibody based T cell engaging immunotherapy, able to bind to a specific antigen signature on tumor cells and not to single antigen positive healthy cells. The technical problems underlying the present application is thus to comply with these needs.SUMMARY OF THE INVENTIONIt is one object of the present invention to provide improved means to specifically identify and / or eliminate specific types of cells. Moreover, it is an object of the present invention to provide improved means to specifically identify and / or eliminate cells that have a specific combination of two and / or three and / or four specific antigens on their cell surface. It is also another object of the present invention to provide improved means to target a heterogeneous cell population and / or different sub clones with loss of single or multi target antigens.Furthermore, it is an object of the present invention to provide improved means to specifically identify and / or eliminate cancerous cells. Furthermore, it is an object of the present invention to provide improved means to specifically identify and / or eliminate cells that belong to a specific cell lineage.It is another object of the present invention to provide antibody constructs which can be produced in an improved way. Furthermore, it is an object of the present invention to provide means for improved (e.g.: more efficacious and / or safer) T cell therapy.The present invention achieves the above objects by providing the antibody constructs of the invention.The present invention also relates to antibody constructs and such constructs for use as a medicament and in immunotherapy to treat cancer, or mixed tumours, benign tumours, or allergic diseases, or infection diseases, or autoimmune diseases. Moreover, the present invention relates to nucleic acid molecule(s) encoding said antibody constructs. The present invention also relates to vectors comprising the nucleic acid molecule(s). Furthermore, the present invention relates to pharmaceutical compositions comprising said antibody constructs. Moreover, the present invention relates to diagnostic compositions in vivo comprising said antibody constructs. Furthermore, the present invention relates to a diagnostic kit in vitro. Moreover, the present invention relates to a kit comprising said antibody constructs.To improve T cell mediated immunotherapy, the inventors designed the antibody constructs of the invention (which are also referred to herein as "KeyLock antibodies”), where different antigen targeting domains are integrated into a single construct. In a KeyLock antibody, the variable heavy (VH) and light chain (VL) of an anti-CD3 effector antibody are separated / split from each other by a protein structure comprising at least one target antigen single chain variable fragments (scFv) (see, for instance, Figure 1A). In the absence of target antigen, the adjacent VH and VL domains interact with each other, termed swift-swapping of antibody variable domains, blocking the anti-CD3 VH and VL domains from correctly pairing with each other and therefore preventing the binding and activation of effector T cells (Figure 1 B). Only when all target antigen scFvs are bound to their respective antigens, the blocking of the separated / split anti-CD3 VH and VL domains is abrogated, allowing them to form the original anti CD3-bindi ng site. This way, CD3-positive T lymphocytes become activated and retargeted for target cell lysis in a highly specific manner (Figure 1C). It is expected that this specificity will result in improved safety of the antibody constructs of the invention.In addition, a KeyLock antibody can be directed against three different antigens (see, for instance, Figure 2A) or four different antigens (see, for instance, Figure 2B). In the absence of the third or fourth target antigen, the adjacent VH and VL domains swift-swapp with each other, blocking the anti-CD3 VH and VL domains from correctly pairing and therefore preventing the binding and activation of effector T cells. Only when all three target antigens (Figure 20), or four target antigens (Figure 2D), are expressed on the same cell and all target antigen directed scFvs are bound to their respective antigens, the blocking of the separated / split anti-CD3 VH and VL domains is abrogated, allowing them to bind and activate the CD3 receptor complex on T cells for target cell killing.An advantage of the invention is, the different target antigen binding domains and the and the split effector binding fragment VH and VL domains, can be arranged in the KeyLock format in different order and orientations from the peptide amino-terminus (N- or NF -terminus) to the carboxyl-terminus (C- or COOH-terminus) (see, for instance, Figure 3). This allows an optimization of KeyLock antibodies depending on target antigen density, target antigen extra cellular size and structure, antibody affinity to the respective antigen and the interaction to the connected other target antigen VH or VL domains.Also an advantage of the invention is, a large serum protein can be integrated in the format (see, for instance, Figure 4). This will increase the serum half live in vivo, or the tissue penetration, or the protease stability. Thus, in a preferred embodiment of the invention, the antibody constructs of the invention further comprise a domain containing a serum protein.In addition, different KeyLock single chain variable fragments (scFv) can be attached to an antibody constant domain (see, for instance, Figure 5). The Ig constant domains will also increase the serum half live in vivo. This also allows to combine two or up to six different KeyLock chains in a single antibody construct, (see, for instance, Figure 6). If six different KeyLock chains, against 4 different target antigens, are fused to pairing immunoglobulin constant chains, a single KeyLock antibody with six different dual-antigen specificities is created (see, for instance, Figure 6D). It is expected that such antibody constructs will allow efficacious targeting of a heterogeneous malignant cell population. The target antigen loss under immunotherapy, like the loss of BCMA on the malignant plasma cells following anti-BCMA CAR T cell therapy, is a major drawback of all current single antigen restricted therapies (77). A KeyLock antibody with six different KeyLock chains, against 4 different target antigens, is still functional against 10 different single or double antigen-loss scenarios.Advantageously, the antibody constructs of the invention can be produced at high yields. Furthermore, they are stable against proteases and exhibit a favourable serum stability and thermostability profile (see, for instance, Figures 30 and 32). Furthermore, they have no or low unspecific T cell activation capability in the absence of their respected target antigens, reducing the risk for cytokine storm in tissue with no target cells (see, for instance, Figure 33). It is expected that this specificity will result in improved safety of the antibody constructs of the invention.The present invention comprises the following preferred embodiments:1. An antibody construct comprising(i) at least one variable heavy chain (VH) of an anti-CD3 antibody,(ii) at least one variable light chain (VL) of the anti-CD3 antibody, and(iii) at least two single chain variable fragments (scFvs),wherein the antibody construct comprises the same number of (i) variable heavy chain(s) (VH) of the anti- CD3 antibody and (ii) variable light chain(s) (VL) of the anti-CD3 antibody,wherein each of the variable heavy chain(s) (VH) and the variable light chain(s) (VL) of the anti-CD 3 antibody are connected to each other by a protein structure comprising at least one or more of the single chain variable fragments (scFvs), and wherein in the antibody construct, at least two of the single chain variable fragments (scFvs) are against different target epitopes of the same target antigen or against different target antigens.The antibody construct according to item 1 , wherein at least one VH and VL of the anti-C D3 antibody form an anti-CD3 binding domain in the presence of said different target epitopes or target antigens on a target cell surface.The antibody construct according to item 1 or 2, wherein the antibody construct is a single covalently linked construct.The antibody construct according to any one of items 1 to 3, wherein the antibody construct or the protein structure further comprises an immunoglobulin Fc region and / or an immunoglobulin constant region.The antibody construct according to item 4, wherein said immunoglobulin Fc region and / or immunoglobulin constant region are an immunoglobulin, preferably an IgG.The antibody construct according to any one of items 1 to 5, wherein the antibody construct or the protein structure further comprises albumin, single albumin-domains, albumin-binding domains, and / or other plasma / serum proteins such as part of membrane proteins cleaved and detected in the plasma / serum. The antibody construct according to any one of items 1 to 6, wherein said different target epitopes or target antigens are tumor and / or cancer epitopes or antigens.The antibody construct according to any one of items 1 to 7, wherein said different target epitopes or target antigens are prostate tissue epitopes or antigens.The antibody construct according to any one of items 1 to 8, wherein said different target epitopes or target antigens are cell type and / or cell lineage specific epitopes or antigens.The antibody construct according to any one of items 1 to 9, wherein said different target epitopes or target antigens are allergens and or auto-epitopes or auto-antigens.The antibody construct according to item any one of items 1 to 10 wherein at least one, two, or all target epitopes or target antigens are selected from the group consisting of CD38, SLAMF7 / CS1 / CD319, ERBB2 / Her2 / NEU / CD340, FGFR1 / CD331, EGFR, EpCAM / CD326, ERBB3, ERBB4, MET, PDGFRA, PDGFRB, FGFR2, FGFR3, FGFR4, KIT, FLT3, IGF1 R, RET, ROS1 , ALK, TGFBR1 , TGFBR2, ACVR2A, ACVR1 B, LRP5, LRP6, E-Cadherin I CDH1, N-Cadherin I CDH2, AQP3, AQP1, AQP4, AQP5, AQP9, CD451 PTPRC, CD34, CD1381 SDC1, CD901 THY1, CD1231 IL3RA, IL1RAP, IL2RB I CD122, CD117 / Kit, CD244, CD49F I ITGA6, ABCG2, ESAM, CD10 I MME, CD81, GHR, PRLR, PSMA, PSCA, CD133, CD166, CD44v6 I CD44, CD29 I ITGB1, CD24, Lgr5, CEA / CEACAM5, VEGFR2 I KDR, CXCR4 / CD33, CD56 / NCAM1, CD19, CD20, B7H3 / CD276, L1CAM, CD37, LFA-1 / ITGB2 / CD18, ROR1, ROR2, CD70, CD123 / IL3RA, IGF1R / CD221, CCR7 I CD197, CCR4 I CD194, TNFRSF9 I 4-1BB, CTLA4 I CD152, GPC3 I Glypican-3, CADM1, CD4, B7-h4 I VTCN1, TYRP1, PDL1 / CD274, PDCD1 / PD-1, PDCD1LG2 / PD-L2, BTLA, DLL3, CEACAM1 / CD66a, LFA-1 I ITGB2, CD22, NRP1 1 CD304, CHRNA1, GD2 I Disialoganglioside, CTAG1A / NY-ESO-1, CD70, CD30 I TNFRSF8, CD98hc I SLC3A2, CD52, CD64 I FCGR1A, CD46 I MCP, CD6, CD10 I MME, CD25 I IL2RA, CD40, CD47, CD49a I ITGA1 , CD49c I ITGA3, CD49e I ITGA5, CD51 1 ITGAV, CD55, CD571 B3GAT1 , CD59, CD61 I ITGB3, CDw75 I ST6GAL1, CD79a, CD82, CD95 I FAS, CD99, CD105 I ENG, CD107a I LAMP1, CD107b I LAMP2, CD131 I CSF2RB, CD147 I BSG, CD151, AGTR1, AGTR2, KRAS, NRAS, HRAS, and BRAF or combinations thereof.The antibody construct according to any one of items 1 to 11, wherein the anti-CD3 antibody is a T cellactivating antibody.The antibody construct according to any one of items 1 to 12, wherein (i) the variable heavy chain (VH) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 274, 275, and 276, respectively, and wherein (ii) the variable light chain (VL) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 277, 278, and 279, respectively, or wherein (I) the variable heavy chain (VH) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 280, 281, and 282, respectively, and wherein (ii) the variable light chain (VL) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 283, 284, and 285, respectively.The antibody construct according to any one of items 1 to 13, wherein (I) the variable heavy chain (VH) of the anti-CD3 antibody comprises the amino acid sequence of SEQ ID NO: 270 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto, and wherein (ii) the variable light chain (VL) of the anti-CD3 antibody comprises the amino acid sequence of SEQ ID NO: 271 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto, or wherein (I) the variable heavy chain (VH) of the anti-CD3 antibody comprises the amino acid sequence of SEQ ID NO: 272 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto, and wherein (ii) the variable light chain (VL) of the anti-CD3 antibody comprises the amino acid sequence of SEQ ID NO: 273 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto.The antibody construct according to any one of items 1 to 14, wherein the anti-CD3 binding domain is capable of binding to CD3 on CD3 positive T cells and activating said cells.The antibody construct according to any one of items 1 to 15, wherein the antibody construct is a construct which forms a functional anti-CD3 binding domain in the presence of said different target antigens on a target cell surface at a concentration which is at least 10 fold (1 -log), at least 100 fold (2-log) or at least 1000 fold (3-log) lower than the concentration at which a functional anti-CD3 binding domain forms in the absence of one or more or all of said different target antigens from a target cell surface.The antibody construct according to any one of items 1 to 16, wherein the antibody construct comprises not more than one VH and not more than one VL of the anti-CD3 antibody and not more than two single chain variable fragments (scFvs) against different target antigens.The antibody construct according to any one of items 1 to 16, wherein the antibody construct comprises two VH and two VL, three VH and three VL, or four VH and four VL of the anti-CD3 antibody.The antibody construct according to any one of items 1 to 16, wherein the antibody construct comprises two, three or four single chain variable fragments (scFvs) against different target epitopes or target antigens. The antibody construct according to any one of items 1 to 16, wherein the antibody construct comprises two, three or four single chain variable fragments (scFvs) against different target antigens and comprises two,three or four single chain variable fragments (scFvs) as pairs or triplicates, direct connected to each other or separated at least by one single chain variable fragments (scFvs) against a different target.The antibody construct according to any one of items 1 to 20, wherein the target antigens are ERBB2 / Her2 / NEU / CD340 and EpCAM / CD326 or CD38 and SLAMF7 / CS1 / CD319.The antibody construct according to any one of items 1 to 21, wherein all of the at least one VH and at least one VL of the anti-CD3 antibody are linked to one of said single chain variable fragments (scFvs) comprised by the protein structure by a peptide linker.The antibody construct according to any one of items 1 to 22, wherein the peptide linker allows formation of an anti-CD3 binding domain from at least one VH and VL of the anti-CD3 antibody in the presence of said different target epitopes or target antigens.The antibody construct according to any one of items 1 to 23, wherein the antibody construct is selected from the following (a) to (q):(a) an antibody construct comprising the amino acid sequence of SEQ ID NO: 293 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 293,(b) an antibody construct comprising the amino acid sequence of SEQ ID NO: 294 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 294,(c) an antibody construct comprising the amino acid sequence of SEQ ID NO: 295 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 295,(d) an antibody construct comprising the amino acid sequence of SEQ ID NO: 296 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 296,(e) an antibody construct comprising the amino acid sequence of SEQ ID NO: 297 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 297,(f) an antibody construct comprising the amino acid sequence of SEQ ID NO: 298 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 298,(g) an antibody construct comprising the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 299,(h) an antibody construct comprising the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 300,(i) an antibody construct comprising the amino acid sequence of SEQ ID NO: 301 or an amino acid sequenceat least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 301,(j) an antibody construct comprising the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 302,(k) an antibody construct comprising the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 303,(l) an antibody construct comprising rises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 304,(m) an antibody construct comprising the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 305,(n) an antibody construct comprising the amino acid sequence of SEQ ID NO: 306 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 306,(o) an antibody construct comprising the amino acid sequence of SEQ ID NO: 307 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 307, and(p) an antibody construct comprising the amino acid sequence of SEQ ID NO: 308 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 308.The antibody construct according to any one of items 1 to 24, further comprising an additional protein-binding group selected from a single-domain antibody (also known as a Nanobody or VHH), a monobody (derived from fibronectin type III), an anticalin (derived from lipocalins), an affibody (derived from immunoglobulin-binding protein A) and a DARPin (Designed Ankyrin Repeat Protein).The antibody construct according to any one of items 1 to 25, wherein (i) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270 or SEQ ID NO: 272, and / or wherein (ii) the at least one variable light chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271 or SEQ ID NO: 273.The antibody construct according to item 26, wherein (i) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270, and / or wherein (ii) the at least one variable light chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or morebut preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271.The antibody construct according to item 26, wherein (i) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 272, and / or wherein (ii) the at least one variable light chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 273.The antibody construct according to any one of items 26 to 28, wherein the amino acid substitutions or deletions decrease the affinity of the antibody construct against CD3 on CD3 positive T cells in the absence of one or more or all of the different target antigens from a target cell surface when compared to an antibody construct which lacks said substitutions or deletions but is otherwise identical, andwherein at least one VH and VL of the anti-CD3 antibody form an anti-CD3 binding domain in the presence of said different target antigens on a target cell surface.The antibody construct according to any one of items 26 to 29, wherein(A) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270 which are selected from Table 1, wherein the amino acid positions are determined based on Seq ID NO: 415 as a reference sequence but without counting the first two amino acids of Seq ID NO: 415, and / or(B) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271 which are selected from Table 2, wherein the amino acid positions are determined based on Seq ID NO: 415 as a reference sequence but without counting the first two amino acids of Seq ID NO: 415, and / or(C) the at least one variable heavy chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 272 which are selected from Table 3, wherein the amino acid positions are determined based on Seq ID NO: 419 as a reference sequence but without counting the first two amino acids of Seq ID NO: 419, and / or(D) the at least one variable heavy chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 273 which are selected from Table 4, wherein the amino acid positions are determined based on Seq ID NO: 419 as a reference sequence but without counting the first two amino acids of Seq ID NO: 419.The antibody construct according to any one of items 26 to 30, wherein the substitution is a substitution by flexible linkers to replace the deleted amino acids for variable domain stability, wherein optionally the flexible linkers are selected from the amino acid sequences of SGGSG, SGG or SG.The antibody construct according to any one of items 26 to 31, wherein (i) the variable heavy chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 273 which are selected from R169E and Y171A, whereinthe amino acid positions are determined based on Seq ID NO: 415 as a reference sequence but without counting the first two amino acids of Seq ID NO: 415.The antibody construct according to any one of items 26 to 32, wherein the antibody construct is selected from the following (a) to (c):(a) an antibody construct comprising the amino acid sequence of SEQ ID NO: 525 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 525,(b) an antibody construct comprising the amino acid sequence of SEQ ID NO: 526 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 526, and(c) an antibody construct comprising the amino acid sequence of SEQ ID NO: 527 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 527.The antibody construct according to any one of items 1 to 33, wherein the antibody construct further comprises one or more blocking domains to block formation of an anti-CD3 binding domain in the presence of said different target antigens in non-tumor tissue and / or to block formation of an anti-CD3 binding domain in the absence of one or more or all of said different target antigens from a target cell surface.The antibody construct according to item 34, wherein one or more of the blocking domains are connected to at least one of the variable heavy chain(s) (VH) of an anti-CD3 antibody (I), and / or one or more of the blocking domains are connected to at least one of the variable light chain(s) (VL) of the anti-CD3 antibody (ii), wherein the connection is optionally by a cleavable linker.The antibody construct according to any one of item 34 or 35, wherein the one or more blocking domain comprises a variable heavy chain (VH) of the anti-CD3 antibody comprising an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270 or SEQ ID NO: 272 or a variable light chain (VL) of the anti-CD3 antibody comprising an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271 or SEQ ID NO: 273 wherein the substitutions or deletions reduce the formation of an anti-CD3 binding domain in the presence of said different target antigens on a target cell surface.A nucleic acid molecule, or a set of nucleic acid molecules, encoding the antibody construct according to any one of items 1 to 36.A recombinant vector, or a set of recombinant vectors, comprising the nucleic acid molecule or set of nucleic acid molecules according to item 37.A recombinant host cell comprising the recombinant vector or set of recombinant vectors according to item 38 and optionally expressing the antibody construct according to any one of items 1 to 36.A pharmaceutical composition comprising one or more antibody constructs according to any one of items 1 to 36.A kit comprising one or more antibody constructs according to any one of items 1 to 36.42. An antibody construct according to any one of items 1 to 36 for use as a medicament.43. An antibody construct according to any one of items 1 to 36 for use in immunotherapy to treat cancer.44. The antibody construct for use according to item 42 or 43, wherein the antibody construct is to be administrated into the patient intra venous, sub cutaneous, intra thecal or intra peritoneal, via injections, short infusion (1 minute to 8 hours) or via a continuous infusion (> 8 hours).45. The antibody construct for use according to any one of items 42 to 44, wherein the antibody construct is to be administrated locally into a benign tumor or a cancer via injections, to increase local concentrations of the antibody construct and reduce systemic serum levels of the antibody construct.46. The antibody construct for use according to any one of items 42 to 45, wherein the antibody construct is to be administrated locally into a benign tumor or a cancer via injections, with the antibody construct embedded into a semi solid matrix to delay the antibody construct release over time and to reduce a wash out from the local injection site.In addition, also disclosed herein are the following embodiments:In a first additional aspect, the present invention relates to an antibody construct comprising:a) A binding moiety from an antibody variable light and heavy chain, capable of binding an antigen, comprising a first binding site for a first antigen,b) A binding moiety from an antibody variable light and heavy chain, capable of binding an antigen, comprising a second binding site for a second antigen,c) A binding moiety from an antibody variable light and heavy chain, capable of binding an antigen, with the variable light and heavy chain separated from each other by the binding moieties against the first antigen, or the second antigen or both antigens, comprising a third binding site for a third antigen,d) A peptide chain comprising a first linker connecting the antibody variable light and heavy chain against the first antigen,e) A peptide chain comprising a second linker connecting the antibody variable light and heavy chain against the second antigen,f) A peptide chain comprising a third linker connecting the first binding moiety with the second binding moiety,g) A peptide chain comprising a fourth linker connecting the variable light chain of the third binding moiety with the first or second binding moiety,h) A peptide chain comprising a fifth linker connecting the variable heavy chain of the third binding moietywith the first or second binding moietyIn a second additional aspect, the present invention relates to an antibody construct similar to the first aspect, comprising a binding molecule for a third antigen, with the variable light and heavy chain separated from each other between the binding moieties against the first antigen, or the second antigen. With peptide chains comprising two linkers connecting the variable heavy chain or variable light chain of the third binding moiety with the first or second binding moiety.In a third additional aspect, the present invention relates to an antibody construct similar to the first or second aspect, comprising additional binding moieties from antibody variable light and heavy chains, capable of binding an antigen, comprising a fourth, fifth, sixth or more binding site for a fourth, fifth, sixth or more antigen. With peptide chains comprising linkers connecting the antibody variable light and heavy chains of the fourth, fifth, sixth or more binding moiety. In addition with peptide linkers connecting the different binding moieties.In a fourth additional aspect, the present invention relates to an antibody construct similar to the first or second or third aspect, comprising a binding molecule for a third antigen, with one, two, three or more variable light chains and one, two, three or more variable heavy chains separated from each other by the binding moieties against the other antigens. With peptide chains comprising linkers connecting the antibody variable light and heavy chains with each other.In a fifth additional aspect, the present invention relates to an antibody construct similar to the first, second, third or fourth aspect, comprising with linkers optimized for a dual antigen restricted functional complementation of the split / separated effector binding domains.For optimization, the linkers can differ in their amino acid compositions.The linkers can differ in their ability to modulate the surface hydrophobicity of the entire proteinaceous binding molecule or of individual domains of this. With a Heiden score for predicted hydrophobicity between 0.7 and 1.6, or a hydrophobic interaction chromatography (HIC) score between -0.1 and +1.0.The linkers can be flexible glycine serine linkers, with specific glycine to serine (G to S) ratios. For example a G to S ratio of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or more than 10:1. Another example is a G to S ratio of 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 or more than 1:10.The linkers can differ in their length. From 10 to 20 amino acids, or 20 to 30 amino acids, or more than 30 amino acids.The linkers can form specific secondary structures like alpha helix (n = 3.6), 310 helix (n = 3) and the pi helix (n =4.4), with n the number of amino acids per turn. The number of turns can be 3, 4, 5, 6, 7, 8, 9, 10 or more than 10.The linkers can have one, two, three or more glycosylation sites. This could be N-linked glycosylation sites, attaching N-linked glycans to asparagine or arginine side-chains. Or this could be O-linked glycosylation sites, attaching O-linked glycans to serine, threonine, tyrosine, hydroxylysine, or hydroxyproline side-chains.In a sixth additional aspect, the present invention relates to an antibody constructsimilar to the first, second, third, fourth or fifth aspect, comprising different amino acid mutations.The mutations can be point mutations with amino acid substitution, replacing one amino acid with another.The point mutations can be in the antibodies variable domain framework 1, 2 or 3 of the heavy and / or light chains.The mutations can replace the antibody variable domain complementarity-determining region (CDR) 1, 2 or 3 of the heavy and / or light chains. For the CDR replacement flexible linkers can be used, for bridging the distance between the adjacent frameworks, to reduce the CDR loss caused negative effect on the variable domain stability.In a seventh additional aspect, the present invention relates to an antibody construct similar to the first, second, third, fourth, fifth or sixth aspect, comprising a blocking domain to prevent the functional complementation of an antibody variable light and heavy chain.One blocking domain can be used to black one antibody variable light and heavy chain complementation.Two or more blocking domains can be used to increase the blocking of one antibody variable light and heavy chain complementation.Two or more blocking domains can be used to block two or more different antibody variable light and heavy chains complementation.The blocking domains can be used to disable or reduce the binding to the effector T cell.The blocking domains are connected with a linker at the amino-terminus end and / or the carboxy-terminus end of the recombinant proteinaceous binding molecule.The blocking domain linker possesses a protease cleaving site. Specific for proteases found in the tumor microenvironment.In an eighth additional aspect, the present invention relates to methods to define new variants of binding moieties from antibody variable light and heavy chains similar to the first, second, third, fourth, fifth, sixth or seventh aspect, comprising amino acids mutations, substitutions, deletions or insertions.This can be an in silico based method using affinity modulation by rational design.This can be an in-silico based method using affinity modulation by semi-rational saturation mutagenesis.This can be an in-silico based method using affinity modulation by chain shuffling or CDR walking.This can be an in-silico based method using affinity modulation by template-based design, like comparative / homology modeling or threading methods.This can be an ab-initio method with deep learning for affinity modulation, in the absence of good homologue structures.This can be an in-silico based method using molecular docking for identification of interaction surfaces.This can be an in-vitro method using a large antibody library, with a naive library, or immune library, or synthetic library or semi-synthetic library design.This can be an in-vitro method using a phage display, or mammalian display, or yeast display, or ribosome display or bacterial display.BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 shows the principle of the invention. (A) Design of a KeyLock single chain polypeptide, targeting two different antigens (x and y), with two antibody variable domains anti x (T 1 black spotted) and anti y (T2 black waves) in VL-VH orientation (from the NH2-terminus to COOH terminus), covalently connected with a linker (gray solid line). The anti-CD3 receptor complex directed effector binding domain (F), from an anti-CD3 antibody, is split / separated into the VH fragment (F1 light solid gray) at the NH2-terminus and into the VL fragment (F2 dark solid gray) at the COOH terminus with a short 6 amino acid His-tag (H). The linker, the position and the orientation of the different variable domains allows swift-swapping (SWSW) between these domains, causing the blocking of the F1 and F2 fragments, to pair and build a functional F domain. (B) If a cell expresses one target antigen, only one target antigen specific domain is bound (left T 1 and right T2), and only one oCD3 domain (left F1 and right F2) is not blocked any more. The single F1 and F2 domains are not able to restore the biological effector function. (C) If a cell expresses both antigens (X and Y) at its cell surface, simultaneous binding of both T1 and T2 domains to the surface of the cell is abrogating the blocking of both F1 and F2 fragments, bringing them in close proximity, causes association of fragments F1 and F2 and restoration of the biological function of the F domain by complementation.Figure 2 shows the principle of the invention against a triple- or quadruple-antigen signature. (A) Tri-specific KeyLock antibody. For a tri-specific KeyLock antibody, in a single chain polypeptide format, three different target antigen binding domains (T1 black spots, T2 black waves and T3 black mesh) are connected with the split / separated anti-CD3 receptor complex variable F1 (light solid gray) and F2 (dark solid gray) fragments. The F1 fragment is at the NH2-terminus and the F2 fragment is between the T2 and T3 domains. (B) Quadruple-specific KeyLock antibody. For a quadruple-specific KeyLock antibody, in a single chain polypeptide format, four differenttarget antigen binding domains (T1 black spots, T2 black waves, T3 black mesh and T4 whites spotted) are connected with the spl it / separated anti-CD3 receptor complex variable F1 (light solid gray) and F2 (dark solid gray) fragments. The F1 fragment is between the T4 and T1 domains and the F2 fragment is between the T2 and T3 domains. If a cell expresses all three (C) or four antigens (D) at its cell surface, simultaneous binding of T 1 +T2+T3 (C) or T1+T2+T3+T4 (D) domains to the surface of this cell is abrogating the blocking of the F1 and F2 fragments, bringing them in close proximity, causes association of fragments F1 and F2 and restoration of the biological function of the F domain by complementation.Figure 3 shows alternative combinations of the antigen binding domains in the antibody construct of the invention. At position C1 and C3 are the spl it / separated effector domain binding variable F1 (light solid gray) and F2 (dark solid gray) fragments. To the F1 and F2 fragments, different target antigen binding domains (T) can be connected. No T connected, one T connected, two same T connected, two different T connected. At position C2, between the F1 and F2 fragments, different connected target antigen binding domains (T) are possible. Two different T connected, three or more T connected with the same or different target antigen specificity. For a KeyLock antibody, different arranged C1, C2 and C3 variants are possible. Each C1 peptide can directly connect to each C3 peptide (C1-C3). Each C1 peptide can directly connect to each C2 peptide (C1-C2). Each C3 peptide can directly connect to each C2 peptide (C2-C3). Each C1 peptide can directly connect to each C2 and C3 peptide (C1-C2-C3). Each C1 , C2 and C3 peptide can be connected alone, and / or with a C2 and / or with a C3 peptide, to a serum protein. The serum proteins can be albumin, immunoglobulins (IgG, IgA, IgD, IgM), lipoproteins, receptors, cytokines, hormones.Figure 4 shows alternative formats of the invention in connection with serum proteins. (A) At position P1 , P2, P3, P4 and / or P5 can a peptide, full length serum protein, part of a serum protein or serum protein binding domain be connected. (B) The protein is between target antigen binding domains. (C) The protein is at the NH2-terminus (N) connected. (D) The protein is at the COOH terminus (C) connected. The serum proteins can be albumin, immunoglobulins (IgG, IgA, IgD, IgM), lipoproteins, receptors, cytokines, hormones.Figure 5 shows examples for alternative immunoglobulin formats of the invention. Top left, sketch of an IgG immunoglobulin with the constant domains, constant light (CL) and constant heavy (CH). Disulfide bridges (black solid lines). Different peptides from C1, C2 and / or C3 (Figure 3), can be connected to the CH or CL domains. (A) The spl it / separated anti-CD3 receptor complex variable F1 (light solid gray) and F2 (dark solid gray) fragments are on the same peptide chain, connected to CL, CH1 and / or CH2 domains. (B) The F1 and F2 fragments are on separate / different peptide chains, connected to a CH1 and / or CL domain, of the same antibody. The formation of a correct heterodimer, with pairing F1 and F2 fragments, is building the final KeyLock antibody. (C) The F1 and F2 fragments are on separate / different peptide chains, connected to CH2 domains of the same antibody. The formation of a correct hetero-dimer, with pairing F1 and F2 fragments, is building the final KeyLock antibody.Figure 6 shows examples for escaping target antigen-loss by the invention. (A) Against four different target antigens (triangle, pentagon, circle and square) are four specific target antigen binding domains directed (anti-triangle = black waves, anti-pentagon = black spots, anti-circle = white spots and anti-square = black mesh). If a target cell is losing one or two of the target antigens on its cell surface, up to ten different antigen loss scenarios are possible. These single or double antigen negative cells can still be targeted with a KeyLock antibody, if different KeyLock chains are connected to an antibody construct. (B) Two different KeyLock binders connected to the CH2 domain. (C) Four different KeyLock binders connected to the CH1 and CL domains. (D) Six different KeyLock binders connected to the CH1, CL and CH3 domains. Specific mutants (black circle) in the CH and CL domains allow for correct pairing and formation of the respected heterodimers. A Key Lock-anti body with six different binders, is able to target all 10 different antigen-loss scenarios, significantly reducing the risk of tumor escape under therapy.Figure 7 shows alignment of different antibody VH (A) and VL (B) sequences. Two anti-CD3 receptor complex binders (diL2K and UCHT1), anti-Erbb2 (HER2 / neu), anti-EpCAM, anti-CD38 and anti-SLAMF7 binders. With a grey box the constant frame work (FR) 1 to 4, and with a black box the three CDR regions, of the two anti-CD3 binders are marked. The programm Jalview (© EMBL 2022 | EMBL-EBI) was used. * (asterisk) indicates positions which have a single, fully conserved residue, (colon) indicates conservation between groups of strongly similar properties, roughly equivalent to scoring > 0.5 in the Gonnet PAM 250 matrix, (period) indicates conservation between groups of weakly similar properties, roughly equivalent to scoring =< 0.5 and > 0 in the Gonnet PAM 250 matrixFigure 8 shows different orientation of within connected antibody variable domains, VHA / L or VLA / H (polypeptide orientation from the NH2-terminus to the COCH terminus), has an impact on the antibody dissociation constant KD against the respected target antigen. (A) ScFv fragments from the anti CD3 clone LIGHT 1 , VH / VL (top, black circles) and VL / VH (bottom, black squares), against the human CD3 epsilon-gamma dimer (EG). For the ELISA assay, a recombinant protein IgG fused with the human CD3 epsilon and CD3 gamma chain, was labeled to a 96-well cell culture plate. After incubating the plates with different concentrations of the anti-CD3-VHA / L and anti-CD3- VL / VH ScFv constructs, washing with PBS, the binding of the ScFv was detected using an HRP-labeled secondary antibody against the 6x His-tag of the ScFv constructs. (B) Quantification of the results shown in (A).Figure 9 shows KeyLock antibodies targeting HER2 / neu and EpCAM. Different antigen targeting varaible domains (VH / VL). OCD3 VH (light solid gray) and VL domain (dark solid gray), anti-HER2 / neu domain (black spots), anti-EpCAM domain (black waves), flexible glycine-serine linkers (gray solid line), GS-6x histidine tag (H). Constructs T05.2, T06.2, T07.2 and T08.2 with oCD3 sequence from the UCHT 1 clone.Figure 10 shows KeyLock antibodies targeting CD38 and SLAMF7. Different antigen targeting varaible domains (VH / VL). OCD3 VH (light solid gray) and VL (dark solid gray) domain, anti-CD38 domain (black spots), anti-SLAMF7 domain (black waves), flexible glycine-serine linkers (gray solid line), GS-6x histidine tag (H). Constructs T01, T02, T03 and T04 with oCD3 sequence from the diL2K clone.Figure 11 shows the recombinant protein production of the KeyLock antibody T05.2 targeting HER2 / neu and EpCAM using eukaryote cells. Expi-HEK293 cells are transfected with pCEP4 Mammalian Expression Vector (Invitrogen ™) carrying the respective KeyLock antibody sequence. Five days after transfection, the cell culture supernatant is harvested, dialyzed against 1x PBS (pH 7.4 at 4 °C overnight) and the KeyLock antibody, carrying a His-tag at the C terminus, are extracted and purified with CO-IMAC beads (at 4 °C for 2 h in rotation). The fraction not binding to the CO-IMAC beads is the flow through (FT). The protein-bead complex is washed with CO-IMAC Loading buffer with 20 column volumes. Samples from the consecutive washing steps are the wash 1-2 (W1 and W2). For eluting the KeyLock antibodies, CO-IMAC Elution buffer with two column volumes is used for 3 consecutive times (E1, E2 and E3). The different wash and elution fractions are loaded onto a 10% SDS-PAGE Gel and Coomassie Brilliant Blue (CBB) stained. Abbreviations: FT = Flow through, W1-2 = Wash 1-2, E1-3 = Elution 1-3, kDa = Kilodalton;Figure 12 shows the recombinant protein production of the KeyLock antibody T06.2 targeting HER2 / neu and EpCAM using eukaryote Expi-HEK293 cells. Abbreviations: FT = Flow through, W1-2 = Wash 1-2, E1-3 = Elution 1-3, kDa = Kilodalton;Figure 13 shows the recombinant protein production of the KeyLock antibody T07.2 targeting HER2 / neu and EpCAM using eukaryote Expi-HEK293 cells. Abbreviations: FT = Flow through, W1-2 = Wash 1-2, E1-3 = Elution 1-3, kDa = Kilodalton;Figure 14 shows the recombinant protein production of the KeyLock antibody T08.2 targeting HER2 / neu and EpCAM using eukaryote Expi-HEK293 cells.Figure 15 shows the recombinant protein production of the KeyLock antibodies T01 and T02 targeting CD38 and SLAMF7 using eukaryote Expi-HEK293 cells. Abbreviations: FT = Flow through, W1-2 = Wash 1-2, E1-3 = Elution 1-3Figure 16 shows the recombinant protein production of the KeyLock antibodies T03 and T04 targeting CD38 and SLAMF7 using eukaryote Expi-HEK293 cells. Abbreviations: FT = Flow through, W1-2 = Wash 1-2, E1-3 = Elution 1-3Figure 17 shows the final purified KeyLock antibodies, targeting HER2 / neu and EpCAM, used for in vitro experiments. After CO-IMAC extraction and elution of the KeyLock proteins, the elution fractions are desalted and the protein was concentrated and buffer exchanged into storage buffer. The final KeyLock protein purity and concentration was analysed, loading them onto a 10% SDS-PAGE Gel, with a bovine serum albumin protein standard (BSA) and CBB stained.Figure 18 shows the final purified KeyLock antibodies, targeting CD38 and SLAMF7, used for in vitro experiments.Figure 19 pCold_T02 bacterial clone screening. Fig 19 shows recombinant production of KeyLock antibody T02,targeting CD38 and SLAMF7, in prokaryote E. coli cells. SHuffle® T7 Express Competent E. coll cells are transfected with pCOLD™ IV bacterial Expression Vector (TaKaRa Bio Inc) carrying the respective KeyLock antibody sequence. (A) For each bacteria clone, the cell pellet (P) and cell supernatant after cell disruption (S), a fraction was loaded onto a 10% SDS-PAGE Gel (reducing) and total protein load was analysed with a CBB stain (top row). (B) To analyze what protein bands are from the KeyLock antibodies, a Western blot was performed with unstained 10% SDS-PAGE Gels and protein lysate from the different clones (bottom row). The Western blot membranes are stained with an anti-His-tag antibody (1:3000 anti-6xHis) to detect the KeyLock antibodies. The colorimetric detection system used was alkaline phosphatase.Figure 20 (A) to (C) shows extracted KeyLock antibodies T02, T03 and T04, targeting CD38 and SLAMF7, produced in E. coli cells. For each KeyLock antibody, a bacteria clone is growing in 2x YT medium supplemented with kananmycin and carbenicilin and 0.2% glucose. KeyLock protein production was induced adding 0.1 mM IPTG and incubated at 16°C for 18 - 20 hours. Afterward from the E. coli cell pellet the antibodies are extracted using cobalt beads. After incubation with the cobal beads at 4° C over night, the beads are loaded onto a purification column and washed with CO-IMAC Loading, washing and elution Buffer. All fractions were loaded onto a SDS PAGE gel to check the KeyLock protein production. (A) KeyLock antibody T02 production, (B) KeyLock antibody T03 production and (C) KeyLock antibody T04 production.Figure 21 shows the final purified KeyLock antibodies T02, T03 and T04, targeting CD38 and SLAMF7, produced in E. coli cells, used for in vitro experiments. From the column elution fractions, the fractions with the highest and most clean KeyLock protein concentrations are pooled and loaded onto a 10% SDS PAGE gel with a BSA standard to determine total protein concentrations. The production yield per 1 liter (L) bacterial culture, with an optical density (OD) between 1.0 and 2.0, and the yield per E. coli cells, was calculated.Figure 22 shows KeyLock antibodies targeting HER2 / neu and EpCAM, linked to human albumin. (A) Sketch of single chain antibody format with the full-length human albumin (P02768, amino acid 19 - 601) covalent attached at the NH2-terminus, via a long (58 amino acids) flexible glycine-serine linker (gray solid line). (B) Recombinant production yields of Albumin-KeyLock fusion antibodies in eukaryote cells. Final purified protein was loaded onto a 10% SDS-PAGE Gel and CBB stained.Figure 23 shows for different KeyLock antibodies (i.e. T05.2, T06.2 and T07.2 according to the invention), no engagement of T cells against single antigen positive cells. Briefly, three different KeyLock antibodies, produced in eukaryote cells, with antibody variable domains in different orientations, were titrated to co-cultures of HER2 / neu (A) or EpCAM (B) single positive and luciferase positive CHO-cells and T cells as described. After two days coculture, the viability of the CHO cells was measured, using a luciferase substrate. As positive and negative controls were used, two bi-specific antibodies (BITE_Her2 = aCD3-aHER2 / neu and BITE_EpCAM = aCD3-aEpCAM), a final 5% Dimethylsulfoxid (DMSO) solution, T cells and target cells combination and target cells only. The data represent the means of three independent experiments. These results show that, using antigen specific VL and VHdomains and to connect them with split / separated anti-CD3 VL and VH domains in a single antibody format, is blocking FvCD3 formation, if not both target antigens are expressed on the target cells. The BITE antibodies used in this Figure were as follows: Figure 23A: BiTE_Her2 = SEQ ID NO: 325 + SEQ ID NO: 329; BiTE_EpCAM = SEQ ID NO: 325 + SEQ ID NO: 328; Figure 23B: BITE_Her2 = SEQ ID NO: 325 + SEQ ID NO: 329; BITE_EpCAM = SEQ ID NO: 325 + SEQ ID NO: 328.Figure 24 shows specific killing of dual antigen positive target cells with different KeyLock antibodies in a dose dependent manner (i.e. T05.2, T06.2 and T07.2 according to the invention). Briefly, three different KeyLock antibodies, produced in eukaryote cells, two different bi-specific antibodies (BITE_Her2 = aCD3-aHER2 / neu and BITE_EpCAM = aCD3-aEpCAM) and a final 5% Dimethylsulfoxid (DMSO) solution, were titrated to co-cultures of HER2 / neu and EpCAM double positive and luciferase positive CHO-cells and T cells as described. After two days co-culture, the viability of the OHO cells was measured, using a luciferase substrate. The KeyLock-antibodies T05.2 (aCD3VH-aHER2 / neuVL / VH-a EpCAM VL / VH-OCDSVL), T06.2 (aCD3VH-aEpCAMVL / VH-aHER2 / neuVL / VH-aCD3VL) and T07.2 (aCD3VL-aHER2 / neuVH / L-aEpCAMVH / VL-aCD3VH) are dual-antigen-restricted. These results from Figures 23 and 24 show that, using antigen specific VL and VH domains and to connect them with split / separated anti-CD3 VL and VH domains in a single antibody format, is blocking FvCD3 formation. Only in the presence of both respective target antigens, the FvCD3 are able to cooperate in order to reconstitute or complement T cell engaging function. Importantly, the scFvHER2 / neu and scFvEpCAM targeting moieties of the KeyLock antibodies could be switched from (VL-VH) to the (VH-VL) orientation, and the anti-CD3 VL and VH domains could be switched from the NH2-terminus to the COOH terminus, clearly indicating the modular character of the invention. The BITE antibodies used in this Figure were as follows: BITE_Her2 = SEQ ID NO: 325 + SEQ ID NO: 329; BITE_EpCAM = SEQ ID NO: 325 + SEQ ID NO: 328.Figure 25 shows for the KeyLock antibodies (i.e. T01 , T02, T03 and T04 according to the invention) no engagement of T cells against single antigen positive cells. Briefly, four different KeyLock antibodies, produced in eukaryote cells, with different variable domain orientation / arrangement, were titrated to co-cultures of CD38 (A) or SLAMF7 (B) single positive and luciferase positive CHO-cells and T cells as described. After two days co-culture, the viability of the OHO cells was measured, using a luciferase substrate. As positive and negative controls were used, a final 5% Dimethylsulfoxid (DMSO) solution, T cells and target cells combination and target cells only. The data represent the means of three independent experiments.Figure 26 shows specific killing of dual antigen positive target cells for different KeyLock antibody in a dose dependent manner (i.e. T01, T02, T03 and T04 according to the invention). Briefly, four different KeyLock antibodies, produced in eukaryote cells and a final 5% Dimethylsulfoxid (DMSO) solution, were titrated to cocultures of CD38 and SLAMF7 double positive and luciferase positive CHO-cells and T cells as described. After two days co-culture, the viability of the OHO cells was measured, using a luciferase substrate. The KeyLock-antibodies T02 (OCD3VH-CISLAMF7VL / VH-CICD38VL / VH-CICD3VL), T03 (aCD3VL-aCD38VH / VL-aSLAMF7VH / VL-OCD3VH) and T04 (OCD3VL- OSLAMF7VH / L-CICD38VH / L-CICD3VH) are dual-antigen-restricted. These results fromFigures 25 and 26 show that, using antigen specific VL and VH domains and to connect them with split / separated anti-CD3 VL and VH domains in a single antibody format, is blocking FvCD3 formation. Only in the presence of both respective target antigens, the FvCD3 are able to cooperate in order to reconstitute or complement T cell engaging function. Importantly, the scFvCD38 and scFvSLAMF7 targeting moieties could be switched from (VL-VH) to the (VH-VL) orientation / configuration, and the anti-CD3 VL and VH domains could be switched from the NH2-terminus to the COOH terminus, clearly indicating that the modular character of the constructs allows replacement of a targeting moiety by another targeting moiety with desired specificity.Figure 27 shows specific killing of dual antigen positive target cells with different KeyLock antibodies in a dose dependent manner (i.e. T02, T03 and T04 according to the invention) recombinant produced in prokaryotic cells. Briefly, three different KeyLock antibodies, produced in E. coll cells, a bi-specific antibody produced in eukaryotic HEK293 cells (KiH-aCD3-aCD38), and a final 5% Dimethy Isulfoxid (DMSO) solution, were titrated to co-cultures of CD38 and SLAMF7 single (A and B) and double (C) positive and luciferase positive CHO-cells and T cells as described. After two days co-culture, the viability of the CHO cells was measured, using a luciferase substrate. At low nM concentration, the KeyLock-antibodies T03 (OCD3VL-CICD38VH / L-CISLAMF7VH / L-CICD3VH) and T04 (OCD3VL- OSLAMF7VH / VL-CICD38VH / VL-CICD3VH) are dual-antigen-restricted. The BITE antibodies used in this Figure were as follows: Figure 27A: KiH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 27B: KiH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 270: KIH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327.Figure 28 shows side by side comparison of specific killing of dual antigen positive target cells for eukaryotic and prokaryotic produced KeyLock antibodies in a dose dependent manner (i.e. T03 and T04 according to the invention). Briefly, two different KeyLock antibodies, produced in prokaryotic E. coll cells (pColdJ and eukaryotic HEK293 cells (pCEP4_), a bi-specific antibody produced in eukaryotic HEK293 cells (KiH-aCD3-aCD38), and a final 5% Dimethylsulfoxid (DMSO) solution, were titrated to co-cultures of CD38 and SLAMF7 single (A, B) and double (C) positive and luciferase positive CHO-cells and T cells as described. After two days co-culture, the viability of the CHO cells was measured, using a luciferase substrate. At low nM concentration the KeyLock-antibodies T03 (OCD3VL-CICD38VH / VL-CISLAMF7VH / VL-CICD3VH) and T04 (oCD3VL- aSLAMF7VH / VL-aCD38VH / VL-OCD3VH) are dual-antigen-restricted. These results show that, independent of the cellular origin of the KeyLock antibody production, the KeyLock antibodies are dual-antigen-restricted. This clearly indicates the overall stability of the constructs and no eukaryotic post-translational modification is necessary for the KeyLock antibody function. The BITE antibodies used in this Figure were as follows: Figure 28A: KIH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 28B: KIH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 28C: KIH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327.Figure 29 shows side by side comparison of specific killing of dual antigen positive target cells for different KeyLock antibody formats, with or without human albumin attached, in a dose dependent manner (i.e. T02 and T04 according to the invention). Briefly, two KeyLock antibodies in a single chain scFv format (T02 (OCD3VH-CISLAMF7VL / H-OCD38VL / VH-CICD3VL) and T04 (OCD3VL- OSLAMF7VH / L-CICD38VH / L-CICD3VH), and two KeyLock antibodies ina single chain scFv format with the human albumin attached at the NH2-terminus (A1+T02 (Albumin-oCD3VH-CISLAMF7VL / H-CICD38VL / H-CICD3VL) and A1+T04 (Albumin-aCD3VL- OSLAMF7VH / L-CICD38VH / L-CICD3VH), two bi-specific antibodies as controls (BiTE_SLAMF7 = aCD3-aSLAMF7, (BiTE_CD38 = aCD3-aCD38), and a final 5% Dimethylsulfoxid (DMSO) solution, were titrated to co-cultures of CD38 and SLAMF7 single (A and B) and double (C) positive and luciferase positive CHO-cells and T cells as described. After two days co-culture, the viability of the CHO cells was measured, using a luciferase substrate. At low nM concentration KeyLock-antibodies with and without the human albumin attached are dual-antigen restricted. These results show that, integrating large protein structures not directly involved in target antigen binding, has no negative impact on the KeyLock antibody dual-antigen-specificity. This clearly indicates the overall robustness and versatility of the KeyLock antibody format. The BiTE antibodies used in this Figure were as follows: Figure 29A: BiTE_CD38 = SEQ ID NO: 325 + SEQ ID NO: 327; BiTE_SLAMF7 = SEQ ID NO: 325 + SEQ ID NO: 326; Figure 29B: BiTE_CD38 = SEQ ID NO: 325 + SEQ ID NO: 327; BiTE_SLAMF7 = SEQ ID NO: 325 + SEQ ID NO: 326; Figure 290: BiTE_CD38 = SEQ ID NO: 325 + SEQ ID NO: 327; BiTE_SLAMF7 = SEQ ID NO: 325 + SEQ ID NO: 326.Figure 30 shows serum stability of different KeyLock antibodies (i.e. T02, T03 and T04 according to the invention). Briefly, three different KeyLock antibodies, produced in eukaryotic cells, were incubated in fresh human serum at 36°C for 48 hours. Afterward these constructs (-Serum), together with constructs not incubated with human serum, were titrated to co-cultures of CD38 and SLAMF7 single (A, B) and double (C) positive and luciferase positive CHO-cells and T cells as described. As control a bi-specific antibody (KiH-aCD3-aCD38), final 5% Dimethylsulfoxid (DMSO) solution and target cells only or target cells with T cells as described. After two days co-culture, the viability of the CHO cells was measured, using a luciferase substrate. At low nM concentration the incubation with fresh human serum had no negative effect on the dual-antigen-restricted function of the KeyLock-antibodies T02 (OCD3VH-CISLAMF7VL / H-CICD38VL / H-CICD3VL), T03 (aCD3VL-aCD38VH / L-aSLAMF7VH / L-aCD3VH) and T04 (OCD3VL- OSLAMF7VH / VL-CICD38VH / VL-CICD3VH). These results show that, fresh human serum with all its varius proteases has no negative effect on the KeyLock format with its long flexible protein linkers. This clearly indicates the overall stability of the KeyLock antibodies. The BiTE antibodies used in this Figure were as follows: Figure 30A: KiH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 30B: KiH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 300: KiH_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327.Figure 31 shows size exclusion chromatography (SEC) profiles of four different KeyLock antibodies targeting HER2 / neu and EpCAM, produced in eukaryotic cells. (A) to (D): For each of the constructs next to the SEC profile the protein SDS-gel with CBB staining is shown (small insert pictures). T05.2 (aCD3VH-aHER2 / neuVL / H-a EpCAM VL / H-OCDSVL), T06.2 (aCD3VH-aEpCAMVL / VH-aHER2 / neuVL / H-aCD3VL), T07.2 (aCD3VL-aHER2 / neuVH / VL-aEpCAMVH / L-aCD3VH) and T08.2 (aCD3VL-aEpCAMVH / L-aHER2 / neuVH / L -aCD3VH) show a mostly monomer fraction in the elution peak. These results shows for different KeyLock antibodies in physiological solution, with different target antigen scFv (VL-VH) and (VH-VL) orientations and split anti-CD3 VL and VH domains at the NH2-terminus or the COCH terminus, the majority is in the monomere fraction. This clearly indicates the overall low protein-aggregation rate of the KeyLock antibody format.Figure 32 shows the thermostability of different KeyLock antibodies (i.e. T02, T03 and T04 according to the invention). Three different constructs, produced in prokaryotic cells (pColdJ and eukaryotic cells (pCEP4_) were analyzed. As control the anti-CD38 IgG antibody Daratumumab (Darzalex®) was used. The thermostability of the KeyLock antibodies is high, 54.5°C, independent if they are produced in prokaryotic or eukaryotic cells. All three constructs had similar thermostability (A) T02 (OCD3VH-CISLAMF7VL / VH-CICD38VL / VH-CICD3VL), (B) T03 (OCD3VL-OCD38VH / VL-CISLAMF7VH / L-CICD3VH) and (C) T04 (oCD3VL- aSLAMF7VH / L-aCD38VH / L-aCD3VH). These results shows the thermostability for different KeyLock antibodies in physiological solution, with different target antigen scFv (VL-VH) and (VH-VL) orientations and split anti-CD3 VL and VH domains at the NH2-terminus or the COOH terminus. This clearly indicates the overall stability of the KeyLock antibody format.Figure 33 shows no unspecific T cell activation of different KeyLock antibodies (i.e. T01, T02, T03, T04, T05.2, T06.2, T07.2 and T08.2 according to the invention). (A) Eight different KeyLock antibodies were tested for their ability to activate cytotoxic T cells in the absence of their respective target antigens at a final concentration of 10 nM. As positive control for T cell activation, a bi-specific antibody aCD3-aCD28 was used. None of the KeyLock constructs were able to activate T cells, in contrast to the positive control. (B) Quantification of the results shown in (A). The data represent the mean of two independent experiments. These are important data, showing that different KeyLock antibodies, against different antigens, with different target antigen scFv (VL-VH) and (VH-VL) orientations and split anti-CD3 VL and VH domains at the NH2-terminus or the COOH terminus, have no unspecific T cell activation in the absence of target cells. This clearly indicates the overall reduced risk of the KeyLock antibody format for unspecific T cell activation and unwanted cytokine release syndrome.Figure 34 shows that KeyLock antibodies (i.e. T02 and T05.2 according to the invention) have to bind all their respective target antigens on the surface of a cell to release the blocked antiCD3 domain and complement T cell engaging functions. It is not possible for a KeyLock antibody to be activated via binding with only one arm to a target cell and with the second arm to an antigen in solution. Briefly, KeyLock antibodies at different concentrations, together with titrated soluble human target antigens were co-cultured with single antigen positive and Luziferase positive OHO cells and T cells as described and OHO cell viability was determined through the Luziferase signal after 24 hours cell culture. For soluble target antigens, only the extracellular domain of the respective human antigen was fused the human Ig constant Fc domain, expressed and purified in HEK293 cells. As positive and negative controls were used a final 5% Dimethylsulfoxid (DMSO) solution, T cells and target cells combination and target cells only. A bi-specific antibody against CD38 (aCD3-aCD38) and EpCAM (aCD3-aEpCAM) was used as control for T cell activation and target cell killing. The KeyLock antibody T02 against CD38 and SLAMF7 (OCD3VH-OSLAMF7VL / H-CICD38VL / H-CICD3VL) was not able to redirect T cells against single antigen positive cells in the presence of both (CD38 and SLAMF7) soluble target antigens (A, target cells CD38+) and (B, target cells SLAMF7+), or in the presence of only one target antigen in culture (C, target cells CD38+ and soluble antigen SLAMF7) and (D, target cells SLAMF7+ and soluble antigen CD38). The same imperative, dual antigen expression on target cells for KeyLock antibody effector function, is the case for a different KeyLock antibody T05.2 againstHer2 and EpCAM (aCD3VH-aHER2 / neuVL / VH-aEpCAMVL / VH-aCD3Vi_). The T05.2 KeyLock antibody is not able to redirect T cells against single antigen positive cells in the presence of both (Her2 / neu and EpCAM) soluble target antigens (E, target cells Her2 / neu+) and (F, target cells EpCAM+), or in the presence of only one target antigen in culture (G, target cells Her2 / neu+ and soluble antigen EpCAM) and (H, target cells EpCAM+ and soluble antigen Her2 / neu). These results clearly indicate that a KeyLock antibody has to bind first with all its target antigen binding domains onto the surface of a cell in order to release the blocked antiCD3 effector domains to restore T cell engaging function. The BiTE antibodies used in this Figure were as follows: Figure 34A: BITE_anti-CD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 34B: BITE_anti-CD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 340: BITE_anti-CD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 34D: BITE_aSLAMF7 = SEQ ID NO: 325 + SEQ ID NO: 326; Figure 34G: BiTE_aHer2 = SEQ ID NO: 325 + SEQ ID NO: 329; Figure 34H: BITE_aEpCAM = SEQ ID NO: 325 + SEQ ID NO: 328.Figure 35 shows competitive blocking experiments for the invention. For this KeyLock antibodies (i.e. T02 and T05.2 according to the invention) at different concentrations, together with titrated soluble human target antigens were co-cultured with dual antigen positive and Luziferase positive OHO cells and T cells and OHO viability was determined through the Luziferase signal after 24 hours cell culture. As positive and negative controls were used, a final 5% D imethy Isulfoxid (DMSO) solution, T cells and target cells combination and target cells only, a bi-specific antibody against CD38 (aCD3-aCD38) and a bi-specific antibody against EpCAM (aCD3-aEpCAM). The T cell mediated target cell killing was blocked, in a concentration dependent manner, by soluble target antigen (A, target cells CD38+ and SLAMF+, the soluble antigen CD38) and (B, target cells Her2 / neu+ and EpCAM+, the soluble antigen EpCAM). These results clearly indicate again, that KeyLock antibodies have to bind with all their target antigens binding domains onto the surface of a cell in order to release the blocked antiCD3 effector domains to restore T cell engaging function and target cell killing. Importantly, these results again show that the targeting module can be easily replaced by another module with appropriate specificity. The BiTE antibodies used in this Figure were as follows: Figure 35A: BITE_aCD38 = SEQ ID NO: 325 + SEQ ID NO: 327; Figure 35B: BITE_aEpCAM = SEQ ID NO: 325 + SEQ ID NO: 328.Figure 36 (A) to (D) shows the principle of the invention. (A) Design of a KeyLock single chain polypeptide antibody, targeting two different antigens (x and y), with two antibody variable domains anti-x (T1 black spotted ovals) and anti-y (T2 black waves ovals) in VL-VH orientation (from the NH2-terminus to COOH terminus), covalently connected with linkers (gray solid line). The anti-CD3 receptor complex directed effector binding domain (F), from an anti-CD3E antibody, is split / separated into the VH fragment (F1 light gray oval) at the NH2-terminus and into the VL fragment (F2 dark gray oval) at the COOH terminus. In a basic KeyLock antibody format, targeting two different target antigens (T 1 and T2) and one effector cell antigen (CD3), there are different stronger and weaker affinities for the different antibody variable domains (strong affinities with dark grey filled arrows, weaker affinities with lighter grey filled arrows):The affinities (i) between the VH and VL domains against their respective antigens on the target cells. Because these domains are directly connected to each other and therefore can for a scFv moiety stabilized through the connected linker, these scFv moieties have a strong target antigen affinity (dark grey wide arrow with one arrowhead).The affinities (ii) between the anti-CD3 VH and VL domains against the CD3E chain on the effector cell. These domains are split / separated from each other and their VH and VL complementation is not stabilized thru a direct connecting linker (light grey arrow with one arrowhead). Alone, the affinity of the VH or VL domain is so low and not enough to bind CD3E on T cells and to activate them.The affinities (ill) between the VH and VL interface for each binding moieties (from the same antibody clone), if they are directly connected through a linker (VH-VL or VL-VH) or not (anti-CD3 VH and VL domains) (straight medium grey arrows with two arrowhead).The affinities (iv) of the VH and VL interfaces between different binding moieties (from different antibody clones) (light grey bend arrows with two arrowhead).(B) These different affinities combine for the total avidity of the KeyLock construct. The affinity-strength for each wild-type moiety against its target is extremely strong (dark grey wide arrow with one arrowhead), because most antibodies are selected in their development processes for high affinity binders. Reducing the affinity of VH and / or VL domains through mutations in their antigen binding sites (black filled circle, see e.g. F1 VH anti-CD3), or in their VH and VL interface (black filled star, see e.g. F2 VL anti-CD3) will shift the much weaker affinity-balance between the different VH and VL interface to each other, especially if not all target moieties are bound to their antigens. For the fine modifying between inter-domain balances, the connected linkers flexibility, length and composition plays also an important role. These linkers allow in the absence of target antigens for a transient separation ("breathing”) and swaping of the VH and VL domains with connected domains. Therefore, through modulating the structure of the KeyLocks by means of amino acid mutations in different binding moieties and different linkers connecting them, it will be possible to optimize the cellular antigen restricted functional complementation of the KeyLock antibody format.(C) Depicts single antigen positive cells (left side X, right side Y). If only one antigen specific moiety is bound, only one aCD3 domain (left side VH anti-CD3, right side VL anti-CD3) is unblocked. The single F1 and F2 anti-CD3 domains are not able for functional complementation by themselves. Their single affinity is therefore to low. (D) Depicts a double antigen positive target cell (X and Y). The simultaneous binding of both T1 and T2 domains to the surface of the cell is abrogating the blocking of both F1 and F2 anti-CD3 fragments, bringing them in close proximity, causing association of fragments F1 and F2. Now the combined affinity of the complemented anti CD3E directed VH and VL domains is strong enough to activate the T cell and to redirect it as effector cell against the dual-antigen positive target cell for cell lysis.Figure 37 (A) to (D) gives an overview of the different antibody formats used herein. (A) Design of a single chain variable fragment (scFv), targeting the CD3E antigen (aCD3). With the antibody variable heavy (VH) domain (light grey filled oval) and the antibody variable light (VL) domain (dark grey filled oval), in VH-VL orientation on the left (from the NH2-terminus to COOH terminus) and the VL-VH orientation on the right. The domains are covalently connected with a flexible GS-linker (gray solid line). With a short 6 amino acid His-tag (H). (B) Design of a bi-specific T cell engager (BITE) in the knob-into-hole format. The OCD3E SCFV binder (filled black ovals) is at the N-terminal end of the IgG Fc knob construct, linked via a flexible glycine serine linker (grey solid line) to the constant CH2 domain. The target antigen directed scFv binder (white ovals) is attached at the C-terminal end of the IgG Fc hole construct, to the constant CH3 domain. At the C-terminal end of the target antigen scFv is a His-tag (grey rectangle). Straight black lines are disulfide bridges (-S-S-) and curved grey lines are flexible GS-linkers. (C) Design of a split-KeyLock consisting of two separate protein fragments (top and bottom). Each KeyLock fragment is targeting the same two individual antigens (x and y), with two antibody variable domains anti x (T1 black spotted ovals) and anti y (T2 black waves ovals) both in the VL-VH orientation (from the NH2-terminus to COOH terminus), covalently connected with linkers (gray solid line). The anti-CD3 receptor complex directed effector binding domain (F), from an anti-CD3fi antibody, is split into the VH fragment (F1 light gray oval) at the NH2-terminus of the first fragment, and the pairing VL fragment (F2 dark gray oval) is split and separated at the COOH terminus of the second KeyLock fragment. Both fragments have a short 6 amino acid His-tag (H). (D) Design of a KeyLock single chain polypeptide antibody, similar to Figure36 (A).Figure 38 (A) to (B) shows for in silico generation of the different CD3 point mutations, the used crystal structure models of the: (A) wild type antibody diL2K (SEQ ID NO: 419) in complex with the CD3fiy chains, and (B) for wild type UCHT1 antibody (SEQ ID NO: 415) in complex with the CD3E5 chains. Using murine crystal structures as templates, using a (G4S)3 linker between the heavy and light chains and a 8-His tag at the light chain C-terminal end. The different domains of the antibody and the CD3 chains are marked (black arrow).Figure 39 (A) to (D). (A) shows the in silico results for the UCHT1 clone with 10 different point mutants (SEQ ID Nos: 470-479). The amino acid numbering of the different mutants is based on the numbering used in the scFv format (SEQ ID NO: 415). (B) Shows for the G33R mutant (asterisk) the formation of 2 salt bridges in the structure (right side). (C) Shows for the Y171 F mutant (asterisk) the loss of water-mediated hydrogen bonds in the structure (right side). (D) Shows for the K57S mutant (asterisk) the loss of a salt bridge and a hydrogen bond and the formation of a new hydrogen bond in the structure (right side).Figure 40 (A) to (D). (A) shows the in silico results for the di L2K clone with 11 different point mutants (SEQ ID Nos: 459-469). The amino acid numbering of the different mutants is based on the numbering used in the scFv format (SEQ ID NO: 419). (B) Shows for the T35L mutant (asterisk) the displacement of unfavourable water in the structure (right side). (C) Shows for the Y106V mutant (asterisk) a loss of n-cation interaction in the structure (right side). (D) Shows for the D185L mutant (asterisk) the loss of a salt bridge in the structure (right side).Figure 41 (A) to (B) shows for the in silico generation of different CDR deletion mutants the sequence alignments for the homology modeling. (A) Sequence alignment between diL2K and antibody from 1SY6. (B) Sequence alignment between humanized UCHT1 and musculus UCHT1 from 1X1 W.Figure 42 (A) to (B) shows for the in silico generation of the CDR deletion mutants the modeled structures of diL2K and hUCHTI in alignment with the template structure. (A) For structural model of diL2K (SEQ ID Nos: 419) superimposed to OKT3 from 1SY6. The proteins are represented in cartoon model. The diL2K, OKT3 and CD3 gamma / epsilon are colored differently. (B) For structural model of hUCHTI (SEQ ID Nos: 415) superimposed to musculus UCHT1 from 1XIW. The proteins are represented in cartoon model. The hUCHTI, musculus UCHT1 and CD3 epsilon / delta are colored differently. The predicted 3D structures superimposed well with the antibodies from the crystal structures.Figure 43 (A) to (B) shows for the in silico generation of the CDR deletion mutants the generated Ramachandran plots and evaluate the quality of the modeled structures using PROCHECK

[0016] for (A) diL2K and (B) UCHT1. The Ramachandran plots of diL2K model shows that 93.1% and 5.4% residues are located in the favored region or additional favored region, respectively. For UCTH1 model, it is shown that 90.9% and 7.1% residues are located in the favored region or additional favored region, respectively. The results demonstrate high quality structural models for both antibodies.Figure 44 (A) to (C). (A) shows for the in silico generation of the CDR deletion mutants the comparison of diL2K Top 1 docking pose with OKT3- CD3 gamma / epsilon complex crystal structure. The proteins are represented in cartoon model. The diL2K, OKT3 and CD3 gamma / epsilon are colored differently. (B) Shows the top ten ranked poses of diL2K with their respective ITScorePeP. The top ten binding poses were obtained according to the knowledge-based scoring function (ITScorePeP). The best ranked docking pose (Top 1) presented a very similar binding mode as the OKT3 in complex with CD3 (A). (C) Is listing the energy contributions of interface residue pairs in diL2K- CD3 gamma / epsilon complex. The residues making energy contribution lower than -8.0 kcal / mol are defined as key residues and might be important for antibody-antigen binding. Except TYR50 and LYS74, most of the key residues are from CDRs, including THR30 and ARG31 from H1, ARG55from H2, TYR99, ASP101, TYR104 from H3, TRYR168 from L1, ASP186 from L2 and TRP227 from L3. The amino acid numbering of the different mutants is based on the numbering used in the scFv format (SEQ ID NO: 415 and 419).It seems that removing any of the CDRs, especially H3, will cause significant decrease in binding free energy and abolish the binding between diL2K and CD3 gamma / epsilon.Figure 45 (A) to (C). (A) shows for the in silico generation of the CDR deletion mutants the comparison of UCHT 1 Top 1 docking pose with musculus UCHT1- CD3 epsilon / delta complex crystal structure. The proteins are represented in cartoon model. The UCTH1 , musculus UCHT 1 and CD3 epsilon / delta are colored in magentas, cyan and green, respectively. (B) Shows the top ten ranked poses of UCHT 1 with their respective ITScorePeP. The best ranked docking pose (Top 1) presented a very similar binding mode as the musculus UCTH1 in complex with CD3(A). (C) Is listing the energy contributions of interface residue pairs in UCHT1- CD3 epsilon / delta complex. The residues making energy contribution lower than -8.0 kcal / mol are defined as key residues and might be important for antibody-antigen binding. Except TYR186 and SER204, most of the key residues are from CDRs, including TYR54 from H2, TYR101, TYR102, ASP106 from H3, ARG167, TYR169 from L1, TYR187, ARG190 from L2. The amino acid numbering of the different mutants is based on the numbering used in the scFv format (SEQ ID NO: 415 and 419).For H1 and L3, several residues contact with the CD3 antigen but the energy contribution is not as high as other CDR regions. However, removing the H3 region will cause significant decrease in binding free energy and abolish the binding between UCTH1 and CD3 epsilon / delta because a number of residues from H3 provide favorable contacts with CD3 residues.Figure 46 shows a table for the in silico generation of the CDR deletion mutants (SEQ ID Nos: 480 to 491), different CDR deletions based on the structure models of dil_2K and UCTH1. Distances of main chain carbon atoms from the terminal residues of deleted sequences were measured and used as clues for CDR replacement with flexible serine-glycine (GS) linkers. The longer the distance is, the more SG residues were used. And the estimated binding energy loss is also calculated. A large the absolute value indicates a great loss of the binding affinity.Figure 47 shows for the different OCD3E VH and VL point-mutants the recombinant production in a scFv format. For the dil_2K mutants (left) and the UCHT1 mutants (right). For this, HisTag-purified scFvs were loaded at 1 pig per lane under denaturing plus reducing conditions on a 12% polyacrylamide gel. PageRuler™ Unstained Protein Ladder for kilo Dalton size (kDa) was used as a marker (M). For diL2K mutants SEQ ID NOs: 459 to 469, for UCHT 1 mutants SEQ ID NOs: 470 to 479.Figure 48 (A) to (C) shows the binding affinities for the different OCD3E SCFV point-mutations and the wild type scFv against their respective antigens using an ELISA assay. (A) UCHT 1 clone derived mutant scFv (SEQ ID NOs: 470 to 479) and wild type (SFV0102_VH / VL and SFV0102_VL / VH) scFv (SEQ ID NOs: 415 and 523), against the human CD3 epsilon-gamma dimer (EG), or (B) against the human CD3 epsilon-delta dimer (ED). (C) diL2K clone derived mutant scFv (SEQ ID NOs: 459 to 469) and wild type (native) scFv (SEQ ID NOs: 419), against the human CD3 epsilon-delta dimer (ED). For the ELISA assay, a recombinant protein IgG fused with the human CD3 epsilon and CD3 gamma or CD3 delta chain, was labeled to a 96-well cell culture plate. After incubating the plates with different concentrations of the wild type and mutant anti-CD3 scFv constructs, the binding of the individual scFvs was detected using an HRP-labeled secondary antibody against the 6x His-tag of the scFv constructs. Quantification of the results are shown in the tables.These are important data, showing with a specific in silico modulation method it is possible to generate antibody point mutants in the VH or VL domains, with changed affinity against their respected target antigens.Figure 49 (A) to (D) shows the binding affinities for the different OCD3E SCFV CDR deletion mutants and the wild type scFv against their respective antigens using an ELISA assay. (A) UCHT 1 clone derived VH chain CDR mutantscFv (SEQ ID NOs: 480 to 482) and wild type (UCHT1_Native) scFv (SEQ ID NOs: 415), against the human CD3 epsilon-gamma dimer (EG), or (B) against the human CD3 epsilon-delta dimer (ED). (C) dil_2K clone derived VH and VL chain CDR mutant scFv (SEQ ID NOs: 486 to 491) and wild type (dil_2K_native) scFv (SEQ ID NOs: 419), against the human CD3 epsilon-gamma dimer (EG), or (D) against the human CD3 epsilon-delta dimer (ED). Again, these are important data showing, with a specific in silico modulation method it is possible to generate antibody mutants with complete loss of a CDR region in the VH or VL domain, with reduced affinity but sustained binding their respective antigens.Figure 50 shows the recombinant production of two BiTE antibodies targeting CD38, one with mutant oCD3 scFv (Y171F) and one with wild-type oCD3 scFv (VH / VL) in the Fc knop-into-hole format. For this, HisTag-purified BiTEs were loaded at 1 pig per lane on a 12% polyacrylamide gel. PageRuler™ Unstained Protein Ladder for kilo Dalton size (kDa) was used as a marker (M).Figure 51 (A) to (C) shows in vitro target cell killing for BiTE knop-into-hole antibodies (SEQ ID Nos: 492 to 508) with different mutant or wild-type binding domains against CD3E in the scFv format. DMSO was used as a positive control for cell killing and Target cells only and target cells with CD8+ T cells were used as negative control to exclude a possible T-cell response against neoantigens of the specific cell line. The BiTE antibody effector function, termed cytotoxicity, is measured by the drop in target cell viability, after incubating target cells with T cells and BiTE antibodies for 24 to 48 hours. (A) oCD3- oCD38 BiTE antibodies targeting CD38 positive cells. On the left, FACS analysis for target antigen surface expression using viable CD38 transfected CHO cells, showing low CD38 but no SLAMF7 expression on the cells. In the middle, cytotoxicity of different BiTE antibodies using oCD38 Fc_hole_CD38 (SEQ ID NO: 492) in combinattion with different Fc_knop SFV01 (diL2K) (SEQ ID NOs: 494, 495, 498 to 502). On the rigth, cytotoxicity of different BiTE antibodies using oCD38 Fc_hole_CD38 (SEQ ID NO: 492) in combinattion with different Fc_knop SFV0102 (UCHT1) (SEQ ID NOs: 496, 497, 503 to 507). (B) The same aCD3- aCD38 BiTE antibodies described in Figure 51 (A) were used. But this time against CD38 and SLAMF7 double positive cells. On the left, FACS analysis for target antigen surface expression using viable transfected CHO cells, showing extreme high expression of CD38 and low SLAMF7 expression. In the middle, cytotoxicity of different BiTE antibodies using oCD38 Fc_hole_CD38 (SEQ ID NO: 492) in combinattion with different Fc_knop SFV01 (diL2K) (SEQ ID NOs: 494, 495, 498 to 502). On the rigth, cytotoxicity of different BiTE antibodies using oCD38 Fc_hole_CD38 (SEQ ID NO: 492) in combinattion with different Fc_knop SFV0102 (UCHT1) (SEQ ID NOs: 496, 497, 503 to 507). (C) oCD3- oHer2 BiTE antibodies targeting Her2 positive cells. In the left, cytotoxicity of different BiTE antibodies using oHer2 Fc_hole_Her2 (SEQ ID NO: 493) in combinattion with different Fc_knop SFV01 (diL2K) (SEQ ID NOs: 494, 495, 498 to 502). On the rigth, cytotoxicity of different BiTE antibodies using oHer2 Fc_hole_Her2 (SEQ ID NO: 493) in combinattion with different Fc_knop SFV0102 (UCHT1) (SEQ ID NOs: 496, 497, 503 to 507).These are important data, showing for different oCD3 antibody clones and mutants, modulation of an antibody VH or VL domains through point mutations, causing a drop in affinity against their respected target antigen, is not correlating with their functional activity in a T cell recruiting antibody format.For example, the Y171 A mutant of the UCHT 1 clone showed no binding affinity against both antigens (CD3 epsilondelta and epsilon-gamma), but showed similar cytotoxicity as the wild-type antibody against CD38 and Her2 positive cells. Different antigen expression levels on the target cells (CHO CD38 low expressing (CHO_CD38+), versus CHO CD38 high expressing (CHO_CD38+_SLAMF+), had no significant negative effect on their cytotoxicity. In contrast, the flipping of the UCHT1 clone wild-type domains VH-VL to the VL-VH orientation reduced the killing activity against CD38 low expressing cells from 90% to 70%, correlating with the reduced binding affinity of the wild-type VL-VH scFv compared to the wild-type VH-VL scFv against both of their antigens (CD3 epsilon-delta and epsilon-gamma). This reduced antibody cytotoxicity, caused by its reduced affinity against OCD3E, could be overcome by higher CD38 antigen expression on the target cells (CHO_CD38+_SLAMF+ cells). This changing target cell killing function, by changing antigen expression levels on the target cells, is also seen for the antibody mutant D185L from the diL2K clone (SEQ ID NO: 469). With only 60% cytotoxicity against CD38 low expressing cells (CHO_CD38+) and up to 90% cytotoxicity against CD38 high expressing cells (CHO_CD38+_SLAMF+). These important data indicate that the hight of target antigen expression levels on the tumor cells can modulate the functional complementation of some antibody constructs of the present invention. This could be a great advantage for antibody-based tumor immunotherapy, because many tumor antigens used in clinic today are significantly overexpressed compared to their non-transformed counterparts. For example, upregulation of CD38 expression on non-small cell lung cancer (NSCLC) is involed in the tumor resistance to anti-PD-1 / PD-L1 immunotherapy

[0035] , This increased functional complementation of some mutant recombinant proteinaceous molecules of this invention against antigen high expressing cells, can also be used for combination therapies with other drugs inducing antigen expression on tumor cells. For example, the upregulation of CD38 on multiple myeloma cells by all-trans retinoic acid (ATRA) improves the efficacy of the anti-CD38 antibody daratumumab

[0035] ,Most OCD3E antibody mutants showed similar killing, irrespective of the addressed antigen on the target cells (CD38 or Her2). But there are also some exceptions of the rule, for example diL2K clone (SF01) derived mutant scFv Y167A (SEQ ID NO: 468) and D185L (SEQ ID NO: 469) had only a maximal killing activity of 60% against CD38 positive cells, but reached a significant higher killing of up to 90% against Her2 positive cells. Another example is for the diL2K clone (SF01) derived mutant scFv N54A (SEQ ID NO: 460) with 90% killing activity against CD38 positive cells but no killing activity against Her2 positive cells.These important data indicate, novel oCD3 scFv mutants can modulate the efficacy of an BITE antibody against specific target antigens and of the antibody construct of the present invention. Also, different target antigens on the tumor cells can modulate the functional complementation of some antibody constructs of the present invention.Figure 52 (A) to (C) shows the recombinant production of spl it-Key Lock fragments targeting Her2 and EpCAM with different oCD3 mutant and wild-type domains (SEQ ID NOs: 508 to 517). In this format the oCD3 VH and VL domains are separated / split from each other. One split-KeyLock fragment only carries a VH domain at his N-terminus end, or the VL domain at his C-terminus. Both fragments target Her2 and EpCAM with connected scFvs in the VL- VH orientation. For recombinant protein purification, there is a short 6 histidine tag (H) at the C-terminus. Modelling analysis with diL2K and UCHT2 clones with this H-tag attached at their C-terminus showed no negative interference with the connected VL or VH domain complementation or pairing with other domains. For this, HisT ag-purified split-KeyLock fragments were loaded at 1 pig per lane under denaturing plus reducing conditions on a 12% polyacrylamide gel. PageRuler™ Unstained Protein Ladder for kilo Dalton size (kDa) was used as a marker (M). Different elution fraction (E) were loaded on the gel. These data show different split-KeyLock fragment mutants are produced at high yields and high purity.Figure 53 (A) to (J) shows in vitro target killing, of single and double antigen positive cells, for split-KeyLock fragments with different combinations of point mutants (SEC ID NOs: 509 to 512, 515 to 516) and wild-type (SEC ID NOs: 508, 514) VH and VL domains from the OCD3E antibody clone UCHT1. In this special method structure it was possible to analyze various important variables for different combinations of mutant or wild-type VH with VL domains. (I) Are they able to reconstitute a functional effector binding oCD3 domain? (ii) When they are functional, do they have different restricted functional complementation against single or double antigen positive cells? (ill) Is the targeting window for killing double antigen positive cells compared to single antigen cells, increasing for specific mutants compared to the wild-type constructs? (iv) Are different ratios of VH to VL domains increasing the targeting window for killing double antigen positive cells compared to single antigen cells? DMSO was used as a positive control for cell killing and target cells only and target cells with CD8+ T cells were used as negative control to exclude a possible T-cell response against neoantigens of the specific cell line. The data for the single antigen (CHO-Her2+ and CHO-EpCAM+) cells and the double antigen positive cells (CHO-Her2+_EpCAM+) are presented in a heat-blot style, comparing the activity of the combined split-KeyLock fragments on the X- and Y-aches, over a large dose range (from maximal 200 nM down to 0.024 nM). WT stands for wild-type fragment. (A) Activity of the wild-type VH and VL fragments. High killing of double antigen positive cells, but also activity at high construct concentrations against single antigen positive cells, especially Her2 positive cells. (B) Retained activity for the VH_wild-type and VL_Y171A combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (C) Retained activity for the VH_wild-type and VL_N231A combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (D) Retained activity for the VH_S30L and VL_wild-type combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (E) Reduced but retained activity for the VH_S30L and VL_N231A combination for killing double antigen positive cells at high concentration, and complete loss of activity against single antigen positive cells. (F) Retained activity for the VH_G33R and VL_wild-type combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (G) Reduced but retained activity for the VH_G33R and VL_N231 A combination for killing double antigen positive cellsat high concentration, and complete loss of activity against single antigen positive cells. (H) Retained activity for the VH_K57S and VL_wi Id-type combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (I) Retained activity for the VH_V59S and VL_wi Id-type combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (J) Reduced but retained activity for the VH_V59S and VL_N231A combination for killing double antigen positive cells at high concentration, and complete loss of activity against single antigen positive cells.These are important data, showing: (I) The combination of different point mutants (mutant with mutant or mutant with wild-type) of spli t / separated OCD3E antibody VH and VL domains, in a KeyLock like antibody format targeting two different antigens, is possible and reconstitute a functional T cell activating antibody complex, (ii) Different combinations of mutant and wild-type VH and VL domains have different activity against single and double antigen positive cells, (ii) Specific combinations of mutant and wild-type VH and VL domains are increasing the dose dependent targeting window for killing double antigen positive cells compared to the wild-type constructs, (iv) The combination of different ratios of VH to VL domains (mutant-mutant or mutant-wild-type) can also increase the targeting window for killing double antigen positive cells compared to a 1 to 1 ratio.These data again demonstrate, modulating and combining mutant-mutant or mutant-wild-type VH or VL domains with each other can improve the dual antigen restricted functional complementation of antibody constructs of this invention.Figures 54 (A) to (B) shows in vitro target killing, of single and double antigen positive cells, for split-KeyLock fragments with different combinations of CDR deletion mutants (SEQ ID NOs: 513, 517) and wild-type (SEQ ID NOs: 508, 514) VH and VL domains from the OCD3E antibody clone UCHT 1. The data are presented the same way as for the point mutants (Figure 53). (A) Retained activity for the VH_wild-type and VL_CDR3-deletion combination for killing double antigen positive cells, and significant reduced activity against single antigen positive cells. (B) Retained high activity for the VH_CDR1 -deletion and VL_wild-type combination for killing double antigen positive cells, and reduced activity against single antigen positive cells, especially against EpCAM positive cells.These are again important data, showing: (I) The combination of different spli t / separated OCD3E antibody VH or VL CDR-deletion mutants with a corresponding wild-type VH or VL domain, in a KeyLock like antibody format targeting two different antigens, is possible and reconstitute a functional T cell activating antibody complex, (ii) Individual CDR-deletion mutants have different activity against single and double antigen positive cells, (ii) For some of the CDR-deletion mutants the combination with the wild-type VH or VL domains is increasing the dose dependent targeting window for killing double antigen positive cells compared to the wild-type constructs, (iv) The combination of different ratios of mutant and wild-type VH and VL domains can also increase the targeting window for killing double antigen positive cells compared to a 1 to 1 ratio.These data in addition demonstrate, modulating CDR-deletion mutants and wild-type VH or VL domains with each other can improve the dual antigen restricted functional complementation of recombinant proteinaceous molecules of this invention.Figures 55 shows examples for using different ratios of mutant or wild-type VH to VL domains of a spli t / separated OCD3E antibody, in a single IgG antibody knop-into-hole format. Different KeyLock chains are connected to different constant domains, constant light (CL) and constant heavy (CH). Disulfide bridges (black solid lines). Connecting linkers are grey curved lines. Fc knop mutants (black filled circle). The mutant OCD3E VH domain (light solid gray) and the pairing wild-type OCD3E VL domain (dark solid gray). The KeyLock single chain polypeptide is targeting four different antigens, with four antibody variable domains (Antigen 1, ovals with black and white rectangles) (Antigen 2, ovals with black vertical stripes) (Antigen 3, white ovals with black spots) (Antigen 4, ovals with black waves), in different VL-VH or VH-VL orientations (from the NH2-terminus to COCH terminus). Using 4 or 6 different KeyLock chains connected to the single antibody, a 2 / 1 or 3 / 1 or 4 / 1 or 5 / 1 ratio of mutant VH to wild-type VL domains is possible. This will increase the dual-antigen restricted functional complementation of recombinant proteinaceous molecules of this invention, in a single antibody (termed Kraken-antibody) targeting four different antigens on tumor cells.Figure 56 shows one example for the high recombinant production of a KeyLock mutant antibody (SEQ ID NO: 525), oCD3-VH(UCHT1)-wt_aHer2(VL-VH)_aEpCAM(VL-VH)_aCD3-VL(UCHT1)-R169E. The aCD3 VH domain is at the N-terminus and the oCD3 VL domain is at the C-terminus. The anti-Her2 and anti-EpCAM scFv domains are in VL- VH orientation connected. For recombinant protein purification, there is a short 6 histidine tag (H) at the C-terminus. For this, HisTag-purified KeyLock antibody was loaded at 1 pig per lane under denaturing conditions on a 12% polyacrylamide gel. PageRuler™ Unstained Protein Ladder for kilo Dalton size (kDa) was used as a marker (M). Different elution fraction (E) were loaded on the gel. The arrow marks the expected molecular size of the KeyLock antibody.Figures 57 (A) to (C) shows in vitro target killing, of single and double antigen positive cells, for different mutant KeyLock antibodies (SEQ ID NOs: 525 to 527) in comparison to the wild-type KeyLock antibody (SEQ ID NO: 524). DMSO was used as a positive control for cell killing and Target cells only and target cells with CD8+T cells were used as negative control to exclude a possible T-cell response against neoantigens of the specific cell line. (A) Activity of the wild-type KeyLock antibody (VH-wt_VL-wt) (SEQ ID NO: 524) with oCD3 moiety derived from the UCHT1 clone, at high concentrations (from 2 nM to 0.125 nM) against single antigen positive cells (CHO_Her2+). In contrast, two mutant KeyLock constructs, with oCD3 moiety derived from the UCHT1 clone and with the R169E (SEQ ID NO: 525) or Y171A (SEQ ID NO: 526) mutation the VL chain and a wild-type VH chain, completely lost the activity against single antigen positive cells, even at the highest concentrations. In addition, for a mutant KeyLock antibody (SEQ ID NO: 527) with a combination of two oCD3 moieties derived from different clones (UCHT 1 and diL2K), with a wild-type VH chain (from the diL2K clone) and a Y171 A mutation the VL chain (from the UCHT1 clone), showed no activity against single antigen positive cells, even at the highest concentrations. (B) Using thesame antibodies as in (A) now targeting a different antigen on single antigen positive cells (CHO_EpCAM+), the activity of the UCHT1 derived wild-type KeyLock antibody (VH-wt_VL-wt) was the same at high concentrations (from 2 nM to 0.125 nM). In contrast, for the UCHT1 derived mutant KeyLock construct with a Y171 A mutation in the VL chain and a wild-type VH chain, there was a reduced activity at lower dose concentrations (1 nM to 0.125 nM) compared to the wild-type KeyLock. (C) In contrast, using the same antibodies as in (A and B) now against double antigen positive cells (CHO_Her2+EpCAM+), the cytotoxic activity for both UCHT1 derived mutant KeyLocks (R169E and Y171 A) were similar to the wild-type KeyLock antibody, over a large dose range (from 2 nM down to 0.0039 nM). Surprisingly, the mutant KeyLock antibody using a combination of oCD3 moieties from different antibody clones, with a wild-type VH chain (from the diL2K clone) and a Y171A mutation VL chain (from the UCHT1 clone), also showed activity with target cell cytotoxicity at higher concentrations (2nM to 0.125 nM). These are important data, showing: (I) The use of mutants in the split / separated OCD3E antibody variable domains, in a single-chain KeyLock format targeting two different antigens, is possible and it is increasing the antigen restricted function of the antibody, (ii) Different combinations of mutant and wild-type VH and VL domains have different effects on the antigen restricted function of the antibody, (ill) At lower KeyLock antibody concentrations, the cytotoxic effect on single antigen positive cells is reduced, (iv) In the KeyLock format it is even possible to combine pairing oCD3 VL and VH chains from different antibody clones.These first mutant KeyLock antibodies with improved antigen restricted activity compared to the wild-type antibodies (KeyLock mutants with high cytotoxicity against Her2 and EpCAM double positive cells, low cytotoxicity against EpCAM single positive cells and no activity against Her2 single positive cells), could improve the safety of current immunotherapies. For example, overexpression of Her2 and EpCAM is observed in approximately 30% to 70% of ovarian cancer patients, respectively, allowing for co-targeting treatment

[0037] , A major drawback for targeting Her2 is the co-expression on the heart, often causing severe cardiotoxicity for current Her2-targeting therapies

[0038] , In contrast, expression of EpCAM on benign cells is reported for endodermal structures (like lung or colon epithelia), but not for healthy mesodermal structures like the heart

[0039] , Therefore, a mutant KeyLock antibody of this invention could be used in sub-groups of ovarian cancer patients with Her2 and EpCAM double positive tumors, with reducing the on-target / off-tumor side effect for targeting Her2, with lowering the risk for severe cardiotoxicity.These data again demonstrate, modulating the effector cell binding moieties through amino acid mutations can improve the dual antigen restricted functional complementation of antibody constructs of the present invention. In addition, the combination of VL and VH chains from different antibody clones, targeting the same antigen, can also improve the dual antigen restricted functional complementation ofantibody constructs of the present invention. Figures 58 (A) to (D) shows the in vitro target killing, of double antigen positive cells, can be abrogated by combining specific mutant (SEQ ID NOs: 509 to 512, 515 to 516) with wild-type (SEQ ID NOs: 508, 514) VH or VL domains. This is demonstrated using split-Key Lock fragments with different combinations of point mutants and wildtype VH and VL domains from the OCD3E antibody clone UCHT1. DMSO was used as a positive control for cell killing and Target cells only and target cells with CD8+ T cells were used as negative control to exclude a possibleT-cell response against neoantigens of the specific cell line. The data for the double antigen positive cells (CHO-Her2+_EpCAM+) are presented in a heat-blot style, comparing the activity of the combined split-KeyLock fragments on the X- and Y-aches, over a large dose range (from maximal 200 nM down to 0.024 nM). WT stands for wild-type fragment. (A) On the left, high target cell cytotoxicity for the combination of mutant VH_G33R with mutant VL_N231 A fragments. In contrast on the right, complete loss of target cell cytotoxicity over a large dose range if the mutant VH_G33R domain is replaced with the mutant VH_K57S domains. (B) Again on the left, high target cell cytotoxicity for the combination of mutant VH_V59S with wild-type VL (wt) fragment. In contrast on the right, complete loss of target cell cytotoxicity over a large dose range if the wild-type VL fragment is replaced by a mutant VL_Y171 A fragment. (C) In addition on the left, high target cell cytotoxicity for the combination of mutant VH_K57S with wild-type VL (wt) fragment. In contrast on the right, complete loss of target cell cytotoxicity over a large dose range if the wild-type VL fragment is replaced by a mutant VL_N231 A fragment. (D) Also on the left, high target cell cytotoxicity for the combination of mutant VH_S30L with wild-type VL (wt) fragment. In contrast on the right, complete loss of target cell cytotoxicity over a large dose range if the wild-type VL fragment is replaced by a mutant VL_Y171 A fragment.These are important data, showing: (i) The use of oCD3 VH or VL blocking domains can abrogate the target cell cytotoxicity of a functional oCD3 VH or VL domain, (ii) These oCD3 VH or VL blocking domains can be mutated or not, depending on the pairing VH or VL domain, (iii) These oCD3 VH or VL blocking domains sustain their blocking function over a large concentration gradient and over a large blocking to functional V-Domain ratio.The incorporation of these VH and VL blocking domains in the KeyLock format can improve antigen restricted activity and safety compared to other T-cell activating antibodies, like BiTE antibodies or Hemibodies, with unchangeable active oCD3 binding moiety. In addition, the unique single-chain KeyLock format has an important advantage over current immunotherapies using oCD3 VH or VL blocking domains, like the PrecisionGATE or twoGATETM technologies. All these competitive strategies, using different effector cell blocking domains, consist of multiple antibody parts or fragments. This is a major drawback with increase in production cost, resources and more complex clinical usability.Figures 59 (A) to (G) shows different examples for incorporating oCD3 VH or VL blocking domains in the KeyLock antibody format. (A) Design of a KeyLock single chain polypeptide antibody with attached blocking domains. The KeyLock construct has two different target antigen binding scFv moieties (black spotted ovals) and (black waves ovals), connected in VL-VH orientation (from the NH2-terminus to COOH terminus). The anti-CD3 receptor complex directed effector binding domain (F), from an anti-CD3s antibody, is split / separated into the VH fragment (F1 light gray oval) at the NH2-terminus and into the VL fragment (F2 dark gray oval) at the COOH terminus. A pairing blocking domain (Mutant VL, dark gray half-cut oval) is covalent connected with a specific linker (black dotted line) to the F1 VH fragment, and a pairing blocking domain (Mutant VH, light gray half-cut oval) is covalent connected with a specific linker (black dotted line) to the F2 VL fragment. As long the blocking domains are connected to the KeyLock, they are preventing the pairing of the functional oCD3 VH or VL domains, preventing T cell activation.The specific linkers (black dotted line) used to connect the blocking domains compromise protease recognize and cleaving domains / sequences. For protease highly expressed in the tumor tissue. Therefore, the amount of functional KeyLock antibodies, with removed / cleaved blocking domains, is higher in the tumor tissue.Such a concentration gradient for active KeyLock antibodies from tumor to healthy tissues could be an important advantage for their use in clinic. Because one factor influencing the unwanted cytotoxicity of KeyLock antibodies against single antigen positive cells depends on the construct concentration. In tissues with low linker specific protease activity, the concentration of active KeyLock antibodies is low. Selecting specific cleavable linkers for individual proteases, could in addition allow to redirect KeyLock activation to specific tumors or organs, where these proteases are expressed. This will further increase the therapeutic use of KeyLock antibodies with connected blocking domains. (B) shows single-chain KeyLock antibodies and covalent connected oCD3 VH and VL blocking domains (x) at the N- and C-terminal end, with three different tumor-targeting scFv moieties (top, T1, T2 and T3) or with four different tumor-targeting scFV moieties (bottom, T1 , T2, T3 and T4). (C) shows a single-chain KeyLock antibody with four different tumor-targeting scFV moieties (T1, T2, T3 and T4), where the functional split / separated aCD3 VL domain (dark gray oval) and the connected blocking domains (light grey ovals with X) are incorporated between different tumor-targeting scFV moieties (T2 and T3). (D) shows ways to improve the serum half-life of single-chain KeyLock antibodies with connected oCD3 VH and VL blocking domains (x), through covalent connecting a serum protein or part of a serum protein (black filled square) at the end of the antibody (top) or between different tumor-targeting scFv moieties (T1 and T2) (bottom). For the top KeyLock, after cleaving the blocking peptide at the protein end, the half-life of the activated KeyLock will decrease. This could be important in clinic, if fast tumor killing together with fast antibody elimination is wanted. For the bottom KeyLock, after cleaving the blocking peptides the half-life of the activated KeyLock will stay the same. This could be important in clinic, if tumor killing or tumor surveillance is wanted over a longer time-period. (E) shows the design for single-chain twin-KeyLocks with connected oCD3 VH and VL blocking domains. These antibodies consist of two individual KeyLock constructs (Twins) covalent connected to each other, each KeyLock (Twin) has two different tumor-targeting scFv moieties. T1 and T2 for the first Twin, and T3 and T4 for the second twin. In addition, on the bottom is a KeyLock twin with an additional serum protein connected for improving the half-life of the antibody.The advantage for this Twin KeyLock format for clinic use is, only one antibody has to be recombinant produced and administrated. Only in the body or in the tumor tissue, proteases will cleave the specific linkers and release the now active different KeyLock antibodies. Now two antibodies target different antigen combinations, this could help to increase the eliminate rate of tumors consisting of different tumor-subclones with different antigen expression profiles. In this Twin KeyLock format two, three, four or more individual KeyLock constructs can be connected to each other.(F) shows examples for incorporating oCD3 VH or VL blocking domains in the KeyLock antibody Fc format. Different KeyLock chains with attached blocking domains (x) are connected to the constant CH2 domain of an IgG antibody.The advantage of this Fc based KeyLock format with attached blocking domains is, different homo- or heterodimers can be created, with improved half-life in serum, similar to regular IgG antibodies.(G) shows examples for incorporating oCD3 VH or VL blocking domains in the KeyLock antibody IgG format, with constant-heavy and constant-light chains attached. Different KeyLock chains with attached blocking domains (x) are connected to the constant CH1 or constant CL domain of an antibody.The advantage of this Ig based KeyLock format with attached blocking domains is, different tetramers can be created, targeting two, three, four or more target antigens in a single construct.DETAILED DESCRIPTION OF THE INVENTIONDefinitions and General TechniquesUnless otherwise defined below, the terms used in the present invention shall be understood in accordance with their common meaning known to the person skilled in the art.Literature references referred to herein may be cited by using the full reference, or by using an abbreviation such as a number, for instance, "(76)”, and by specifying the corresponding full reference in the "References” section. All literature reference referred to herein are incorporated by reference for all purposes in their entirety.The term "antibody” as used herein refers to any functional antibody that is capable of specific binding to the antigen of interest, as generally outlined in chapter 7 of Paul, W.E. (Ed.).: Fundamental Immunology 2nd Ed. Raven Press, Ltd., New York 1989, which is incorporated herein by reference. Without particular limitation, the term "antibody” encompasses antibodies from any appropriate source species, including chicken and mammalian such as mouse, goat, non-human primate and human. Preferably, the antibody is a humanized antibody. The antibody is preferably a monoclonal antibody which can be prepared by methods well-known in the art. The term "antibody” encompasses an lgG-1, -2, -3, or -4, IgE, IgA, IgM, or IgD isotype antibody. The term "antibody” encompasses monomeric antibodies (such as IgD, IgE, IgG) or oligomeric antibodies (such as IgA or IgM). The term "antibody” also encompasses - without particular limitations - isolated antibodies and modified antibodies such as genetically engineered antibodies, e.g. chimeric antibodies.Single-chain variable fragments (scFvs) are known in the art. A single-chain variable fragment (scFv) is a fusion protein comprising the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a linker peptide of preferably 10 to 25 amino acids. It is understood that in accordance with the invention, the protein N-to-C-terminal order of the VH and VL chains of the scFvs is not particularly limited, i.e., scFvs may comprise the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins in a VH to VL order or in a VL to VH order.The nomenclature of the domains of antibodies follows the terms as known in the art. Each monomer of an antibody comprises two heavy chains and two light chains, as generally known in the art. Of these, each heavy and light chain comprises a variable domain (termed V|_] for the heavy chain and V|_ for the light chain) which is importantfor antigen binding. These heavy and light chain variable domains comprise (in an N-terminal to C-terminal order) the regions FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 (FR, framework region; CDR, complementarity determining region which is also known as hypervariable region). The identification and assignment of the above-mentioned antibody regions within the antibody sequence is generally in accordance with Kabat et al. (Sequences of proteins of immunological interest, U.S. Dept, of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, Md. 1983), or Chothia et al. (Conformations of immunoglobulin hypervariable regions. Nature. 1989 Dec 21 -28;342(6252):877-83.), or may be performed by using the IMGT / V-QUEST software described in Giudicelli et al. (IMGT / V-QUEST, an integrated software program for immunoglobulin and T cell receptor V-J and V-D-J rearrangement analysis. Nucleic Acids Res. 2004 Jul 1;32(Web Server issue): W435-40.), which is incorporated herein by reference. Preferably, the antibody regions indicated above are identified and assigned by using the IMGT / V-QUEST software.As used herein, the terms "binding” or "bind” refer to specific binding to the antigen of interest. Preferably, the Kd value is less than 100 nM, or less than 50 nM, or less than 10 nM, or less than 5 nM, or less than 1 nM, or less than 0.1 nM, or less than 0.01 nM, or less than 0.001 nM or less than 0.0001 nM.In the context of the present invention, binding or competitive binding of antibodies or antigen-binding portions or scFvs to the antigen of interest can be measured by using surface plasmon resonance measurements as a reference standard assay, as described below, by using Enzyme-linked Immunosorbent Assay (ELISA) or by other measurements such as cell-based assays.The terms "KQ” or "KQ value” relate to the equilibrium dissociation constant as known in the art. In the context of the present invention, these terms relate to the equilibrium dissociation constant of an antibody or scFv with respect to a particular antigen of interest. The equilibrium dissociation constant is a measure of the propensity of a complex (e.g. an antigen-antibody or antigen-scFv complex) to reversibly dissociate into its components (e.g. the antigen and the antibody or scFv). For the antibody constructs according to the invention and the antibodies and scFvs contained therein, KQ are preferably determined by using surface plasmon resonance measurements.The terms "cancer” and "cancer cell” is used herein in accordance with their common meaning in the art (see for instance Weinberg R. et al.: The Biology of Cancer. Garland Science: New York 2006. 850p.).The cancers to the treated according to the present invention are not particularly limited. Such cancers are preferably selected from myeloid and or lymphoid origin (e.g., acute myeloid leukemia (AML), AML with defining genetic abnormalities, AML defined by differentiation, myeloid sarcoma, myelodysplastic neoplasms (MDS), myeloproliferative neoplasms (MPN), mastocytosis, chronic myelomonocytic leukemia (CMML), acute leukemia of ambiguous lineage (ALAL), acute leukemia of mixed phenotype (MPAL), histiocyte / dendritic cell neoplasms, precursor B cell neoplasms, b cell lymphoblastic leukaemias / lymphomas, mature B cell neoplasms, neoplastic small lymphocytic proliferation, splenic B cell lymphomas and leukemias, lymphoplastic lymphoma, marginal zone lymphoma, follicular lymphoma, cutaneous follicle centre lymphoma, mantel cell lymphoma, transformed indolentB cell lymphoma, large B cell lymphomas, Burkitt lymphoma, KSHV / HHV8 associated B cell lymphoid prolifarations and lymphoma, lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation, Hodgkin lymphoma, T cell plasma cell dyscrasias (e.g., Multiple Myeloma, plasmacytoma, plasma cell leukemia and amyloidosis), precursor T cell neoplasms, T lymphoblastic leukaemia / lymphoma, mature T cell and NK cell leukaemias, primary cutaneous T cell lymphomas, intestinal T cell and NK cell lymphomas, hepatosplenic T cell lymphoma, anaplastic large cell lymphoma, nodal T follicular helper cell lymphoma, peripheral T cell lymphoma, EBV positive NK / T cell lymphomas, mesenchymal dendritic cell neoplasms, myofibroblastic tumour, spleen vascular stromal tumours) or solid tissue origin (e.g. melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma of the skin / lung / mouth / nasal cavity / nasopharynx / throat / esophagus or vagina, gastric cancer, colon cancer, pancreatic cancer, liver cancer, rectal cancer, prostate cancer, urothelial cancer, testis cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, breast cancer, renal cell carcinoma, Ewing's sarcoma, non-small cell lung cancer and small cell lung cancer, neuroendocrine carcinoma, soft tissue sarcomas, osteosarcomas, gallbladder carcinomas, papillary adenocarcinoma, Ewing sarcoma).The cancers to be treated according to the present invention can be selected, for instance, from solid cancers and hematopoietic malignancies. A "solid cancer” is a cancer which forms one or more solid tumors. Such solid cancers forming solid tumors are generally known in the art. The term "solid cancer” encompasses both a primary tumor formed by the cancer and possible secondary tumors, which are also known as metastases.Preferred solid cancers to be treated according to the invention are selected from the group consisting of melanoma, colorectal cancer, prostate cancer, head and neck cancer, urothelial cancer, stomach cancer, pancreatic cancer, liver cancer, testis cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, breast cancer, gastric cancer, renal cell carcinoma, Ewing's sarcoma, non-small cell lung cancer and small cell lung cancer.Preferred hematopoietic malignancies cancers to be treated according to the invention are selected from the group consisting of leukemias (e.g., acute myeloid leukemias (AML), myelodysplastic neoplasms (MDS), T cell acute lymphoblastic leukemia (T-ALL), large granular lymphocyte leukemia, and B-cell chronic lymphocytic leukemia (B-CLL)), lymphomas (e.g., Natural killer / T cell lymphoma), and plasma cell dyscrasias (e.g., Multiple Myeloma and amyloidosis).The term "cancer immunotherapy” is known in the art and generally relates to a treatment of cancer in which the immune system of the patient is used to treat the cancer. Cancer cells harbor genomic mutations which give rise to cancer cell antigens that are specific to the cancer cells and different from the antigens of non-cancerous cells. Thus, in a preferred aspect of cancer immunotherapy in accordance with the present invention, a cancer immunotherapy is a cancer immunotherapy wherein such cancer cell antigens are recognized by the immune system (e.g., by T cells or NK-cells), and wherein cancer cells expressing these antigens are killed by the immune system. Preferred methods to assess cancer immunotherapy are the methods according to Gouttefangeas C et al.: "Flow Cytometry in Cancer Immunotherapy: Applications, Quality Assurance and Future.” (2015) In: Cancer Immunology: Translational Medicine from Bench to Bedside (N. Rezaei editor). Springer. Chapter 25: pages 471 -486; and the methods according to Van der Burg SH, et al.: "Immunoguiding, the final frontier in the immunotherapy of cancer.” (2014) In Cancer Immunotherapy meets oncology (CM Britten, S Kreiter, M. Diken & HG Rammensee eds). Springer International Publishing Switzerland p37-51 ISBN: 978-3-319-05103-1.As used herein, a "cancer immunotherapy” optionally encompasses a treatment where in addition to the immune system which is used to treat the cancer, additional mechanisms of cancer treatment are used. According to the present invention, a cancer immunotherapy in human patients can also encompass additional treatment effects which are independent from the immune system. Another example of a cancer immunotherapy where additional mechanisms of cancer treatment can be used is a combination therapy with known chemotherapeutic agent(s) and / or small molecule inhibitors (inhibiting enzyme function via reducing / blocking their catalytic activity and / or stabilizing an enzyme inactive state and / or increasing enzyme degradation by binding to them). Such combination therapy with known chemotherapeutic agent(s) or small molecule inhibitors may, for instance, not only include the treatment of cancer in which the immune system is used to treat the cancer but also include a treatment of cancer in which the cancer cells are killed by said chemotherapeutic agent(s) or small molecule inhibitors directly. Another combination therapy could be immune check point inhibitors, blocking inhibitory signals on cancer cells and / or immune cells, to activate T cells and / or to abrogate immune cells inhibitory signals for cancer immunotherapy. Another combination therapy could be small molecules (like all trans retinoic acid) to upregulate antigen expression on cancers cells for immunotherapy. Another combination therapy could be chimeric antigen receptor (CAR) T cells. Another combination therapy could be different types of radiation therapy (e.g. 3D conformal radiation therapy, intensity-modulated radiation therapy (IMRT), volumetric modulated radiation therapy (VMAT), image-guided radiation therapy (IGRT), stereotactic radiosurgery (SRS), brachytherapy, superficial x-ray radiation therapy (SXRT) or intraoperative radiation therapy (IORT)).Terms such as "wherein at least one VH and VL of the anti-CD3 antibody form an anti-CD3 binding domain in the presence of said different target epitopes or target antigens on a cell surface” in connection with the invention will be understood and mean that in the presence of said different target epitopes or target antigens on a cell surface, the antibody construct of the invention will bind to said different target epitopes or target antigens on the cell surface, such that least one VH and VL of the anti-CD3 antibody form an anti-CD3 binding domain.The variable heavy chain(s) (VH) of the anti-CD3 antibody and variable light chain(s) (VL) of the anti-CD3 antibody are functional variable heavy chain(s) (VH) and functional variable light chain(s) (VL) of the anti-CD3 antibody. Functional VH and VL of the anti-CD3 antibody means that the VH and VL of the anti-CD3 antibody are able to form a functional anti-CD3 binding domain in the presence of the respective target antigens. Said functional anti-CD3 binding domain can bind and activate the CD3 receptor, thereby activating T cells.In accordance with the present invention, each occurrence of the term "comprising” may optionally be substituted with the term "consisting of”.KeyLock antibody technologyTo improve T cell mediated immunotherapy, the inventors designed a novel antibody based format, termed KeyLock antibodies, where different antigen targeting domains are integrated into a single construct. In a single chain KeyLock antibody the variable heavy (VH) and light chain (VL) of an anti-CD3 effector antibody are separated / split from each other by at least two target antigen single chain variable fragments (scFv) (Figure 1). In an IgG based hetero-dimer KeyLock antibody the variable heavy (VH) and light chain (VL) of an anti-CD3 effector antibody are separated / split from each other by at least one target antigen single chain variable fragments (scFv) (Figure 5B and 5C).In the absence of target antigen, the adjacent VH and VL domains interact with each other, termed swift-swapping of antibody variable domains, blocking the anti-CD3 VH and VL domains from correctly pairing with each other and therefore preventing the binding and activation of effector T cells. Only when all target antigen scFvs are bound to their respective antigens, the blocking of the separated / split anti-CD3 VH and VL domains is abrogated, allowing them to align, re-associate, and reconstitute the original anti CD3-binding site. This way, CD3-positive T lymphocytes become activated and retargeted for target cell lysis. Using individual target antigen scFv domains against different antigens, KeyLock antibodies against a dual-, triple- or quadruple-antigen signature can be designed (Figure 1 and 2).In the KeyLock antibody format, the individual VH and VL domains are joined by peptide linkers via genetic engineering. Different scFv moieties can be employed as antigen specific modules in different order, relative to the separated / split anti-CD3 VH and VL domains (Figure 3 and Figure 5). Stability of the KeyLock antibodies can be optimized by adding constant immunoglobulin domains, albumin, single albumin-domains, albumin binding domains or plasma proteins in the antibody format in order to mimic naturally occurring antibodies or serum proteins and to simultaneously enhance pharmacokinetic properties like prolonged half-life in serum and protection from proteolytic digestion by proteases (Figure 4). Moreover, stability of the KeyLock format can be enhanced by optimizing the recombinant production. Production cell lines have been established that first produce two or three polypeptides that can be easily reassembled in order to generate a functional drug. Such techniques utilize directed disulphide-bridges, crosslinking reagents to covalently join two different polypeptides, hetero- or homo-dimerization domains like leucine-zipper domains, Fc-domains, coiled-coil domains and others like IgG knob into hole technologies (19, 20, 21, 22, 23, 24) (Figure 5 and Figure 6). A single KeyLock chain can target at least two different antigens. Two different KeyLock chains, against four different targets, can be fused to a constant antibody Ig chain, creating a single antibody with dual-antigen specificity against two different antigen combinations / antigen signatures (Figure 6B) . If six different KeyLock chains, against 4 different target antigens, are fused to pairing immunoglobulin constant chains, a single KeyLock antibody with six different dual-antigen specificities is created (Figure 6D). Such an antibody would be of great importance targeting a heterogeneous malignant cell population. The target antigen loss under immunotherapy, like the loss of BCMA on the malignant plasma cells following anti-BCMA CAR T cell therapy, is a major drawback of all current single antigen restricted therapies (77). A KeyLock antibody with sixdifferent KeyLock chains, against 4 different target antigens, is still functional against 10 different single or double antigen-loss scenarios.The KeyLock technology is using circular permutation for changing the order of the effector anti CD3 VH and VL domains, but with preserved ability for the separated / split anti CD3 VH and VL domains to interact correctly and to bind and activate T cells. Circular permutation is known to function in a variety of proteins when the original protein N and C termini are fairly close in space, as it is true for the KeyLock format using scFvs and specific linkers, connecting the different antibody VH and VL domains with each other. Circular permutation describes a type of relationship between proteins, whereby the proteins have a changed order of amino acids in their protein sequence (25). Circular permutation can be done by artificially engineering individual antibody binders into a single chain format. The result is a single structure with different connectivity, but overall similar function. The high homology between antibodies VH and VL sequences, caused by the similar amino acid sequences in the framework constant regions (Figure 7), allows the VH and VL domains of antibodies with different antigen specificity to interact with each other, as we term it swift-swapping (SWSW).Depending on the location in the polypeptide chain, and the connecting linkers, different SWSW of the individual VH and VL domains is possible. This allows different VH and VL pairs to form (26, 27, 28). Pairing is possible between:(I) The variable domains from the same antibody-clone can interact and form heterodimeric VH / VL or VL / VH pairs. These pairs will sustain their original ability to bind their respective target antigen, but with possible changes in their affinity (Figure 8).(ii) The variable domains from two different antibody-clones can SWSW and form heterodimeric VH / VL or VL / VH pairs, as well as homodimeric VL / VL pairs or even VH / VH pairs. These pairs will lost their ability to bind their respective target antigen (28, 29).Development of the multivalent KeyLock formatIt is reported for a long time, it is possible to covalently connect split / separated variable domains from different antibody clones with each other, targeting different antigens, to form multivalent sFvs, Diabodies, Demibodies or hemibodies (11, 29, 30, 50, 73, 74). The split / separated VH and VL domains sustain their ability to pair with their corresponding split / separated VH and / or VL domain, even if they are not on the same construct, and to bind their respective antigens. The original split / separated VH and VL format of the sFvs, bispecific binders and Diabodies was designed to improve recombinant production and not for therapeutic use in vivo against target cells with a dualantigen signature (30, 50, 51, 74).The multivalent Fvs and the Diabodies both are taking advantage of the intermolecular pairing of VH and VL domains. Interestingly only Diabodies with a short (5 amino acid) or no linker connecting the VH and VL domains on the same chain, form functional and bivalent dimers. If a long linker (15 amino acids) is used, the Diabodies form mostly monomers, due to intermolecular pairing of the two VH and VL domains connected to each other onthe same chain. These monomers are not able to bind their respective antigens. For the multivalent Fvs it is shown, there is a rapid equilibrium between the interconversion of nonbinding monomers into functional multivalent dimers (29). In the presence of antigen there is a shift towards more functional dimer formation. This demonstrates (I) The interconversion of non-functional into functional VH and VL pairs is transient and reversible, (ii) The presence of an antigen is causing the non-functional VH and VL monomer to disassociate, following the rearrangement of the respective VH and VL domains from two antibody fragments and the formation of a functional dimer. The antigen has generally contact with both VH and VL domains, increasing for the antigen bound VH / VL pair the activation energy barrier to disassociate, (ill) The linker between the VH and VL domains is important for correct pairing. Therefore, for novel multivalent dual-antigen restricted binders for immunotherapy, the inventors combined different ideas in a single-partite antibody format: (I) Separating the VH from the VL domain from an antiCD3 effector antibody, (ii) using the connected VH and VL domains from target antigen directed scFvs as blocking domains of the antiCD3 Fv domain, in the absence of their respective target antigens, (ill) abandon proteolytic cleavage sites, allowing flexible linkers to reverse the blocking and release of the antiCD3 Fv effector domain.The different ideas behind this new design are: (I) The effector cell directed VH and VL domains are not directly connected to each other (separated / split), but they are still able to successfully pair and reconstitute the original antibody binding site, (ii) The effector cell directed VH and VL domains are covalently connected (in a single chain format, Figure 1, 2, 3 and 4), or in close proximity (in a IgG format, Figure 5 and 6), to a target antigen directed antibody VH and / or VL domain, (ill) Antibody variable domains against different target antigens can be expressed in the VH-VL and / or VL-VH orientation, (iv) Specific linkers between the different VH and VL domains allow for an optimized SWSW. This improves blocking the effector cell specific VH and VL domains if no target antigen is there for binding, (v) Binding to the target antigens is stabilizing the antigen specific VH and VL pairs, reducing the SWSW with the connected and / or in close proximity effector cell directed VH and VL domains, (vi) Only when all target antigen specific VH and VL domains are bound to a cell expressing all the respective antigens, the effector cell binding domains are free for correct pairing, to recruit effector cells for target cell killing.All antibody constructs in accordance with the invention can be obtained by methods known in the art. Such methods include methods for the production of recombinant polypeptides. The antibody constructs of the invention can be expressed in recombinant host cells according to the invention. Recombinant host cells of the invention are preferably mammalian cells such as CHO, Sp2 / 0, NSO, PER. 06 and HEK cells. Recombinant host cells can also be prokaryote cells as Escherichia coll or Corynebacterium.For recombinant production it will be understood that the antibody constructs of the invention are meant to optionally include a secretion signal peptide sequence, which is optimized for each producer cell line and antibody construct which is cleaved from the final antibody in the cellular secretion process, into the cell culture medium or into the bacteria periplasm. Similarly, the antibody constructs of the invention are meant to also optionally include affinity tags, e.g. in order to facilitate purification and / or detection, and optional protease cleavage sites between the tag and the polypeptide, e.g. in order to facilitate removal of the tags by protease cleavage in the production process.It is also understood that any reference to amino acid sequences referred to herein is meant to encompass not only the unmodified amino acid sequence but also typical posttranslational modifications of these amino acid sequences (e.g., glycosylation, phosphorylation, S-nitrosylation, methylation, deamidation or the clipping of particular amino acids) occurring in cellular expression systems known in the art, including mammalian cells such as CHO and HEK cells.Target antigens and scFvs capable of binding to target antigensThe antibody construct of the present invitations comprises at least two of the single chain variable fragments, wherein at least two of the single chain variable fragments (scFvs) are against different target epitopes of the same target antigen or against different target antigens, i.e., are capable of binding to said different target epitopes of the same antigen or to binding to said different target antigens.In one embodiment, said different target epitopes or target antigens may be cancer antigens.The target antigens and / or cancer antigens may be selected from CD38 (e.g., UniProtKB - P28907, Gene ID: 952), SLAMF7 / CS1 / CD319 (e.g., UniProtKB - Q9NQ25, Gene ID: 57823), ERBB2 / Her2 / NEU / CD340 (e.g., UniProtKB - P04626, Gene ID: 2064), FGFR1 / CD331 (e.g., UniProtKB - P11362, Gene ID: 2260), EGFR (e.g., UniProtKB -P00533, Gene ID: 1956), EpCAM / CD326 (e.g., UniProtKB - P16422, Gene ID: 4072), ERBB3 (e.g., UniProtKB -P21860, Gene ID: 2065), ERBB4 (e.g., UniProtKB - Q15303, Gene ID: 2066), MET (e.g., UniProtKB - P08581, Gene ID: 4233), PDGFRA (e.g., UniProtKB - P16234, Gene ID: 5156), PDGFRB (e.g., UniProtKB - P09619, Gene ID: 5159), FGFR2 (e.g., UniProtKB - P21802, Gene ID: 2263), FGFR3 (e.g., UniProtKB - P22607, Gene ID: 2261), FGFR4 (e.g., UniProtKB - P22455, Gene ID: 2264), KIT (e.g., UniProtKB - P10721, Gene ID:3815), FLT3 (e.g., UniProtKB - P36888, Gene ID: 2322), IGF1R (e.g., UniProtKB - P08069, Gene ID: 3480), RET (e.g., UniProtKB -P07949, Gene ID: 5979), ROS1 (e.g., UniProtKB - P08922, Gene ID: 6098), ALK (e.g., UniProtKB - Q9UM73, Gene ID: 238), TGFBR1 (e.g., UniProtKB - P36897, Gene ID: 7046), TGFBR2 (e.g., UniProtKB - P37173, Gene ID: 7048), ACVR2A (e.g., UniProtKB - P27037, Gene ID: 92), ACVR1B (e.g., UniProtKB - P36896, Gene ID: 91), LRP5 (e.g., UniProtKB - 075197, Gene ID: 4041), LRP6 (e.g., UniProtKB - 075581, Gene ID: 4040), E-Cadherin I CDH1 (e.g., UniProtKB - P12830, Gene ID: 999), N-Cadherin I CDH2 = (e.g., UniProtKB - P19022, Gene ID: 1000), AQP3 (e.g., UniProtKB - Q92482, Gene ID: 360), AQP1 (e.g., UniProtKB - P29972, Gene ID: 358), AQP4 (e.g., UniProtKB - P55087, Gene ID: 361), AQP5 (e.g., UniProtKB - P55064, Gene ID: 362), AQP9 (e.g., UniProtKB - 043315, Gene ID: 366), CD45 I PTPRC (e.g., UniProtKB - P08575, Gene ID: 5788), CD34 (e.g., UniProtKB - P28906, Gene ID: 947), CD1381 SDC1 (e.g., UniProtKB - P18827, Gene ID: 6382), CD90 I THY1 (e.g., UniProtKB - P04216, Gene ID: 7070), CD1231 IL3RA (e.g., UniProtKB - P26951, Gene ID: 3563), IL1RAP (e.g., UniProtKB - Q9NPH3, Gene ID: 3556), IL2RB / CD122 (e.g., UniProtKB - P14784, Gene ID: 3560), CD117 I Kit (e.g., UniProtKB - P10721,Gene ID: 3815), CD244 (e.g., UniProtKB - Q9BZW8, Gene ID: 51744), CD49F I ITGA6 (e.g., UniProtKB - P23229, Gene ID: 3655), ABCG2 (e.g., UniProtKB - Q9UNQ0, Gene ID: 9429), ESAM (e.g., UniProtKB - Q96AP7, Gene ID: 90952), CD10 I MME (e.g., UniProtKB - P08473, Gene ID: 4311), CD81 (e.g., UniProtKB - P60033, Gene ID: 975), GHR (e.g., UniProtKB - P10912, Gene ID: 2690), PRLR (e.g.,UniProtKB - P16471 , Gene ID: 5618), PSMA (e.g., UniProtKB - Q04609, Gene ID: 2346), PSCA (e.g, UniProtKB -043653, Gene ID: 8000), CD133 (e.g., UniProtKB -043490, Gene ID: 8842), CD166 (e.g., UniProtKB -Q13740, Gene ID: 214), CD44v6 I CD44 (e.g., UniProtKB - P16070, Gene ID: 960), CD29 I ITGB1 (e.g., UniProtKB -P05556, Gene ID: 3688), CD24 (e.g., UniProtKB -P25063, Gene ID: 100133941), Lgr5 (e.g., UniProtKB -075473, Gene ID: 8549), CEA / CEACAM5 (e.g., UniProtKB - P06731, Gene ID: 1048), VEGFR2 I KDR (e.g., UniProtKB - P35968, Gene ID: 3791), CXCR4 (e.g., UniProtKB - P61073, Gene ID: 7852), CD33 (e.g., UniProtKB - P20138, Gene ID: 945), CD56 I NCAM1 (e.g., UniProtKB - P13591, Gene ID: 4684), CD19 (e.g., UniProtKB - P15391, Gene ID: 930), CD20 (e.g., UniProtKB -P11836, Gene ID: 931), B7H3 / CD276 (e.g., UniProtKB - Q5ZPR3, Gene ID: 80381), L1CAM (e.g., UniProtKB - P32004, Gene ID: 3897), CD37 (e.g., UniProtKB - P11049, Gene ID: 951), LFA-1 1 ITGB21 CD18 (e.g., UniProtKB - P05107, Gene ID: 3689), R0R1 (e.g., UniProtKB - Q01973, Gene ID: 4919), R0R2 (e.g., UniProtKB -Q01974, Gene ID: 4920), CD70(e.g., UniProtKB -P32970, Gene ID: 970), CD123 I IL3RA (e.g., UniProtKB - P26951, Gene ID: 3563), IGF1R / CD221 (e.g., UniProtKB - P08069, Gene ID: 3480), CCR71 CD197 (e.g., UniProtKB - P32248, Gene ID: 1236), CCR41 CD194 (e.g., UniProtKB - P51679, Gene ID: 1233), TNFRSF914-1 BB (e.g., UniProtKB - Q07011, Gene ID: 3604), CTLA41 CD152 (e.g., UniProtKB - P16410, Gene ID: 1493), GPC3 I Glypican-3 (e.g., UniProtKB - P51654, Gene ID: 2719), CADM1 (e.g., UniProtKB -Q9BY67, Gene ID: 23705), CD4 (e.g., UniProtKB - P01730, Gene ID: 920), B7-h4 I VTCN1 (e.g., UniProtKB -Q7Z7D3, Gene ID: 79679), TYRP1 (e.g., UniProtKB - P17643, Gene ID: 7360), CTLA4 I (e.g., UniProtKB -P16410, Gene ID: 1493), PDL1 I CD274 (e.g., UniProtKB - Q9NZQ7, Gene ID: 29126), PDCD1 I PD-1 (e.g., UniProtKB - Q15116, Gene ID: 5133), PDCD1LG2 / PD-L2 (e.g., UniProtKB - Q9BQ51, Gene ID: 80380), BTLA (e.g., UniProtKB - Q7Z6A9, Gene ID: 151888), DLL3 (e.g., UniProtKB - Q9NYJ7, Gene ID: 10683), CEACAM1 1 CD66a (e.g., UniProtKB - P13688, Gene ID: 634), LFA-1 I ITGB2 (e.g., UniProtKB - P05107, Gene ID: 3689), CD22 (e.g., UniProtKB - P20273, Gene ID: 933), NRP1 I CD304 (e.g., UniProtKB - 014786, Gene ID: 8829), CHRNA1 (e.g., UniProtKB - P02708, Gene ID: 1134), GD21 Disialoganglioside (CAS Registry Number® 65988-71-8), CTAG1A / NY-ESO-1 (e.g., UniProtKB -P78358, Gene ID: 246100), CD70 (e.g., UniProtKB -P32970, Gene ID: 970), CD30 I TNFRSF8 (e.g., UniProtKB - P28908, Gene ID: 943), CD98hc I SLC3A2 (e.g., UniProtKB -P08195, Gene ID: 6520), CD52 (e.g., UniProtKB - P31358, Gene ID: 1043), CD641 FCGR1 A (e.g., UniProtKB -P12314, Gene ID: 2209), and CD461 MOP (e.g., UniProtKB - P15529, Gene ID: 4179).The target antigens and / or cancer antigens may be intracellular proteins, aberrantly expressed on extra cellular part of the cell plasma membrane domain. These target antigens and / or cancer antigens may be selected from KRAS (e.g., UniProtKB -P01116, Gene ID: 3845), NRAS (e.g, UniProtKB -P01111, Gene ID: 4893), HRAS (e.g, UniProtKB - P01112, Gene ID: 3265), KRAs isoform KRAS4A (NM_033360.4), KRAS isoform KRAS4B (NM_004985.5), HSPD1 (e.g., UniProtKB - P10809, Gene ID: 3329), HSPA5 (e.g., UniProtKB - P11021, Gene ID: 3309), ATP5A1 (e.g., UniProtKB - P25705, Gene ID: 11946), CALR (e.g., UniProtKB - P27797, Gene ID: 811), HSP90B1 (e.g., UniProtKB -P14625, Gene ID: 7184), GANAB (e.g., UniProtKB - Q14697, Gene ID: 23193),EEF1A1P5 (e.g, UniProtKB -Q5VTE0, Gene ID: 158078), TXNDC5 (e.g, UniProtKB -Q8NBS9, Gene ID: 81567), RPS27A (e.g., UniProtKB - P62979, Gene ID: 6233), RAF1 (e.g., UniProtKB - P04049, Gene ID: 5894).Preferably, the target antigens and / or cancer antigens may be selected from CD38 (e.g., UniProtKB - P28907, Gene ID: 952), SLAMF7 / CS1 / CD319 (e.g., UniProtKB - Q9NQ25, Gene ID: 57823), ERBB2 / Her2 / NEU / CD340 (e.g., UniProtKB - P04626, Gene ID: 2064) and EpCAM / CD326 (e.g., UniProtKB - P16422, Gene ID: 4072). These target antigens and / or cancer antigens may comprise the following amino acid sequences, respectively:SEQ ID NO: 1 - CD38 antigen = P28907 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVWLAVWPRWRQQWSGPGTTKRFPETVLARCVKYTEIHP EMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLL GYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDWHVMLNGSRSKIFDKNSTFG SVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEISEQ ID NO: 2 - SLAMF7 antigen = Q9NQ25 MAGSPTCLTLIYILWQLTGSAASGPVKELVGSVGGAVTFPLKSKVKQVDSIVWTFNTTPLVTIQPEGGTIIVTQNRN RERVDFPDGGYSLKLSKLKKNDSGIYYVGIYSSSLQQPSTQEYVLHVYEHLSKPKVTMGLQSNKNGTCVTNLTCC MEHGEEDVIYTWKALGQAANESHNGSILPISWRWGESDMTFICVARNPVSRNFSSPILARKLCEGAADDPDSSM VLLCLLLVPLLLSLFVLGLFLWFLKRERQEEYIEEKKRVDICRETPNICPHSGENTEYDTIPHTNRTILKEDPANTVYS TVEIPKKMENPHSLLTMPDTPRLFAYENVISEQ ID NO: 3 - ERBB2 antigen = HER2 / neu = P04626 MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNLELTYLPTNASLSFL QDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILK GGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGC ARCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTA CPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFG SLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLG ISWLGLRSLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGP GPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPF CVARCPSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSIISAWGILLVWLGWF GILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWIPDGENVKI PVAIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLN WCMQIAKGMSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSEFSRMARDPQRFWIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHR SSSTRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPS ETDGYVAPLTCSPQPEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGWKDVFAFGGAVENPE YLTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPVSEQ ID NO: 4 - EpCAM antigen = P16422 MAPPQVLAFGLLLAAATATFAAAQEECVCENYKLAVNCFVNNNRQCQCTSVGAQNTVICSKLAAKCLVMKAEMN GSKLGRRAKPEGALQNNDGLYDPDCDESGLFKAKQCNGTSMCWCVNTAGVRRTDKDTEITCSERVRTYWIIIEL KHKAREKPYDSKSLRTALQKEITTRYQLDPKFITSILYENNVITIDLVQNSSQKTQNDVDIADVAYYFEKDVKGESLF HSKKMDLTVNGEQLDLDPGQTLIYYVDEKAPEFSMQGLKAGVIAVIWWIAWAGIWLVISRKKRMAKYEKAEIK EMGEMHRELNAIn another embodiment, the target antigens may be antigens for targeting prostate exocrine and fibromuscular tissue, including PSMA (e.g., UniProtKB — Q04609, Gene ID: 2346), PSCA(e.g., UniProtKB - 043653, Gene ID: 8000), FGFR1 / CD331 (e.g., UniProtKB - P11362, Gene ID: 2260), FGFR2 (e.g., UniProtKB - P21802, Gene ID: 2263), FGFR3 (e.g., UniProtKB - P22607, Gene ID: 2261), FGFR4 (e.g., UniProtKB - P22455, Gene ID: 2264), CD6 (e.g., UniProtKB - P30203, Gene ID: 923), CD10 / MME (e.g., UniProtKB - P08473, Gene ID: 4311), CD24 (e.g., UniProtKB - P25063, Gene ID: 100133941), CD25 / IL2RA (e.g., UniProtKB - P01589, Gene ID: 3559), CD29 / ITGB1 (e.g., UniProtKB - P05556, Gene ID: 3688), CD38 (e.g., UniProtKB - P28907, Gene ID: 952), CD40 (e.g., UniProtKB - P25942, Gene ID: 958), CD44 (e.g., UniProtKB - P16070, Gene ID: 960), CD46 (e.g., UniProtKB - P15529, Gene ID: 4179), CD47 (e.g., UniProtKB - Q08722, Gene ID: 961), CD49a / ITGA1 (e.g., UniProtKB - P56199, Gene ID: 3672), CD49c / ITGA3 (e.g., UniProtKB - P26006, Gene ID: 3675), CD49e / ITGA5 (e.g., UniProtKB -P08648, Gene ID: 3678), CD51 / ITGAV (e.g., UniProtKB - P06756, Gene ID: 3685), CD55 (e.g., UniProtKB - P08174, Gene ID: 1604), CD56 / NCAM1 (e.g., UniProtKB - P13591 , Gene ID: 4684), CD57 / B3GAT1 (e.g., UniProtKB - Q9P2W7, Gene ID: 27087), CD59 (e.g., UniProtKB - P13987, Gene ID: 966), CD61 / ITGB3 (e.g., UniProtKB - P05106, Gene ID: 3690), CDw75 / ST6GAL1 (e.g., UniProtKB -P15907, Gene ID: 6480), CD79a (e.g., UniProtKB - P11912, Gene ID: 973), CD81 (e.g., UniProtKB -P60033, Gene ID: 975), CD82 (e.g., UniProtKB -P27701, Gene ID: 3732), CD90 / THY1 (e.g., UniProtKB - P04216, Gene ID: 7070), CD95 / FAS (e.g., UniProtKB - P25445, Gene ID: 355), CD99 (e.g., UniProtKB - P14209, Gene ID: 4267), CD105 / ENG (e.g., UniProtKB - P17813, Gene ID: 2022), CD107a / LAMP1 (e.g., UniProtKB - P11279, Gene ID: 3916), CD107b / LAMP2 (e.g., UniProtKB - P13473, Gene ID: 3920), CD117 / KIT (e.g., UniProtKB - P10721, Gene ID:3815), CD123 / IL3RA (e.g., UniProtKB -P26951, Gene ID: 3563), CD131 / CSF2RB (e.g., UniProtKB - P32927, Gene ID: 1439), CD147 / BSG(e.g., UniProtKB - P35613, Gene ID: 682), CD151 (e.g., UniProtKB - P48509, Gene ID: 977), AGTR1 (e.g., UniProtKB - P30556, Gene ID: 185), AGTR2 (e.g., UniProtKB - P50052, Gene ID: 186), TGFBR2 (e.g., UniProtKB - P37173, Gene ID: 7048) and EpCAM / CD326 (e.g., UniProtKB - P16422, Gene ID: 4072).The antibody construct of the present invention comprises single chain variable fragments (scFvs) capable of binding to the above target antigens / cancer antigens. Preferably, the antibody construct comprises scFvs comprising the VH and VL sequences of the following antibodies:CD38 (e.g., UniProtKB - P28907, Gene ID: 952)Anti_CD38 antibody - DaratumumabVH - SEQ ID NO: 5 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS VL - SEQ ID NO: 6 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKAnti_CD38 antibody - Morphosys Ag 2004VH - SEQ ID NO: 7 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSS VL - SEQ ID NO: 8 DIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTIS GTQAEDEADYYCSSYDSSYFVFGGGTKLTVLAnti_CD38 antibody - IsatuximabVH - SEQ ID NO: 9 QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTA DKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSS VL -SEQ ID NO: 10 DIVMTQSHLSMSTSLGDPVSITCKASQDVSTWAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTIS SVQAEDLAVYYCQQHYSPPYTFGGGTKLEIKSLAMF7 / CS1 / CD319 (e.q„ UniProtKB - Q9NQ25, Gene ID: 57823)Anti_SLAMF7 antibody - ElotuzumabVH -SEQ ID NO: 11 EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNA KNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSS VL -SEQ ID NO: 12 DIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTI SSLQPEDVATYYCQQYSSYPYTFGQGTKVEIKERBB2 / Her2 / NEU / CD340 (e.g., UniProtKB - P04626, Gene ID: 2064)Anti_Her2 antibody - TrastuzumabVH -SEQ ID NO: 13 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTS KNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS VL -SEQ ID NO: 14 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTIS SLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRAnti_Her2 antibody - PertuzumabVH -SEQ ID NO: 15 EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS VL -SEQ ID NO: 16 DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKREGFR (e.g., UniProtKB - P00533, Gene ID: 1956)Anti_EGFR antibody - CetuximabVH -SEQ ID NO: 17 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNS KSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA VL -SEQ ID NO: 18 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSV ESEDIADYYCQQNNNWPTTFGAGTKLELKRAnti_EGFR antibody - MatuzumabVH -SEQ ID NO: 19 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNYNEKFKSKATMTV DTSTNTAYMELSSLRSEDTAVYYCASRDYDYDGRYFDYWGQGTLVTVSS VL -SEQ ID NO: 20 DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSRFSGSGSGTDYTFTIS SLQPEDIATYYCQQWSSHIFTFGQGTKVEIKAnti_EGFR antibody - NecitumumabVH -SEQ ID NO: 21 QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWIGYIYYSGSTDYNPSLKSRVTMSVD TSKNQFSLKVNSVTAADTAVYYCARVSIFGVGTFDYWGQGTLVTVSS VL -SEQ ID NO: 22 EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS SLEPEDFAVYYCHQYGSTPLTFGGGTKAEIKRAnti_EGFR antibody - NimotuzumabVH -SEQ ID NO: 23 QVQLQQSGAEVKKPGSSVKVSCKASGYTFTNYYIYWVRQAPGQGLEWIGGINPTSGGSNFNEKFKTRVTITADE SSTTAYMELSSLRSEDTAFYFCTRQGLWFDSDGRGFDFWGQGTTVTVSS VL -SEQ ID NO: 24 DIQMTQSPSSLSASVGDRVTITCRSSQNIVHSNGNTYLDWYQQTPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTD FTFTISSLQPEDIATYYCFQYSHVPWTFGQGTKLEIKAnti_EGFR antibody - PanitumumabVH -SEQ ID NO: 25 QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGDYYWTWIRQSPGKGLEWIGHIYYSGNTNYNPSLKSRLTISIDT SKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSS VL -SEQ ID NO: 26 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTIS SLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRAnti_EGFRvlll antibodyVH -SEQ ID NO: 27 LQQSGGGLVKPGASLKLSCVTSGFTFRKFGMSWVRQTSDKRLEWVASISTGGYNTYYSDNVKGRFTISRENAKN TLYLQMSSLKSEDTALYYCTRGYSSTSYAMDYWGQGTTVTVSS VL - SEQ ID NO: 28 DIELTQSPASLSVATGEKVTIRCMTSTDIDDDMNWYQQKPGEPPKFLISEGNTLRPGVPSRFSSSGTGTDFVFTIE NTLSEDVGDYYCLQSFNVPLTFGDGTKLEIKEpCAM / CD326 (e.g., UniProtKB - P16422, Gene ID: 4072)anti_EpCAM_1 antibodyVH - SEQ ID NO: 29 EVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADK SSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGTTVTVSS VL - SEQ ID NO: 30 ELVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGS GTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKanti_EpCAM_2 antibodyVH - SEQ ID NO: 31 DIVMTQSPLSLPVTPGEPASISCRSTKSLLHSDGITYLYWYLQKPGQSPQLLIYQLSNLASGVPDRFSSSGSGTDF TLKISRVEAEDEGVYYCAQNLEIPRTFGCGTKLEIKRT VL - SEQ ID NO: 32QVQLVQSGAEVKKPGESVKISCKASGYTFTNYGMNWVRQQPGQCLKWMGWINTYTGESTYADDFKGRFAFSL DTSASTAYLQLSSLRSEDTAVYFCARFAIKGDYWGQGTLVTVSSanti_EpCAM_3 antibodyVH - SEQ ID NO: 33 MQVKLQQSGAELVRPGASVKLSCKASGYTFTNYWINWVKQRPGQGLEWIGNIYPSYIYTNYNQEFKDKVTLTVD ESSSTAYMQLSSPTSEDSAVYYCTRSPYGYDEYGLDYWGQGTTVTVSS VL - SEQ ID NO: 34 DIELTQSPSSLTVTAGEKVTMNCKSSQSLLNSRNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSG TDFTLTISSVQAEDLAVYYCQNDYVYPLTFGAGTKLEIKRKIT (e.q., UniProtKB - P10721 , Gene ID:3815)Anti_KIT antibodyVH - SEQ ID NO: 35 QVQLVQSGAAVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISAGK SISTAYLQWSSLKASDTAMYYCARHGRGYNGYEGAFDIWGQGTMVTVSS VL - SEQ ID NO: 36 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISS LQPEDFATYYCQQFNSYPLTFGGGTKVEIKFLT3 (e.q., UniProtKB - P36888, Gene ID: 2322)Anti_FLT3 = Klon-Seq-19+22VH - SEQ ID NO: 37 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTR DTSTSTVYMELSSLRSEDTAVYYCARGVGAHDAFDIWGQGTTVTVSS VL - SEQ ID NO: 38 DWMTQSPLSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSDT DFTLQISRVEAEDVGVYYCMQGTHPAISFGQGTRLEIKAnti_FLT3 = Klon-Seq-21+24VH - SEQ ID NO: 39 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWARQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTR DTSTSTVYMELSSLRSEDTAVYYCARWAAAVADYWGQGTLVTVSS VL - SEQ ID NO: 40 DWMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGT DFTLKISRVEAEDVGVYYCMQSLQTPFTFGPGTKVDIK IGF1R (e.g., UniProtKB - P08069, Gene ID: 3480)Anti_IGF1RVH - SEQ ID NO: 41 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKS TSTAYMELSSLRSEDTAVYYCARAPLRFLEWSTQDHYYYYYMDVWGKGTTVTVS VL - SEQ ID NO: 42 ELTQDPAVSVALGQTVRITCQGDSLRSYYATWYQQKPGQAPILVIYGENKRPSGIPDRFSGSSSGNTASLTITGAQ AEDEADYYCK SRDGSGQHLV FGGGTKLTVLN-Cadherin I CDH2 = (e.g., UniProtKB - P19022, Gene ID: 1000)Anti_N-CadherinVH - SEQ ID NO: 43 MAQVQLVQSGGGLAQPGGSLRLSCAASGFTFSRHAMIWVRQAPGKGLEWVSSISGSSDSTSYADSVKGRFTIS RDNSKNTLYLQMNTLRAEDTAVYYCAKATGYSYYYGMD VWGPGTTVTVSSVL VL - SEQ ID NO: 44 DIQMTQSPSSLSASLGDRVTITCRASQGISNYLAWYQQKPGKAPKLLIYGATTLQHGVPSRFSGSGSGTDFSLTIS SLQPEDF AIYFC QQAHSFPPTFGGGTKLEKCD451 PTPRC (e.g., UniProtKB - P08575, Gene ID: 5788)Anti_CD45 = Fred Hutchinson Cancer CenterVH - SEQ ID NO: 45QVQLVESGGGLVQPGGSLKLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPTSSTINFTPSLKDKVFISRDN AKNTLYLQMSKVRSEDTALYYCARGNYYRYGDAMDYWGQGTSVTVS VL - SEQ ID NO: 46 DIVLTQSPASLAVSLGQRATISCRASKSVSTSGYSYLHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSGTDF TLNIHPVEEEDAATYYCQHSRELPFTFGSGTKLEIKAnti_CD45 - RORB_31_7VH - SEQ ID NO: 47 EVQLVESGAEVKKPGASVKVSCKASGYTFTNYIIHWVKQEPGQGLEWIGYFNPYNHGTKYNEKFKGRATLTADK SISTAYMELSSLRSEDTAVYYCARSGPYAWFDTWGQGTTVTVSS VL - SEQ ID NO: 48 DILLTQSPATLSLSPGERATFSCRASQNIGTSIQWYQQKTNGAPRLLIRSSSESISGIPSRFSGSGSGTDFTLTISSL EPEDFAVYYCQQSNTWPFTFGQGTKLEIKAnti_CD45 - RORB_31_8VH - SEQ ID NO: 49 EVQLVESGAEVKKPGASVKVSCKASGYTFTNYIIHWVKQEPGQGLEWIGYFNPYNHGTKYNEKFKGRATLTADK SISTAYMELSSLRSEDTAVYYCARSGPYAWFDTWGQGTTVTVSS VL - SEQ ID NO: 50 DILLTQSPATLSLSPGERATLSCRASQNIGTSIQWYQQKPGQAPRLLIRSSSESISGIPSRFSGSGSGTDFTLTISSL EPEDFAVYYCQQSNTWPFTFGQGTKLEIKAnti_CD45 - RORB_32_7VH - SEQ ID NO: 51 QVQLVESGAEVKKPGASVKVSCKASGYTFTNYIIHWVKQEPGQGLEWIGYFNPYNHGTKYNEKFKGRATLTADK SISTAYMELSSLRSEDTAVYYCARSGPYAWFDTWGQGTTVTVSS VL - SEQ ID NO: 52 DILLTQSPATLSLSPGERATFSCRASQNIGTSIQWYQQKTNGAPRLLIRSSSESISGIPSRFSGSGSGTDFTLTISSL EPEDFAVYYCQQSNTWPFTFGQGTKLEIKAnti_CD45 - RORB_32_8VH - SEQ ID NO: 53QVQLVESGAEVKKPGASVKVSCKASGYTFTNYIIHWVKQEPGQGLEWIGYFNPYNHGTKYNEKFKGRATLTADK SISTAYMELSSLRSEDTAVYYCARSGPYAWFDTWGQGTTVTVSS VL - SEQ ID NO: 54 DILLTQSPATLSLSPGERATLSCRASQNIGTSIQWYQQKPGQAPRLLIRSSSESISGIPSRFSGSGSGTDFTLTISSL EPEDFAVYYCQQSNTWPFTFGQGTKLEIKAnti_CD45 - RA_ChinaVH - SEQ ID NO: 55 QVQLKQSGAELAKPGASVKMSCKASGSTFTTYfflHWVKQRPGQGLEffIGYINPNTGYTEYNQKFKAKATLTADKS SSTAYMQLSSLTSEDSAVYYCVRFITWGGffGQGTTLTVSSVL - SEQ ID NO: 56 QIVLTQSPAIMSAYLGERVTMTCTASSSVSSSHLHWYQQKPGSSPKLfflYSTSNLASGVPARFSGSGSGTSYSLTI SSMETEDAATYYCHQYHRSPLTFGAGTKLELKRAnti_CD45 - RO_ MilteniyVH - SEQ ID NO: 57 QITLKESGPTLVKPTQTLTLTCTFSGFSLTTYGIGVGWIRQPPGKALEWLTHIWWNDNKYYSPSLKSRLTITKDSSK NQWLTMTNMDPVDTATYYCLYGYTYWGQGTLVTVSA VL - SEQ ID NO: 58 DWMTQTPLSLPVTLGQPASISCRSSQSLLYSNGNTYLHWYQQRPGQSPRLLIYKLSNRFSGVPDRFSGSGSGT DFTLKISRVEAEDVGVYYCSQSTHVPWTFGGGTKLEIKCD34 (e.g„ UniProtKB - P28906, Gene ID: 947)Anti_CD34 - ChinaVH - SEQ ID NO: 59 QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTNTGEPKYAEEFKGRFVFSL DTSVSTAYLQISSLKAEDTAVYYCARGYGNYARGAWLAYWGQGTLVTVSS VL - SEQ ID NO: 60 DWMTQSPLSLPVTLGQPASISCRSSQTIVHSNGNTYLEWFQQRPGQSPRRLIYQVSNRFSGVPDRFSGSGSGT DFTLKISRVEAEDVGVYYCFQGSHVPRTFGGGTKVEIKRCD1381 SDC1 (e.q„ UniProtKB - P18827, Gene ID: 6382)anti_CD138 antibody - IndatuximabVH - SEQ ID NO: 61 QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIYNEKFKGKATFTADIS SNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTVSS VL - SEQ ID NO: 62 DIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKPDGTVELLIYYTSTLQSGVPSRFSGSGSGTDYSLTIS NLEPEDIGTYYCQQYSKLPRTFGGGTKLEIKAnti_CD138 - China_Klone58VH - SEQ ID NO: 63 QIQLVQSGPELKKPGETVKISCKASGYTFTDYGMNWVKQAPGKGLKWMVWINTYTGAPTFADDFKGRFALSLET SASTAYLQINNLKNEDTATYFCAKSYGWYFDVWGAGTTVTVSS VL - SEQ ID NO: 64 DVLMTQTPLSLPVSLQASISCRSSQSILHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTL KISRVEAEDLGIYYCFQGSHVPWTFGGGTKLEIKAnti_CD138 - China_Klone59166VH - SEQ ID NO: 65 QIQLVQSGPELKKPGETVKISCKASGYTFTDYGMNWVKQAPGKGLKWMVWINTYTGAPTFADDFKGRFALSLET SASTAYLQINNLKNEDTATYFCAKSYGWYFDVWGAGTTVTVSS VL - SEQ ID NO: 66 DIQMTQTTSSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTIS NLEPEDIATYYCQQYSKRPffTFGGGTKLEIKAnti_CD138 - Klon-58208VH - SEQ ID NO: 67 QIQLVQSGPELKKPGETVKISCKASGYTFTDYGMNWVKQAPGKGLKWMVWINTYTGAPTFADDFKGRFALSLET SASTAYLQINNLKNEDTATYFCAKSYGWYFDVWGAGTTVTVSS VL - SEQ ID NO: 68DVLMTQTPLSLPVSLQASISCRSSQSILHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTL KISRVEAEDLGIYYCFQGSHVPWTFGGGTKLEIKAnti_CD138 antibody = RavtansineVH - SEQ ID NO: 69 QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIYNEKFKGKATFTADIS SNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTVSS VL - SEQ ID NO: 70 DIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKPDGTVELLIYYTSTLQSGVPSRFSGSGSGTDYSLTIS NLEPEDIGTYYCQQYSKLPRTFGGGTKLEIKCD123 / IL3RA (e.g., UniProtKB - P26951, Gene ID: 3563)Anti_CD123 antibodyVH - SEQ ID NO: 71 QIQLVQSGPELKKPGETVKISCKASGYIFTNYGMNWVKQAPGKSFKWMGWINTYTGESTYSADFKGRFAFSLET SASTAYLHINDLKNEDTATYFCARSGGYDPMDYWGQGTSVTVSS VL - SEQ ID NO: 72 DIVLTQSPASLAVSLGQRATISCRASESVDNYGNTFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDF TLTINPVEADDVATYYCQQSNEDPPTFGAGTKLELKCD117 / Kit (e.g., UniProtKB - P10721, Gene ID: 3815)Anti_CD117 antibodyVH - SEQ ID NO: 73 QVQLVQSGAAVKKPGESLKISCKGSGYRFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISAGK SISTAYLQWSSLKASDTAMYYCARHGRGYNGYEGAFDIWGQGTMVTVSS VL - SEQ ID NO: 74 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISS LQPEDFATYYCQQFNSYPLTFGGGTKVEIKPSMA (e.q„ UniProtKB - Q04609, Gene ID: 2346)Anti_PSMA antibody - J591_HC_Seq 1 +10VH - SEQ ID NO: 75 EVQLVQSGAEVKKPGASVKISCKTSGYTFTEYTIHWVKQASGKGLEWIGNINPNNGGTTYNQKFEDRATLTVDKS TSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTTVTVSS VL - SEQ ID NO: 76 DIVMTQSPSSLSASVGDRVTITCKASQDVGTAVDWYQQKPGKAPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTI SSLQPEDFADYFCQQYNSYPLTFGGGTKLEIKAnti_PSMA antibody - J591 _2P_Seq2+11VH - SEQ ID NO: 77 EVQLVQSGPEVKKPGATVKISCKTSGYTFTEYTIHWVKQAPGKGLEWIGNINPNNGGTTYNQKFEDKATLTVDKS TDTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTLLTVSS VL - SEQ ID NO: 78 DIQMTQSPSSLSTSVGDRVTLTCKASQDVGTAVDWYQQKPGQSPKLLIYWASTRHTGIPSRFSGSGSGTDFTLTI SSLQPEDFADYYCQQYNSYPLTFGAGTKVD I KAnti_PSMA antibody - J591_CysDB_Seq9+15VH - SEQ ID NO: 79 EVQLVQSGAEVKKPGASVKISCKTSGYTFTEYTIHWVKQASGKGLEWIGNINPNNGGTTYNQKFEDRATLTVDKS TSTAYMELSSLRSEDTAVYYCAAGWNFDYWGQGTTVTVSS VL - SEQ ID NO: 80 DIVMTQSPSSLSASVGDRVTITCKASQDVGTAVDWYQQKPGKAPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTI SSLQPEDFADYFCQQYNSYPLTFGGGTKLEIKPSCA (e.q., UniProtKB - 043653, Gene ID: 8000)Anti_PSCA - 2B3parentalVH - SEQ ID NO: 81 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKFQGRATISADT SKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSSVL - SEQ ID NO: 82 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQWSSSPFTFGQGTKVEIKAnti_PSCA - 2B3_A2VH - SEQ ID NO: 83 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPEYGDSEFVPKFQGRATMSAD TSKNTAYLQMNSLRAEDTAVYYCKTGGFWGRGTLVTVSS VL - SEQ ID NO: 84 DIQLTQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQWGSSPFTFGQGTKVEIKAnti_PSCA - 2B3_A11VH - SEQ ID NO: 85 EVQLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKFQGRATMSAD TSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS VL - SEQ ID NO: 86 DIQLTQSPSTLSASMGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQWGSSPFTFGQGTKVEIKAntLPSCA - 2B3_C5VH - SEQ ID NO: 87 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKFQGRATISADT SKNTVYLQMNSLRAKDTAVYYCKTGGFWGQGTLVTVSS VL - SEQ ID NO: 88 DIQLIQSPSSLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQWSSSPFTFGQGTKVEIKCD133 (e.q„ UniProtKB - 043490, Gene ID: 8842)Anti_CD133 - AC133VH - SEQ ID NO: 89QVQLQQSGAELVRPGASVKLSCKASGYTFSDFEMHWVKQTPVHGLEWIGDIDPGTGDTAYNLKFKGKATLTTDK SSSTAYMELRSLTSEDSAVYYCTLGAFVYWGQGTLVTVS VL - SEQ ID NO: 90 DVWTQTPLSLPVSFGDQVSISCRSSQSLANSYGNTYLSWYLHKPGQSPQLLIYGISNRFSGVPDRFSGSGSGTD FTLKISTIKPEDLGMYYCLQGTHQPYTFGGGTKLEIKRADAAAAnti_CD133 - clone?VH - SEQ ID NO: 91 LEVKLVESGPELKKPGETVKISCKASGYTFTDYSMHWVNQAPGKGLKWMGWINTETGEPSYADDFKGRFAFSLE TSASTAYLQINNLKNEDTATYFCATDYGDYFDYWGQGTTLTVSSAKTTPPSVTSGQAGQ VL - SEQ ID NO: 92 AQAAELDIVLSQSPAIMSASPGEKVTISCSASSSVSYMYWYQQKPGSSPKPWIYRTSNLASGVPARFSGSGSGTS YSLTISSMEAEDAATYYCQQYHSYPPTFGAGTKLELKCD166 (e.g„ UniProtKB - Q13740, Gene ID: 214)Anti_CD166 antibodyVH - SEQ ID NO: 93 QITLKESGPTLVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWSEDKHYSPSLKSRLTITKDTS KNQWLTMTNMDPVDTATYYCVQIDYGNDYAFTYWGQGTLVTVSS VL - SEQ ID NO: 94 DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSGSGSGTDF TLKISRVEAEDVGVYYCAQNLELPYTFGQGTKLEIKCD44v61 CD44 (e.g„ UniProtKB - P16070, Gene ID: 960)Anti_CD44v6 - BIWA 4 / 8aa+ VL BIWA 4VH - SEQ ID NO: 95 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISSGGSYTYYLDSIKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARQGLDYWGRGTLVTVSS VL - SEQ ID NO: 96EIVLTQSPATLSLSPGERATLSCSASSSINYIYWYQQKPGQAPRLLIYLTSNLASGVPARFSGSGSGTDFTLTISSLE PEDFAVYYCLQWSSNPLTFGGGTKVEIKAnti_CD44v6 - BIWA 4 / 8aa+VL BIWA 8 aaVH - SEQ ID NO: 97 EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISSGGSYTYYLDSIKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARQGLDYWGRGTLVTVSS VH - SEQ ID NO: 98 EIVLTQSPATLSLSPGERATLSCSASSSINYIYWLQQKPGQAPRILIYLTSNLASGVPARFSGSGSGTDFTLTISSLE PEDFAVYYCLQWSSNPLTFGGGTKVEIKCD291 ITGB1 (e.q„ UniProtKB - P05556, Gene ID: 3688)Anti_CD29 antibodyVH - SEQ ID NO: 99 EVQLQQSGPEVGRPGSSVKISCKASGYTFTGYILSWVKQSPGQGLEWIGWVDPEYGSTDSAEKFKKRATLTADI SSNTAYIQLSSLTSEDTATYFCTRYYDGYYRRWFAYWGQGTLVTVSS VL - SEQ ID NO: 100 DIQMTQSPASLSASLGDIVSIECLASEGISNNLAWHQQKPGKSPQLLIYGAHSLHDGVPSRFSGSGSGTQYSLKIS GMQPEDEGVYYCQQGYKYPITFGGGTKLELKCD24 (e.g., UniProtKB - P25063, Gene ID: 100133941)Anti_CD24 antibodyVH - SEQ ID NO: 101 MADVHLQESGPDLVKPSQSLSLTCTVTGYSITSGYTWHWIRQFPGNTVEWMGYIQYTGSTRYNPALRGRLSISR DTSKNQFFLQLISVTTADTGTYFCARGTTASFDYWGQGTTLTVASAGSA VL - SEQ ID NO: 102 DIVMSQSPSSLNVSVGEKVTMRCRSSQSLLYSSDQKNYLTWYQQKPGQSPKLLISWASTRASGVPDRFTGSGS GTDFTLTISSVKAEDLGVYYCQQYFIYPLTFGVGLgr5 (e.q„ UniProtKB - 075473, Gene ID: 8549)Anti_Lgr5 antibodyVH - SEQ ID NO: 103 MEWSWVFLFFLSVTTGVHSEVQLVQSGAEVKKPGESLRISCKGSGYSFTAYWIEWVRQAPGKGLEWIGEILPGS DSTNYNEKFKGHVTISADKSISTAYLQWSSLKASDTAVYYCARSGYYGSSQYWGQGTLVTVSS VL - SEQ ID NO: 104 MSVPTQVLGLLLLWLTDARCDIVLTQSPASLAVSPGQRATITCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLT SNLESGVPDRFSGSGSGTDFTLTINPVEANDAATYYCQQNAEDPRTFGGGTKLEIKCEA / CEACAM5 (e.q„ UniProtKB - P06731 , Gene ID: 1048)Anti_CEA_antibodyVH - SEQ ID NO: 105 EVQLVESGGGWQPGRSLRLSCSSSGFDFTTYWMSWVRQAPGKGLEWVAEIHPDSSTINYAPSLKDRFTISRDN SKNTLFLQMDSLRPEDTGVYFCASLYFGFPWFAYWGQGTPVTVSS VL - SEQ ID NO: 106 DIQLTQSPSSLSASVGDRVTITCKASQDVGTSVAWYQQKPGKAPKLLIYWTSTRHTGVPSRFSGSGSGTDFTFTI SSLQPEDIATYYCQQYSLYRSFGGGTKVGIKVEGFR21 KDR (e.q„ UniProtKB - P35968, Gene ID: 3791)Anti_VEGFR2 antibodyVH - SEQ ID NO: 107 QEQLMESGGGLVTPGGTLTLTCTASGFTISSYYMSWVRQAPGKGLEYIGLIKTDGTTYYANWAKGRVTISRTSTT VDLKMTSLTTEDTATYFCVRDAAYSVGRDDFDPWGPGTLVTISS VH - SEQ ID NO: 108 ELVMTQTPASVSEPVGGTVTIKCQASQNIYSGLAWYQQKPGQPPKLLIYQSSTLASGVPSRFKGSGSGTQFTLTI SGVQREDAATYYCQSGANSNDITFGGGTELEILAnti_VEGFR2 antibody - RamucirumabVH - SEQ ID NO: 109EVQLVQSGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARVTDAFDIWGQGTMVTVSSVL - SEQ ID NO: 110 DIQMTQSPSSVSASIGDRVTITCRASQGIDNWLGWYQQKPGKAPKLLIYDASNLDTGVPSRFSGSGSGTYFTLTIS SLQAEDFAVYFCQQ AKAFPPTFGGGTKVDIKCXCR4 (e.g., UniProtKB - P61073, Gene ID: 7852)Anti_CXCR4 - BMSVH - SEQ ID NO: 111 QVQLVQSGGGLVQPGGSLRLSCAAAGFTFSSYSMNWVRQAPGKGLEWVSYISSRSRTIYYADSVKGRFTISRDN AKNSLYLQMNSLRDEDTAVYYCARDYGGQPPYYYYYGMDVWGQGTTVTVSS VH - SEQ ID NO: 112 AIRMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTIS SLQPEDFVTYYCQQYNSYPRTFGQGTKVEIKAnti_CXCR4 antibody - PfizerVH - SEQ ID NO: 113 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMSWVRQAPGKGLEWVGFIRHKANFETTEYSTSVKGRFTISR DDSKNSLYLQMNSLKTEDTAVYYCARDLPGFAYWGQGTLVTVSS VL - SEQ ID NO: 114 DIVMTQSPDSLAVSLGERATINCKSSQSLFNSHTRKNYLAWYQQKPGQPPKLLIYWASARGSGVPDRFSGSGSG TDFTLTISSLQAEDVAVYYCKQSFNLRTFGGGTKVEIKAnti_CXCR4 antibody - MedarexVH - SEQ ID NO: 115 QVQLVQSGGGLVQPGGSLRLSCAAAGFTFSSYSMNWVRQAPGKGLEWVSYISSRSRSIYYADSVKGRFTISRDN AKNSLYLQMNSLRDEDTAVYYCARDYGGQPPYYYYYGMDVWGQGTTVTVSS VL - SEQ ID NO: 116EIVLTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPPRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYNSYPRTFGQGTKVEIKPDGFRB (e.q„ UniProtKB - P09619, Gene ID: 5159)Anti_PDGFRb antibody - XB1511 + VL_D8VH - SEQ ID NO: 117 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADE STSTAYMELSSLRSEDTAVYYCAIHGGDRSYWGQGTLVTVSS VL - SEQ ID NO: 118 EIVMTQSPGTLTLSPGEGATLSCRASQSVTSNYLAWYQQRPGQAPRLLIYDASNRATGIPDRFSGSGFGTDFTLTI SRLEPEDFAVYYCQQYVNSRTFGQGTKVEIKAnti_PDGFRb antibody - XB2202+VL_A4VH - SEQ ID NO: 119 QVQLVQSGAEVKKPGSSVRVSCKASGGTFSRHAISWVRQAPGQGLEWIGGILPILKTPNYAQRFQGRVTINADES TSTVYMEMSSLRSEDTAVYYCATHGGDRSYWGQGTLVTVSS VL - SEQ ID NO: 120 DWMTQSPSSLSASVGDRVTITCQASQDISNWLNWYQQKPGKAPKLLIYEASNLETGVPSRFSGSGSGTDFTFTI SSLQPEDIATYYCQQYNNVLRTFGQGTKVEIKCD33 (e.g., UniProtKB - P20138, Gene ID: 945)Anti_CD33 antibodyVH - SEQ ID NO: 121 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDINWVRQAPGQGLEWMGWMNPNSGNTGFAQKFQGRVTMT RDTSTSTVYMELSSLRSEDTAVYYCARDRANTDYSLGMDVWGQGTLVTVSS VL - SEQ ID NO: 122 QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNTVNWYQQLPGTAPKLLIYGNNQRPSGVPDRFSGSKSGTSASL AISGLQSEDEADYYC ATWDDSLIGWVFGGGTKLTVLCD56 / NCAM1 (e.q„ UniProtKB - P13591 , Gene ID: 4684)Anti_CD56 antibodyVH - SEQ ID NO: 123 QVQLVESGGGWQPGRSLRLSCAASGFTFSWVRQAPGKGLEWVAYADSVKGRFTISRDNSKNTLYLQMNSLRA EDTAVYYCARWGQGTLVTVSS VL - SEQ ID NO: 124 DWMTQSPLSLPVTLGQPASISCWFQQRPGQSPRRLIYGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFGQG TKVEIKCD19 (e.q„ UniProtKB - P15391 , Gene ID: 930)Anti_CD19 antibody - cA19VH - SEQ ID NO: 125 QVQLQESGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTA DESSSTAYMQLSSLRSEDSAVYSCARRETTTVGRYYYAMDYWGQGTTVTVSS VL - SEQ ID NO: 126 DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDFT LNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLQIKRAnti_CD 19 antibody - hA19VH - SEQ ID NO: 127 QVQLQQSGAEVKKPGSSVKVSCKASGYAFSSYWMNWVRQRPGQGLEWIGQIWPGDGDTNYNGKFKGRATITA DESTNTAYMELSSLRSEDTAFYSCARRETTTVGRYYYAMDYWGQGTTVTVSS VL - SEQ ID NO:128 DIQLTQSPSSLSASVGDRVTITCKASQSVDYDGDSYLNWYQQIPGKAPKLLIYDASNLVSGVPSRFSGSGSGTDY TFTISSLQPEDIATYHCQQSTEDPWTFGGGTKLQIKRAnti_CD19 antibody - BlincytoVH - SEQ ID NO: 129 QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNYNGKFKGKATLTA DESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTVTVSSVL - SEQ ID NO: 130 DIQLTQSPASLAVSLGQRATISCKASQSVDYDDGDSYLNWYQQIPGQPPKLLIYDASNLVSGIPPRFSGSGSGTDF TLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIKCD20 (e.g„ UniProtKB - P11836, Gene ID: 931)Anti_CD20 antibody - GenmabVH - SEQ ID NO: 131 AVQLVESGGGLVQPGRSLRLSCAASGFTFGDYTMHWVRQAPGKGLEWVSGISWNSGSIGYADSVKGRFTISRD NAKNSLYLQMNSLRAEDTALYYCTKDNQYGSGSTYGLGVWGQGTLVTVSS VL - SEQ ID NO: 132 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS SLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKL1CAM (e.g„ UniProtKB - P32004, Gene ID: 3897)Anti_L1CAM antibodyVH - SEQ ID NO: 133 DVHSQVQLQQPGAELVKSGASVNLSCRASGYTFTRYWMLWVRQRPGHGLEWVGEINPRNDRTNYNEKFKTKA TLTVDRSSSTAYMQLTSLTSEDSAVYFCALGGGYAMDYWGQGTSVTVSS VL - SEQ ID NO: 134 DIQMTQTTSSLSAFLGDRVTISCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYSLTIS NLEQEDFATYFCQQGNTLPWTFGGGTKLEIKLFA-1 1 ITGB2 1 CD18 (e.g„ UniProtKB - P05107, Gene ID: 3689)Anti_LFA1 antibodyVH - SEQ ID NO: 135 EVQLVESGGGLVQPGGSLRLSCATSGYTFTEYTMHWMRQAPGKGLEWVAGINPKNGGTSHNQRFMDRFTISVD KSTSTAYMQMNSLRAEDTAVYYCARWRGLNYGFDVRYFDVWGQGTLVTVSS VL - SEQ ID NO: 136DIQMTQSPSSLSASVGDRVTITCRASQDINNYLNWYQQKPGKAPKLLIYYTSTLHSGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPPTFGQGTKVEIKRR0R1 (e.q„ UniProtKB - Q01973, Gene ID: 4919)Anti_ROR1 antibodyVH - SEQ ID NO: 137 QVQLQQSGAELVRPGASVTLSCKASGYTFSDYEMHWVIQTPVHGLEWIGAIDPETGGTAYNQKFKGKAILTADKS SSTAYMELRSLTSEDSAVYYCTGYYDYDSFTYWGQGTLVTVSA VL - SEQ ID NO: 138 DIVMTQSQKIMSTTVGDRVSITCKASQNVDAAVAWYQQKPGQSPKLLIYSASNRYTGVPDRFTGSGSGTDFTLTI SNMQSEDLADYFCQQYDIYPYTFGGGTKLEIKCD123 / IL3RA (e.g., UniProtKB - P26951 , Gene ID: 3563)Anti_CD123 antibodyVH - SEQ ID NO: 139 QIQLVQSGPELKKPGETVKISCKASGYIFTNYGMNWVKQAPGKSFKWMGWINTYTGESTYSADFKGRFAFSLET SASTAYLHINDLKNEDTATYFCARSGGYDPMDYWGQGTSVTVSS VL - SEQ ID NO: 140 DIVLTQSPASLAVSLGQRATISCRASESVDNYGNTFMHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDF TLTINPVEADDVATYYCQQSNEDPPTFGAGTKLELKIGF1R / CD221 (e.g., UniProtKB - P08069, Gene ID: 3480)Anti_IGF1R antibody - 206VH - SEQ ID NO: 141 EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSKGYVDSVKGRFTISRD NAKNSLYLQMNSLRAEDTALYYCAKDIRIGVAASYYFGEDVWGHGTTVTVSS VL - SEQ ID NO: 142AIQLTQSPSSLSASVGDRVTITCRASQGISSVLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISS LQPEDFATYYCQQFNSYPYTFGQGTKLEIKAnti_IGF1R antibody - 9H2VH - SEQ ID NO: 143 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWMGWINAGNGNTRYSQKFQGRVTITR DTSASTVYMELSSLRSEDTAVYYCARGGMPVAGPGYFYYYGMDVWGQGTTVTVSS VL - SEQ ID NO: 144 EIVLTQSPGTLSLSPGERATLSCRASQSVSRSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI SRLEPEDFAVYCCQQYGSSPWTFGQGTKVEIKRTCCR71 CD197 (e.q„ UniProtKB - P32248, Gene ID: 1236)Anti_CCR7 antibody - R735VH - SEQ ID NO: 145 EVQLLESGGGLVQPGGPLRLSCAASGFTFSNYNMHWVRQAPGKGLEWVSGIGPRRGRTYYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCARSYAYQYRGLDYWGQGTLVTVSS VL - SEQ ID NO: 146 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI SRLEPEDFAVYYCQQGSPVTFGQGTKVEIKAnti_CCR7 antibody - R707BIVH - SEQ ID NO: 147 EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAIHWVRQAPGKGLEWVSAITPRGGYTYYADSVKGRFTISRDN SKNTLYLQMNSLRAEDTAVYYCARGLTISYTPGFDYWGQGTLVTVSS VL - SEQ ID NO:148 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI SRLEPEDFAVYYCQQSYSSPITFGQGTKVEIKCCR41 CD194 (e.g., UniProtKB - P51679, Gene ID: 1233)Anti_CCR4 antibodyVH - SEQ ID NO: 149 EVQLVESGGDLVQPGRSLRLSCAASGFIFSNYGMSWVRQAPGKGLEWVATISSASTYSYYPDSVKGRFTISRDN AKNSLYLQMNSLRVEDTALYYCGRHSDGNFAFGYWGQGTLVTVSS VL - SEQ ID NO:150 DVLMTQSPLSLPVTPGEPASISCRSSRNIVHINGDTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTD FTLKISRVEAEDVGVYYCFQGSLLPWTFGQGTKVEIKTNFRSF914-1 BB (e.g., Uni ProtKB - Q07011 , Gene ID: 3604)Anti_4-1BB antibodyVH - SEQ ID NO: 151 EVQLVQSGAEVKKPGESLRISCKGSGYSFSTYWISWVRQMPGKGLEWMGKIYPGDSYTNYSPSFQGQVTISADK SISTAYLQWSSLKASDTAMYYCARGYGIFDYWGQGTLVTVSS VH - SEQ ID NO: 152 SYELTQPPSVSVSPGQTASITCSGDNIGDQYAHWYQQKPGQSPVLVIYQDKNRPSGIPERFSGSNSGNTATLTIS GTQAMDEADYYCATYTGFGSLAVFGGGTKLTVLCTLA41 CD152 (e.g., UniProtKB - P16410, Gene ID: 1493)Anti_CTLA4 antibody - 8H5VH - SEQ ID NO: 153 QVQLVQSGAELKKPGASVKVSCKASGYTFTSYWTNWTRQAPGQGLEWIGRIAPGSGTTYYNEVFKGRVTITVDK STSTAYMELSSLRSEDTAVYFCARGDYGSYWGQGTLVTVSS VL - SEQ ID NO: 154 EIVLTQSPATLSLSPGERATLSCSASSSISYMHWFQQRPGQSPRRWIYDTSKLASGVPARFSGSGSGTDYTLTIS SLEPEDFATYYCHQRTSYPLTFGQGTKLEIKAnti_CTLA4 anitbody - 3B10VH - SEQ ID NO: 155 QVQLVQSGAELKKPGASVKVSCKASGYTFTDYNMDWVRAQPGQGLEWIGNINPNSESTSYNQKFKGRVTITVDK STSTAYMELRSLRSDDTAVYYCTRDGNRYDAWFAYWGQGTLVTVSSVL - SEQ ID NO: 156 EIVLTQSPATLSLSPGERATLSCSASSSVTYMHWFQQKPGKAPKLWIYSTSILASGVPARFSGSGSGTDYTLTISR LEPEDFATYYCQQRTSYPLTFGQGTKLEIKAnti_CTLA4 antibody - INN 8568VH - SEQ ID NO: 157 QVQLVESGGGWQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS VL - SEQ ID NO: 158 EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTI SRLEPEDFAVYYCQ QYGSSPWTFGQGTKVEIKGPC31 Glypican-3 (e.g., UniProtKB - P51654, Gene ID: 2719)Anti_Glypican-3 antibodyVH - SEQ ID NO: 159 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTIQKQGLPTQYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCAKNRAKFDYWGQG TLVTVSS VL - SEQ ID NO: 160 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYNASMLQSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQNRGFPLTFGQGTKVEIKCADM1 (e.g., UniProtKB - Q9BY67, Gene ID: 23705)Anti_CADM1 antibodyVH - SEQ ID NO: 161 QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWDDDKRYSPSLKSRLTITKDTSK NQWLTMTNMDPVDTAIYYCAHRRVEWFALAGNWFDPWGQGSLVTVSS VL - SEQ ID NO: 162 DIQMTQSPSSLSASVGDRVTITCRAWLAWYQQKPEKAPKSLIYAASSLQSSGSGSGTDFTLTISSLQPEDFATYYY PLTFGGGTKVEIKCD4 (e.q„ UniProtKB - P01730, Gene ID: 920)Anti_CD4 antibodyVH - SEQ ID NO: 163 QVQLQQSGPEWKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDT STSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSS VL - SEQ ID NO: 164 DIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGS GTDFTLTI SSVQAEDVAVYYCQQYYSYRTFGGGTKLEI KB7-h4 / VTCN1 (e.g., UniProtKB - Q7Z7D3, Gene ID: 79679)Anti_B7-h4 antibody - c56VH - SEQ ID NO: 165 QVQLQQWGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDT SKNQFSLKLSSVTAADTAVYYCARLSKGYSSSWAYSYYGPDAWGQGTMVTVSS VL - SEQ ID NO: 166 QPVLTQSHSVSESPGKTVTITCTGSGGNIATQYVQWYQQRPGSGPTTVIYDDDQRPSGVPDRFTGSIDSSSNSA SLTISGLKTEDEADYYCQSYDSTNHGVFGGGAKVTVLAnti_B7-h4 antibody - c26VH - SEQ ID NO: 167 QVTLKESGAEVKNPGSSVKVSCKASGGTFSSYAISWLRQAPGQGLEWMGWINPNSGGSDYAQRFQGRVTMTR DTSINTVYMELSRLRSDDTAVYYCARVEKRGYYYGMDVWGQGTMVTVSS VL - SEQ ID NO: 168 DIVMTQTPATLSVSPGKRATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTI SSLQAEDVAVYYCQQYGSSPRTFGQGTKLEIKAnti_B7-h4 antibody - c3#68VH - SEQ ID NO: 169QVTLKESGAEVKNPGSSVKVSCKASGGTFSSYAISWLRQAPGQGLEWMGWINPNSGGSDYAQRFQGRVTMTR DTSINTVYMELSRLRSDDTAVYYCARVEKRGYYYGMDVWGQGTMVTVSS VL - SEQ ID NO:170 QPGLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQFPGTAPKLLIYRNNQRPSGVPDRFSGSKSGTSASL AISGLRSEDEADYYCAAWDDSLSVWVFGGGTKVTVLTYRP1 (e.g„ UniProtKB - P17643, Gene ID: 7360)Anti_TYRP1 antibodyVH - SEQ ID NO: 171 QVQLVQSGSELKKPGASVKISCKASGYTFTSYAMNWVRQAPGQGLESMGWINTNTGNPTYAQGFTGRFVFSMD TSVSTAYLQISSLKAEDTAIYYCAPRYSSSWYLDY WGQGTLVTVSS VL - SEQ ID NO: 172 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS SLEPEDFAVYYCQQRSNWLMYTFGQGTKLEIKPDL1 1 CD274 (e.g„ UniProtKB - Q9NZQ7, Gene ID: 29126)Anti_PD-L1 antibody -AtezolizumabVH - SEQ ID NO: 173 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISAD TSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS VL - SEQ ID NO: 174 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYLYHPATFGQGTKVEIKAnti_PD-L1 antibody - DurvalumabVH - SEQ ID NO: 175 EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRD NAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS VL - SEQ ID NO: 176EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTI SRLEPEDFAVYYCQ QYGSLPWTFGQGTKVEIKRAnti_PD-L1 antibody - NivolumabVH - SEQ ID NO: 177 QVQLVESGGGWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRD NSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS VL - SEQ ID NO: 178 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS SLEPEDFAVYYCQQ SSNWPRTFGQGTKVEIKPDCD1 1 PD-1 (e.q„ UniProtKB - Q15116, Gene ID: 5133)Anti_PD-1 antibody - NivolumabVH - SEQ ID NO: 179 QVQLVESGGGWQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRD NSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS VL - SEQ ID NO: 180 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTIS SLEPEDFAVYYCQQ SSNWPRTFGQGTKVEIKAnti_PD-1 antibody - PembrolizumabVH - SEQ ID NO: 181 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTT DSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS VL - SEQ ID NO: 182 EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDF TLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRPDCD1LG21 PD-L2 (e.g., UniProtKB - Q9BQ51 , Gene ID: 80380)Anti_PD-L2 antibodyVH - SEQ ID NO: 183 QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEYNQKFKDRTTLTAD KSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS VL - SEQ ID NO: 184 DIVMTQSPAFLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGT DFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIKBTLA (e.g., UniProtKB - Q7Z6A9, Gene ID: 151888)Anti_BTLA antibodyVH - SEQ ID NO: 185 QVQLQESGPGLVKPSETLSLTCTVHGGSINHYYWSWIRQPPGKGLEWIGYIYYSGSTKYNPSLKSRVSISVDTSK NQFSLKLTSVTAADTAVYYCAREWPYYYYEMDVWGQGTTVTVSS VL - SEQ ID NO: 186 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTI SRLEPEDFAVYYCQQYGSSFRTFGQGTKVEIKDLL3 (e.g., UniProtKB - Q9NYJ7, Gene ID: 10683)Anti_DLL3 antibody - RovalpituzumabVH - SEQ ID NO: 187 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRVTMTT DTSTSTAYMELRSLRSDDTAVYYCARIGDSSPSDYWGQGTLVTVSS VL - SEQ ID NO: 188 EIVMTQSPATLSVSPGERATLSCKASQSVSNDWWYQQKPGQAPRLLIYYASNRYTGIPARFSGSGSGTEFTLTIS SLQSEDFAVYYCQQDYTSPWTFGQGTKLEIKCEACAM1 1 CD66a (e.g., UniProtKB - P13688, Gene ID: 634)Anti_CEACAM1 antibody - clone 6G5JVH - SEQ ID NO: 189KPGETVKISCKTSGYIFRNYGMKWVKQAPGKGLKWMGWINTYTGEPTYADDFKGRFAFSLETSASTAYLQINNLK NEDMATYFCARRGMITTSNYALDNWGQGTSVTVSS VL - SEQ ID NO: 190 SSLSASLGDRVTISCRASQDISNYLNWYQQKPDGTIKLLIYYTSKLHSGVPSRFSGSGSGTDYSLTISNLDQEDIAT YFCQQGNTLPWTFGGGTKLEIKAnti_CEACAM1 antibody - clone 18-20VH - SEQ ID NO: 191 KPGETVKISCKASGYTFTVYGMNWVKQAPGKDLKWMGWINTYTGEPTYADDFKGRFAFSLETSASTAYLQINNL KNEDMATYFCARKAFYRYDGGMDYWGQGTSVTVSS VL - SEQ ID NO: 192 SSLSASLGGKVTITCKASQDINKFLAWYQHKPGKGPRLLIHYTSTLQPGIPSRFSGSGSGRDYSFSISNLEPEDIAT YYCLQYDNLYTFGGGTKLEIKLFA-1 1 ITGB2 (e.g., UniProtKB - P05107, Gene ID: 3689)Anti_LFA-1 antibody - EfalizumabVH - SEQ ID NO: 193 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGHWMNWVRQAPGKGLEWVGMIHPSDSETRYNQKFKDRFTISV DKSKNTLYLQMNSLRAEDTAVYYCARGIYFYGTTYFDYWGQGTLVTVSS VL - SEQ ID NO: 194 DIQMTQSPSSLSASVGDRVTITCRASKTISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQHNEYPLTFGQGTKVEIKCD22 (e.g., UniProtKB - P20273, Gene ID: 933)Anti_CD22 antibody - PinatuzumabVH - SEQ ID NO: 195 EVQLVESGGGLVQPGGSLRLSCAASGYEFSRSWMNWVRQAPGKGLEWVGRIYPGDGDTNYSGKFKGRFTISA DTSKNTAYLQMNSLRAED TAVYYCARDGSSWDWYFDVWGQGTLVTVSS VH - SEQ ID NO: 196DIQMTQSPSSLSASVGDRVTITCRSSQSIVHSVGNTFLEWYQQKPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCFQGSQFPYTFGQGTKVEIKNRP1 1 CD304 (e.g., UniProtKB - 014786, Gene ID: 8829)Anti_NRP1 antibodyVH - SEQ ID NO: 197 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSQISPAGGYTNYADSVKGRFTISAD TSKNTAYLQMNSLRAED TAVYYCARGELPYYRMSKVMDVWGQGTLVTVSS VL - SEQ ID NO: 198 DIQMTQSPSSLSASVGDRVTITCRASQYFSSYLAWYQQKPGKAPKLLIYGASSRASGVPSRFSGSGSGTDFTLTI SSLQPEDFATYYCQQ YLGSPPTFGQGTKVEIKRCHRNA1 (e.g., UniProtKB - P02708, Gene ID: 1134)Anti_AChR_alpha antibodyVH - SEQ ID NO: 199 ESGGDLVQPGGSLRVSCVASGFTFRTYVMNWVRQAPGKGLEWVAHISPEGTEEYYADPVKGRFTISRDNAKNS VFLQMNSLRGEDTAVYYCARVRRYGPSTLSPFTWKDNHYAMDVWGQGTTVTVSP VL - SEQ ID NO: 200 ELVMTQSPSSLSASVGDRVTITCRASQTISNYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQSYSTPPTYTFGQGTKLEIKGD21 Disialoganglioside (CAS Registry Number® 65988-71-8)Anti_GD2 antibodyVH - SEQ ID NO: 201 EVQLVQSGAEVEKPGASVKISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRATLTVDK STSTAYMHLKSLRSEDTAVYYCVSGMEYWGQGT VL - SEQ ID NO: 202DWMTQTPLSLPVTPGEPASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFSGSGSGT DFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELKSCTAG1A / NY-ESO-1 (e.q„ UniProtKB - P78358, Gene ID: 246100)Anti_CTAGE1 antibodyVH - SEQ ID NO: 203 QVQLVQSGGGWRPGGSLRLSCAASGFSFIDYGMSWVRQVPGKGLEWVAGMNWSGDKKGHAESVKGRFIISR DNAKNTLYLEMSSLRVEDTALYFCARGEYSNRFDPRGRGTLVTVSS VL - SEQ ID NO: 204 DIVMTQTPLSLPVTLGQPASLSCRSSQSLVFTDGNTYLNWFQQRPGQSPRRLIYKVSSRDPGVPDRFSGTGSGT DFTLEISRVEAEDIGVYYCMQGTHWPPI FGQGTKVEIKCD301 TNFRSF8 (e.g., UniProtKB - P28908, Gene ID: 943)Anti_CD30 antibody - 2H9VH - SEQ ID NO: 205 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTKYTPSLKSRVTISVDTS KHQFSLKLSSVTAADTAVYYCARETVYYFDLWGRGTLVTVSS VL - SEQ ID NO: 206 EIVLTQSPATLSLSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYDASNRATGIPARLSGSGSGTDFTLTIS SLEPEDFAVYYCQQRSNWPWTFGQGTKVEIKCD98hc I SLC3A2 (e.q„ UniProtKB - P08195, Gene ID: 6520)Anti_CD98hc antibody - EJ212 / 076-CI 10VH - SEQ ID NO: 207 QVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARSSGWYDGEFDPWGQGTLVTVSS VL - SEQ ID NO: 208SYVLTQPPSASGTPGQRVTISCSGSSSNIGSNTVNWYQQLPGTAPKLLIYSNDQRPSGVPDRFSGSKSGTSASLA ISGLQSEDEADYYCAAWDDSLNGWFGGGTKLTVLCD52 (e.q„ UniProtKB - P31358, Gene ID: 1043)Anti_CD52 antibody - 2E8 HumanisedVH - SEQ ID NO: 209 EVHLVESGGGLVQPGGSLRLSCAASGFTFSRYGMSWVRQAPGKGLELVAMMKTKGGRTYYPDSVKGRFTISRD NAKNSLYLQMNSLRAEDTAIYYCASDGYYWGQGTTVTVSS VL - SEQ ID NO: 210 DWMTQTPLSLSVTLGQPASISCKSSQSLLHSDGKTYLNWLQQRPGQSPRRLIYLVSKLDSGVPDRFSGSGSGTD FTLKIS RVEAEDVGIYYCWQGTH LWTFGGGTKVEIKCD641 FCGR1A (e.g., UniProtKB - P12314, Gene ID: 2209)Anti_CD64 antibodyVH - SEQ ID NO: 211 QVQLVESGGGWQPGRSLRLSCAASGFIFSGYGMHWVRQAPGKGLEWVTVIWYDGSNKYYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCARDTGDRFFDYWGQGTLVTVSS VL - SEQ ID NO: 212 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASSRATGIPARFGGSGSGTDFTLTIS SLEPEDFAVYYCQLRSNWPPYTFGQGTKLEIKCD461 MOP (e.g., UniProtKB - P15529, Gene ID: 4179)Anti_CD46 antibodyVH - SEQ ID NO: 213 QVQLVQSGAEVKRPGASMKVSCKASGYTFTNYYIHWVRQAPGQGLEWMGWINPNSGATNYAQKFQGRVTMTR DTSTSTVYMELSSLRSEDTAVYYCAKSWVSWFASWGQGTLVTVSS VL - SEQ ID NO: 214DIVMTQSPDSLAVSLGERATINCKSSQSVLSSSNNKNYLNWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSG TDFTLTISSLQAEDVAVYYCQQHFNTPFAFGQGTKLEIKMore preferably, the antibody construct comprises scFvs comprising the VH and VL sequences of the following antibodies:antiCD38 - Morphosys Ag 2004SEQ ID NO: 215 - antiCD38 VH = Morphosys Ag 2004 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGR FTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSS SEQ ID NO: 216 - antiCD38 VL = Morphosys Ag 2004 DIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNT ATLTISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLantiSLAMF7 = ElotuzumabSEQ ID NO: 217 - antiSLAMF7 VH = Elotuzumab EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKF IISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSS SEQ ID NO: 218 - antiSLAMF7 VL = Elotuzumab DIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGT DFTLTI SSLQPEDVATYYCQQYSSYPYTFGQGTKVEI KAnti-Erbb2 - TrastuzumabSEQ ID NO: 219 - Anti-Erbb2-VH (Trastuzumab ) EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS SEQ ID NO: 220 - Anti-Erbb2-VL (Trastuzumab ) DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGT DFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKAnti-EpCAM antibodySEQ ID NO: 221 - Anti-EpCAM VHEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGK ATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGTTVTVSS SEQ ID NO: 222 - Anti-EpCAM VL ELVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRF TGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKLinkers used in the present inventionLinkers which can be used to connect VH and VL domains, and / or VH and VH domains, and / or VL and VL domains, and / or VH with human serum protein, and / or VL with human serum protein, and / or VH with Ig constant CH 1 domain, and / or VL with Ig constant CH1 domain, and / or VH with Ig constant CH2 domain, and / or VL with Ig constant CH2 domain, and / or VH with Ig constant CH3 domain, and / or VL with Ig constant CH3 domain, and / or VH with Ig constant CL domain, and / or VL with Ig constant CL domain with each other in the antibody construct of the present invention or which can be used to connect any human protein to a KeyLock antibody may include the following linkers:SEQ ID NO: 223A preferred linkers connecting the antibody VH - VL domains, VL - VH domains, VH - VH domains and VL - VL domains in the antibody constructs of the invention is as follows:GGGGSGGGGSGGGGSGGGGSSEQ ID NO: 224Alternative linker connecting antibody variable domainsGGGGSSEQ ID NO: 225Alternative linker connecting antibody variable domainsGGGGSGGGGSSEQ ID NO: 226Alternative linker connecting antibody variable domainsGGGGSGGGGSGGGGSEQ ID NO: 227Alternative linker connecting antibody variable domains GGGGSGGGGSGGGGGGGGSGGGGSSEQ ID NO: 228Alternative linker connecting antibody variable domains GGGGSGGGGSGGGGGGGGSGGGGSGGGGSSEQ ID NO: 229Linker connecting human albumin to a KeyLock antibody SGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGSEQ ID NO: 230Alternative linker connecting antibody variable domainsGSGGGGSGGGGSGGGGSSEQ ID NO: 231Alternative linker connecting antibody variable domains GSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSSEQ ID NO: 232Alternative linker connecting antibody variable domainsGSGGSGNSSGGGSSEQ ID NO: 233Alternative linker connecting antibody variable domains GSGGSGNSSGGGSGGGGSSEQ ID NO: 234Alternative linker connecting antibody variable domains GGGGSGSGGSGNSSGGGSGGGGSSEQ ID NO: 235Alternative linker connecting antibody variable domains GSGGGGNSSGGGGNSSGGGSSEQ ID NO: 236Alternative linker connecting antibody variable domains GGGGSGSGGGGNSSGGGGNSSGGGSGGGGSSEQ ID NO: 237Alternative linker connecting antibody variable domains AEAWYNLGNAYYKQGDYQKAIEYYQKALELDPNSEQ ID NO: 238Alternative linker connecting antibody variable domains PVPSTPPTPSPSTPPTPSPSSEQ ID NO: 239Alternative linker connecting antibody variable domains EPKSADKTHTAPPAPAPELLGGPSEQ ID NO: 240Alternative linker connecting antibody variable domains EAAAKEAAAKEAAAKSEQ ID NO: 241Alternative linker connecting antibody variable domains APAPAPAPAPAPAPSEQ ID NO: 242Alternative linker connecting antibody variable domains GKSSGSGSESKSSEQ ID NO: 243Alternative linker connecting antibody variable domains TSGSGKSSEGKGSEQ ID NO: 244Alternative linker connecting antibody variable domains GSTSGSGKSSEGSGSTKGSEQ ID NO: 245Alternative linker connecting antibody variable domainsGSTSGKPSEGKGSEQ ID NO: 246Alternative linker connecting antibody variable domains KESGSVSSEQLAQFRSLDSEQ ID NO: 247Alternative linker connecting antibody variable domains DHVPLTSEQ ID NO: 248Alternative linker connecting antibody variable domains DEYDPTIEDSYSEQ ID NO: 249Alternative linker connecting antibody variable domains TAGQEEYSAMRDQYMSEQ ID NO: 250Alternative linker connecting antibody variable domains PKRNKPTVYGVSPNYDKWEMERTDSEQ ID NO: 251Alternative linker connecting antibody variable domains RNKPTVYGVSPNYDKWEMERTSEQ ID NO: 252Alternative linker connecting antibody variable domainsLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDSEQ ID NO: 253Alternative linker connecting antibody variable domainsAPKRNKPTVYGVSPNYDKAlternative second linkers for the present inventionA second flexible linker can be used to covalently connect the linkers from Sequence 223 to 253 to the antibody variable domains, serum proteins and / or Ig constant domains, using standard techniques, in a single polypeptide chain, at the N-terminal and / or C-terminal end. Only one set or multiple set of linkers can be used in various combinations in one Keylock construct. KeyLock constructs with same or different linkers can be connected to any serum protein or constant Ig domains. The flexible linkers may include the following linkers:SEQ ID NO: 254Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GSSEQ ID NO: 255Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains SGSEQ ID NO: 256Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains ASSEQ ID NO: 257Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains SASEQ ID NO: 258Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GGGSEQ ID NO: 259Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GGSSEQ ID NO: 260Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains AAGAATAASEQ ID NO: 261Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains SGGSSEQ ID NO: 262Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains SGGGSSEQ ID NO: 263Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GSGSGSSEQ ID NO: 264Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GGSGGSEQ ID NO: 265Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GGSSGSEQ ID NO: 266Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GTSEQ ID NO: 267Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GSGGGTGGGSGSEQ ID NO: 268Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GGSGGSGGSGGSEQ ID NO: 269Alternative linker connecting linkers with antibody variable domains, serum proteins and / or Ig constant domains GGGGGAnti-CD3 antibodyIn a preferred embodiment, the antibody construct of the present invention may comprise the following VH and VL sequences of the following anti-CD3 antibodies:antiCD3 dil_2K antibodyVH - SEQ ID NO: 270 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSS VL - SEQ ID NO: 271 DIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTIN SLEAEDAATYYCQQWSSNPLTFGGGTKVEIKORantiCD3 humanized UCHT1 antibodyVH - SEQ ID NO: 272 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS VL- SEQ ID NO: 273 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIKIn a preferred embodiment, the VH and VL of the anti-CD3 antibody in the antibody construct comprise the following CDRs (A) or (B):(A)SEQ ID NO: 274 - UCHT1 VH CDR1-IMGT (27 - 38)GYSFTGYT SEQ ID NO: 275 - UCHT1 VH CDR2-IMGT (56 - 65)INPYKGVSSEQ ID NO: 276 - UCHT1 VH CDR3-IMGT (105 - 117) ARSGYYGDSDWYFDVSEQ ID NO: 277 - UCHT1 VL CDR1-IMGT (27 - 38) QDIRNY SEQ ID NO: 278 - UCHT1 VL CDR2-IMGT (56 - 65) YTS SEQ ID NO: 279 - UCHT1 VL CDR3-IMGT (105 - 117) QQGNTLPWTOR(B)SEQ ID NO: 280 - diL2K VH CDR1-IMGT (27 - 38) GYTFTRYT SEQ ID NO: 281 - diL2K VH CDR2-IMGT (56 - 65) INPSRGYT SEQ ID NO: 282 - diL2K VH CDR3-IMGT (105- 117) ARYYDDHYCLDYSEQ ID NO: 283 - diL2K VL CDR1-IMGT (27 - 38) QSVSY SEQ ID NO: 284 - diL2K VL CDR2-IMGT (56 - 65) DTS SEQ ID NO: 285 - diL2K VL CDR3-IMGT (105- 117) QQWSSNPLTAlbuminThe antibody construct of the present invention or the protein structure of the antibody construct of the present invention may further comprise albumin, single albumin-domains, albumin-binding domains and / or other plasma / serum proteins such as part of membrane proteins cleaved and detected in the plasma / serum.In a specific embodiment, the following albumin sequence may be used in accordance with the invention:SEQ ID NO: 286 - human albumin (excluding the signal peptide and propeptide sequence) DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLC TVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYF YAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFP KAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPA DLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLAKTYETTLEKCCAAADPHECYAKVFD EFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAE DYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQ TALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGLAdditional sequences which may be used in accordance with the invention include:SEQ ID NO: 287 - Secretion leader signal peptide for human albumin for KeyLock-albumin fusion constructs MAKWVTFISLLFLFSSAYSSEQ ID NO: 288 - Propeptide at N terminal end of human albumin. Propeptide, which is a part of a protein that is cleaved during maturation or activation. Once cleaved, a propeptide generally has no independent biological function.RGVFRRImmunoglobulin domainsThe antibody construct of the present invention may further comprise an immunoglobulin Fc region and / or an immunoglobulin constant region.In a specific embodiment, an immunoglobulin Fc region and / or an immunoglobulin constant region may comprise any one of the following sequences:SEQ ID NO: 289 - FC_Knop_WDN GGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQ VSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGKSEQ ID NO: 290 - FC_hole_WDN METDTLLVFVLLVWVPAGNGDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKF NWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVC TLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 291 - Human IGHG1 = CH1-CH2-CH3 (AS is for the Nhel restriction site) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKG QPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSPSEQ ID NO: 292 - Human kappa_light_chain = CL (AS is for the Nhel restriction site) ASAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGECExamples of the antibody construct of the present inventionIn a specific embodiment, the antibody construct may comprise any one of the following sequences:SEQ ID NO: 293 - T01 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIELTQP PSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGF TFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNM YRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDV GIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQGTK VEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLE WIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSSGG GGSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVA SGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGSHHHHHH SEQ ID NO: 294 - T02 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQ SPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPE DVATYYCQQYSSYPYTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAAS GFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPD GNYWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIELTQPPSVSVAPGQTARISCSGDNIGNKYVS WYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLG GGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNI YSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSSGG GGSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVA SGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGSHHHHHH SEQ ID NO: 295 - T03 DIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTIN SLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRL SCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARNMYRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIELTQPPSVSVAPGQTARISCS GDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSSYFVF GGGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAP GKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIY WASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQGTKVEIKGGGGSGGGGSGGGGS GGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGR FTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGSHHHHHH SEQ ID NO: 296 - T04DIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTIN SLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYY CARPDGNYWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQ DVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQG TKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGL EWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLV TVSSGGGGSGGGGSGGGGSGGGGSDIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIY GDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLGGGGSGGGGSGGGGS GGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGR FTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGSHHHHHHSEQ ID NO: 297 - T05 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQ SPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPED FATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGF NIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGG DGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKSSQSLLNS GNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGA GTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQRPGHG LEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGTTVTVS SGGGGSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTS KVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGSHHHHHH SEQ ID NO: 298 - T06 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQ SPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLT ISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKI SCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVY FCARLRNWDEPMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRAS QDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQG TKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLE WVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTS KVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 299 - T07 DIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTIN SLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRAS QDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQG TKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQRPGHGL EWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGTTVTVSS GGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGGGGSGGGGSGG GGSGGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSV KGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGSHHHHHHSEQ ID NO: 300 - T08 DIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTIN SLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKI SCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVY FCARLRNWDEPMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQ APGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAP KLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGG GGSGGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSV KGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGSHHHHHHSEQ ID NO: 301 - T05.2 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSC AASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCS RWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKSSQ SLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYP LTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQ RPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGT TVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKL LIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 302 - T06.2 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSE LVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSG TDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVR PGTSVKISCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTF EDSAVYFCARLRNWDEPMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRV TITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTP PTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQA PGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQG TLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPK LLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 303 - T07.2 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRAS QDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQG TKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQRPGHGL EWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGTTVTVSS GGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGGGGSGGGGSGG GGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKF KDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGSHHHHHHSEQ ID NO: 304 - T08.2 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKI SCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVY FCARLRNWDEPMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQ APGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQ GTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAP KLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGG GGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKF KDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGSHHHHHHIn another embodiment, the antibody construct of the present invention or the protein structure may comprise albumin, single albumin-domains, albumin-binding domains or plasma / serum proteins.Such an antibody construct may have the following sequence:SEQ ID NO: 305 - A1 +T01 MAKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAK TCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCT AFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCA SLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLK ECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLAK TYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVS RNLGKVGSKCCKHPEAKRMPCAEDYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKE FNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVA ASQAALGLSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGG GSGGGADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKG RFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGG SDIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTIS GTQAEDEADYYCSSYDSSYFVFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRL SCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVY YCARNMYRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTF GQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAP GKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVT VSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYD TSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 306 - A1 +T02 MAKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAK TCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCT AFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLP KLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECA DDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMF LYEYARRHPDYSWLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNA LLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSWLNQLCVLHEKTPVSDRVTKCCTESL VNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEK CCKADDKETCFAEEGKKLVAASQAALGLSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGG GGSGGGGSGGGGSGGGGSGGGADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLE WIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGG GGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRH TGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNA KNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIELTQP PSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDE ADYYCSSYDSSYFVFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGF TFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNM YRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVS YMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKV EIKGSHHHHHHSEQ ID NO: 307 - A1 +T03 MAKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAK TCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCT AFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLK ECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLAK TYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVS RNLGKVGSKCCKHPEAKRMPCAEDYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKE FNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVA ASQAALGLSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGG GSGGGADIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGS GTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLV QPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNS LRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIELTQPPSVSVAP GQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSS YDSSYFVFGGGTKLTVLGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWM SWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVW GQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGK VPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQGTKVEIKGGGGSGGGG SGGGGSGGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYA DSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGSHHHHHHSEQ ID NO: 308 - A1 +T04 MAKWVTFISLLFLFSSAYSRGVFRRDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAK TCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCT AFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCA SLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLK ECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSWLLLRLAK TYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVS RNLGKVGSKCCKHPEAKRMPCAEDYLSWLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKE FNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVA ASQAALGLSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGG GSGGGADIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGS GTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLV QPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLR AEDTAVYYCARPDGNYWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRV TITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSY PYTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVR QAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPG QAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLGGGGSGGG GSGGGGSGGGGSDVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNY ADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGSHHHHHHAdditional SequencesWhen producing the antibody construct of the present invention, the following sequences may be used:SEQ ID NO: 309 - Eukaryote secretion leaderMETDTLLVFVLLVWVPAGNGSEQ ID NO: 310 - Fusion prokaryote production leader protein Thioredoxin-1 :E. coli, P0AA25 MSDKIIHLTDDSFDTDVLKADGAILVDFWAEWCGPCKMIAPILDEIADEYQGKLTVAKLNIDQNPGTAPKYGIRGIPT LLLFKNGEVAATKVGALSKGQLKEFLDANLAGGSGGGGGSLEVLFQGPMSEQ ID NO: 311 - Linker for connecting prokaryote Thioredoxin-1 :E. coli, P0AA25, to 3C protease domain GGSGGGGGSSEQ ID NO: 312 - 3C protease domain for cutting off the prokaryote Thioredoxin-1 from the KeyLock antibody LEVLFQGPMSEQ ID NO: 313 - Amino acid linker for Kasl restriction site, connecting secretion leader and / or human albumin with KeyLock antibodiesGAHistidine tags which may be used in accordance with the present invention include:SEQ ID NO: 314 - Preferred Histidin tag = 6x His tagGSHHHHHHSEQ ID NO: 315 - Alternative Histidin tag = 8x His tagGSHHHHHHHHSEQ ID NO: 316 - Alternative Histidin tag = 6x His tagHHHHHHSEQ ID NO: 317 - Alternative Histidin tag = 4x His tagHHHHSEQ ID NO: 318 - Alternative Histidin tag = 4x His tagGSHHHHSEQ ID NO: 319 - Alternative Histidin tag = 10x His tagGSHHHHHHHHHHBiTE antibodies which were used as controls for the target cell killing experiments include the following antibodies. The BiTE antibodies are IgG antibodies in the knob-hole format. The “Fc_Knob_antiCD3_UCHT1” (SEQ ID NO: 325) was paired with the "Fc_hole” constructs. The "Fc_hole” constructs are against SLAMF7, CD38, EpCAM and Her2, respectively:SEQ ID NO: 325 Fc_Knob_antiCD3_UCHT1GP EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQS PSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQQGNTLPWTFGQGTKVEIK GS GGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNA KTKPREEQYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGKSEQ ID NO: 326 Fc_hole_anti_SLAMF7 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK GS GGS EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNA KNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLS ASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYY CQQYSSYPYTFGQGTKVEIKGSHHHHHHSEQ ID NO: 327 Fc_hole_anti_CD38 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK GS GGS QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRD NSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIELTQPP SVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEA DYYCSSYDSSYFVFGGGTKLTVLGQGSHHHHHHSEQ ID NO: 328 Fc_hole_anti_EpCAM DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK GS GGS EVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADK SSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQ SPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLT ISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGSHHHHHHSEQ ID NO: 329 Fc_hole_anti_Her2 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK GS GGS EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTS KNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPE DFATYYCQQHYTTPPTFGQGTKVEIKGSHHHHHH SEQUENCESSEQ ID NO: 330 Lx_Split_CD3_Her2 (Diabody back bone, antiCD3-antiHer2, eukaryote secretion leader underlined, amino acids for BamHI restriction site in bold) METDTLLVFVLLVWVPAGNGDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLES GVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 331 Anti-Her2 VH (Pertuzumab) EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSSEQ ID NO: 332 Anti-Her2 VL (Pertuzumab) DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRSEQ ID NO: 333 Diabody linker L1GG SEQ ID NO: 334 Diabody linker L2GGGGSGGSSEQ ID NO: 335 Diabody linker L3 DEYDPTIEDSY SEQ ID NO: 336 Diabody linker L4 GGGGSGGGGSGGG SEQ ID NO: 337 Diabody linker L5 DYMERWYRYYNEF SEQ ID NO: 338 Diabody linker L6 GSTSGSGKSSEGKG SEQ ID NO: 339 Diabody linker L7 GGSGGGGSGGGGSGGG SEQ ID NO: 340 Diabody linker L8 GGGGNSSGGGGNSSGG SEQ ID NO: 341 Diabody linker L9 GSTSGSGKSSEGSGSTKG SEQ ID NO: 342 Diabody linker L10 GSTSGSGKPGSGEGSTKG SEQ ID NO: 343 Diabody linker L11 KESGSVSSEQLAQFRSLD SEQ ID NO: 344 Diabody linker L12 GEGTSTGSGGSGGSGGAD SEQ ID NO: 345 Diabody linker L13 LGQPKSSPSVTLFPPSSNG SEQ ID NO: 346 Diabody linker L14 PVPSTPPTPSPSTPPTPSPS SEQ ID NO: 347 Diabody linker L15 PKRNKPTVYGVSPNYDKWEMERTD SEQ ID NO: 348 Diabody linker L16 PGGNRGTTRPATSGSSPGPTNSHY SEQ ID NO: 349 Diabody linker L17 EPKSADKTHTAPPAPAPELLGGP SEQ ID NO: 350 Diabody linker L18 SSADDAKKDAAKKDDAKKDDAKKDGSEQ ID NO: 351 Diabody linker L19GGGGSGGGGSGGGGSGGGGSGGGGSGGG SEQ ID NO: 352 Diabody linker L20PGGNRGTTTTRRPATTTGSSPGPTQSHYSEQ ID NO: 353 Diabody L1 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 354 Diabody L2 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GGGGSGGS GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 355 Diabody L3 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS DEYDPTIEDSY GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 356 Diabody L4 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GGGGSGGGGSGGG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 357 Diabody L5 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS DYMERWYRYYNEF GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 358 Diabody L6 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GSTSGSGKSSEGKG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 359 Diabody L7 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GGSGGGGSGGGGSGGG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 360 Diabody L8 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GGGGNSSGGGGNSSGG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 361 Diabody L9 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GSTSGSGKSSEGSGSTKG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 362 Diabody L10 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GSTSGSGKPGSGEGSTKG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 363 Diabody L11 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS KESGSVSSEQLAQFRSLD GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 364 Diabody L12 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GEGTSTGSGGSGGSGGAD GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 365 Diabody L13 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS LGQPKSSPSVTLFPPSSNG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 366 Diabody L14 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS PVPSTPPTPSPSTPPTPSPS GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 367 Diabody L15 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS PKRNKPTVYGVSPNYDKWEMERTD GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 368 Diabody L16 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS PGGNRGTTRPATSGSSPGPTNSHY GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 369 Diabody L17 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS EPKSADKTHTAPPAPAPELLGGP GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 370 Diabody L18 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS SSADDAKKDAAKKDDAKKDDAKKDG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 371 Diabody L19 DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS GGGGSGGGGSGGGGSGGGGSGGGGSGGG GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 372 Diabody L20DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTIS SLQPEDFATYYCQQGNTLPWTFGQGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQRFKGRFTLSVD RSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSS GS PGGNRGTTTTRRPATTTGSSPGPTQSHY GS DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTIS SLQPEDFATYYCQQYYIYPYTFGQGTKVEIKR GGGGSGGGGSGGGGSGGGGS EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSS GS HHHHHHSEQ ID NO: 373 PCR_primer_diL2K_mutant_T35L_diL2K_Fwd GCCTGTCGGACCCAGTGCATTAGGTATCTGGTAAAGGTGTAGCSEQ ID NO: 374 PCR_primer_diL2K_mutant_T35L_diL2K_Rev GCTACACCTTTACCAGATACCTAATGCACTGGGTCCGACAGGCSEQ ID NO: 375 PCR_primer_diL2K_mutant_N54A_diL2K_Fwd AGCCCCGAGAGGGGGCGATGTAGCCGATCCSEQ ID NO: 376 PCR_primer_diL2K_mutant_N54A_diL2K_Rev GGATCGGCTACATCGCCCCCTCTCGGGGCTSEQ ID NO: 377 PCR_primer_diL2K_mutant_N54l_diL2K_Fwd CCGAGAGGGGATGATGTAGCCGATCCACTCSEQ ID NO: 378 PCR_primer_diL2K_mutant_N54l_diL2K_Rev GAGTGGATCGGCTACATCATCCCCTCTCGGSEQ ID NO: 379 PCR_primer_diL2K_mutant_S56A_diL2K_VH_Fwd GGTGTAGCCCCGAGCGGGGTTGATGTAGCSEQ ID NO: 380 PCR_primer_diL2K_mutant_S56A_diL2K_VH_Rev GCTACATCAACCCCGCTCGGGGCTACACCSEQ ID NO: 381 PCR_primer_diL2K_mutant_Y59N_diL2K_VH_FwdGCGTAGTTGGTGTTGCCCCGAGAGGGGSEQ ID NO: 382 PCR_primer_diL2K_mutant_Y59N_diL2K_VH_Rev CCCCTCTCGGGGCAACACCAACTACGCSEQ ID NO: 383 PCR_primer_diL2K_mutant_K76A_diL2K_VH_Fwd CGGTGGAGGTGGACGCGTCGGTGGTGATGGSEQ ID NO: 384 PCR_primer_diL2K_mutant_K76A_diL2K_VH_Rev CCATCACCACCGACGCGTCCACCTCCACCGSEQ ID NO: 385 PCR_primer_diL2K_mutant_D103Q_diL2K_VH_Fwd AGGCAGTAGTGGTCCTGGTAGTACCGGGCACSEQ ID NO: 386 PCR_primer_diL2K_mutant_D103Q_diL2K_VH_Rev GTGCCCGGTACTACCAGGACCACTACTGCCTSEQ ID NO: 387 PCR_primer_diL2K_mutant_Y106V_diL2K_VH_Fwd CCCAATAATCCAGGCAGACGTGGTCGTCGTAGTACCSEQ ID NO: 388 PCR_primer_diL2K_mutant_Y106V_diL2K_VH_Rev GGTACTACGACGACCACGTCTGCCTGGATTATTGGGSEQ ID NO: 389 PCR_primer_diL2K_mutant_S166A_diL2K_VL_Fwd ATACCAGTTCATGTAAGCCACGGACTGAGAGGCTC SEQ ID NO: 390 PCR_primer_diL2K_mutant_S166A_diL2K_VL_Rev GAGCCTCTCAGTCCGTGGCTTACATGAACTGGTATSEQ ID NO: 391 PCR_primer_diL2K_mutant_Y167A_diL2K_VL_Fwd TGCTGATACCAGTTCATGGCAGACACGGACTGAGAGGCSEQ ID NO: 392 PCR_primer_diL2K_mutant_Y167A_diL2K_VL_RevGAGCCTCTCAGTCCGTGGCTTACATGAACTGGTATSEQ ID NO: 393 PCR_primer_diL2K_mutant_D185L_diL2K_VL_Fwd GAGGCCACCTTGGAGGTTAGGTAGATCCACCGCTTAGSEQ ID NO: 394 PCR_primer_diL2K_mutant_D185L_diL2K_VL_Rev CTAAGCGGTGGATCTACCTAACCTCCAAGGTGGCCTCSEQ ID NO: 395 PCR_primer_UCHT1_mutant_S30L_UCHT1_VH_Fwd GGTGTAGCCGGTGAATAAGTAGCCGGAGGCGGSEQ ID NO: 396 PCR_primer_UCHT1_mutant_S30L_UCHT1_VH_Rev CCGCCTCCGGCTACTTATTCACCGGCTACACCSEQ ID NO: 397 PCR_primer_UCHT1_mutant_G33R_UCHT1_VH_Fwd CAGTTCATGGTGTAGCGGGTGAAAGAGTAGCCGSEQ ID NO: 398 PCR_primer_UCHT1_mutant_G33R_UCHT1_VH_Rev CGGCTACTCTTTCACCCGCTACACCATGAACTGSEQ ID NO: 399 PCR_primer_UCHT1_mutant_L52R_UCHT1_VH_Fwd CTTATAGGGGTTGATCCGGGCGACCCATTCCAGSEQ ID NO: 400 PCR_primer_UCHT1_mutant_L52R_UCHT1_VH_Rev CTGGAATGGGTCGCCCGGATCAACCCCTATAAGSEQ ID NO: 401 PCR_primer_UCHT1_mutant_K57S_UCHT1_VH_Fwd GTGGACACGCCGCTATAGGGGTTGATCAGGGCGASEQ ID NO: 402 PCR_primer_UCHT1_mutant_K57S_UCHT1_VH_Rev TCGCCCTGATCAACCCCTATAGCGGCGTGTCCACSEQ ID NO: 403 PCR_primer_UCHT1_mutant_V59S_UCHT1_VH_Fwd CTTCTGGTTGTAGGTGGACGAGCCCTTATAGGGGTTGATCSEQ ID NO: 404 PCR_primer_UCHT1_mutant_V59S_UCHT1_VH_Rev GATCAACCCCTATAAGGGCTCGTCCACCTACAACCAGAAGSEQ ID NO: 405 PCR_primer_UCHT1_mutant_Y104W_UCHT1_VH_Fwd CGGAGTCGCCCCAGTAGCCGCTTCTAGCACASEQ ID NO: 406 PCR_primer_UCHT1_mutant_Y104W_UCHT1_VH_Rev TGTGCTAGAAGCGGCTACTGGGGCGACTCCGSEQ ID NO: 407 PCR_primer_UCHT1_mutant_R169E_UCHT1_VL_Fwd ACCAGTTCAGGTAGTTCTCGATGTCCTGAGAGGCTCSEQ ID NO: 408 PCR_primer_UCHT1_mutant_R169E_UCHT1_VL_Rev GAGCCTCTCAGGACATCGAGAACTACCTGAACTGGTSEQ ID NO: 409 PCR_primer_UCHT1_mutant_Y171A_UCHT1_VL_Fwd GCTGATACCAGTTCAGGGCGTTCCGGATGTCCTGAGSEQ ID NO: 410 PCR_primer_UCHT1_mutant_Y171A_UCHT1_VL_Rev CTCAGGACATCCGGAACGCCCTGAACTGGTATCAGCSEQ ID NO: 411 PCR_primer_UCHT1_mutant_Y171 F_UCHT1_VL_Fwd GATACCAGTTCAGGAAGTTCCGGATGTCCTGAGASEQ ID NO: 412 PCR_primer_UCHT1_mutant_Y171F_UCHT1_VL_Rev TCTCAGGACATCCGGAACTTCCTGAACTGGTATCSEQ ID NO: 413 PCR_primer_UCHT1_mutant_N231A_UCHT1_VL_Fwd GTCCAAGGCAGGGTGGCGCCCTGCTGGCAATASEQ ID NO: 414 PCR_primer_UCHT1_mutant_N231A_UCHT1_VL_Rev TATTGCCAGCAGGGCGCCACCCTGCCTTGGACSEQ ID NO: 415 UCHT 1_WT used for in silico mutant generation GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVS TYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQG TKVEIKGSHHHHHHHHSEQ ID NO: 416 UCHT1_WT_CDR_kabat GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVS TYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQG TKVEIKGSHHHHHHHHSEQ ID NO: 417 UCHT1_WT_CDR_chothia GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVS TYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQG TKVEIKGSHHHHHHHHSEQ ID NO: 418 UCHT1_WT_CDR_IMGT GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVS TYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 419 diL2K_WT used for in silico mutant generation GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYT NYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPK RWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVE IKGSHHHHHHHHSEQ ID NO: 420 diL2K_WT_CDR_kabat GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYT NYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPK RWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVE IKGSHHHHHHHHSEQ ID NO: 421 diL2K_WT_CDR_chothia GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYT NYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSySYMNWYQQKPGKAPK RWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVE IKGSHHHHHHHHSEQ ID NO: 422 diL2K_WT_CDR_IMGT GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYT NYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSySYMNWYQQKPGKAPK RWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVE IKGSHHHHHHHHSEQ ID NO: 423 UCHT1_WT_VH_kabat CDR-H1GYTMNSEQ ID NO: 424 UCHT1_WT_VH_kabat CDR-H2 LINPYKGVSTYNQKFKDSEQ ID NO: 425 UCHT1_WT_VH_kabat CDR-H3 SGYYGDSDWYFDVSEQ ID NO: 426 UCHT1_WT_VL_kabat CDR-L1 RASQDIRNYLNSEQ ID NO: 427 UCHT1_WT_VL_kabat CDR-L2 YTSRLESSEQ ID NO: 428 UCHT1_WT_VL_kabat CDR-L3 QQGNTLPWTSEQ ID NO: 429 UCHT1_WT_VH_Chothia CDR-H1 GYSFTGYSEQ ID NO: 430 UCHT1_WT_VH_Chothia CDR-H2 PYKGVSEQ ID NO: 431 UCHT1_WT_VH_Chothia CDR-H3 SGYYGDSDWYFDVSEQ ID NO: 432 UCHT1_WT_VL_Chotia CDR-L1 SQDIRNYSEQ ID NO: 433 UCHT1_WT_VL_Chotia CDR-L2 YTSSEQ ID NO: 434 UCHT1_WT_VL_Chotia CDR-L3GNTLPWSEQ ID NO: 435 UCHT1_WT_VH_IMGT CDR-H1 GYSFTGYTSEQ ID NO: 436 UCHT1_WT_VH_IMGT CDR-H2 INPYKGVSSEQ ID NO: 437 UCHT1_WT_VH_IMGT CDR-H3 ARSGYYGDSDWYFDVSEQ ID NO: 438 UCHT1_WT_VL_IMGT CDR-L1 QDIRNYSEQ ID NO: 439 UCHT1_WT_VL_IMGT CDR-L2 YTSSEQ ID NO: 440 UCHT1_WT_VL_IMGT CDR-L3 QQGNTLPWTSEQ ID NO: 441 diL2K_WT_VH_kabat CDR-H1 RYTMHSEQ ID NO: 442 diL2K_WT_VH_kabat CDR-H2 YINPSRGYTNYADSVKGSEQ ID NO: 443 diL2K_WT_VH_kabat CDR-H3 YYDDHYCLDYSEQ ID NO: 444 diL2K_WT_VL_kabat CDR-L1 RASQSVSYMNSEQ ID NO: 445 diL2K_WT_VL_kabat CDR-L2 DTSKVASSEQ ID NO: 446 diL2K_WT_VL_kabat CDR-L3 QQWSSNPLTSEQ ID NO: 447 diL2K_WT_VH_Chothia CDR-H1 GYTFTRYSEQ ID NO: 448 diL2K_WT_VH_Chothia CDR-H2 PSRGYSEQ ID NO: 449 diL2K_WT_VH_Chothia CDR-H3 YYDDHYCLDYSEQ ID NO: 450 diL2K_WT_VL_Chotia CDR-L1 SQSVSYSEQ ID NO: 451 diL2K_WT_VL_Chotia CDR-L2 DTSSEQ ID NO: 452 diL2K_WT_VL_Chotia CDR-L3 WSSNPLSEQ ID NO: 453 diL2K_WT_VH_IMGT CDR-H1 GYTFTRYTSEQ ID NO: 454 diL2K_WT_VH_IMGT CDR-H2 INPSRGYTSEQ ID NO: 455 diL2K_WT_VH_IMGT CDR-H3 ARYYDDHYCLDYSEQ ID NO: 456 diL2K_WT_VL_IMGT CDR-L1QSVSYSEQ ID NO: 457 diL2K_WT_VL_IMGT CDR-L2DTSSEQ ID NO: 458 diL2K_WT_VL_IMGT CDR-L3QQWSSNPLTSEQ ID NO: 459 SFV01 anti-CD3(diL2K)_T35L GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYiMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 460 SFV01 anti-CD3(diL2K)_N54A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYlJPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 461 SFV01 anti-CD3(dil_2K)_N54l GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYl|PSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 462 SFV01 anti-CD3(diL2K)_S56A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPARGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 463 SFV01 anti-CD3(diL2K)_Y59N GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGNTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 464 SFV01 anti-CD3(diL2K)_K76A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DASTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 465 SFV01 anti-CD3(diL2K)_D103Q GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYQDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 466 SFV01 anti-CD3(diL2K)_Y106V GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHVCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 467 SFV01 anti-CD3(diL2K)_S166A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVAYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 468 SFV01 anti-CD3(diL2K)_Y167A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSAMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 469 SFV01 anti-CD3(diL2K)_D185L GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYLTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSHHHHHHSEQ ID NO: 470 SFV0102 anti-CD3(UCHT1)_S30L GAEVQLVESGGGLVQPGGSLRLSCAASGYLFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 471 SFV0102 anti-CD3(UCHT1)_G33R GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTRYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 472 SFV0102 anti-CD3(UCHT1)_L52R GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVARINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 473 SFV0102 anti-CD3(UCHT1)_K57S GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYSGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 474 SFV0102 anti-CD3(UCHT1)_V59S GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGSSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 475 SFV0102 anti-CD3(UCHT1)_Y104W GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYWGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 476 SFV0102 anti-CD3(UCHT1)_R169E GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIENYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 477 SFV0102 anti-CD3(UCHT1)_Y171A GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNALNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 478 SFV0102 anti-CD3(UCHT1)_Y171F GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNFLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 479 SFV0102 anti-CD3(UCHT1)_N231A GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGATLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 480 UCHT1_H1 EVQLVESGGGLVQPGGSLRLSCAASSGGSGTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKS KNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPS SLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFAT YYCQQGNTLPWTFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 481 UCHT1_H2 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALISGVSTYNQKFKDRFTISVDKSK NTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSS LSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATY YCQQGNTLPWTFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 482 UCHT1_H3 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVG DRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQG NTLPWTFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 483 UCHT1_L1 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQS PSSLSASVGDRVTITCRSGGSGNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATY YCQQGNTLPWTFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 484 UCHT1_L2 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQS PSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYSGGSGGVPSRFSGSGSGTDYTLTISSLQPEDFA TYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 485 UCHT1_L3 EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQS PSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDF ATYYCQSGFGQGTKVEIKGSHHHHHHHHSEQ ID NO: 486 diL2K_H1 DVQLVQSGAEVKKPGASVKVSCKASSGGSGTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKS TSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSLS PGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYC QQWSSNPLTFGGGTKVEIKGSHHHHHHHHSEQ ID NO: 487 diL2K_H2 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYISGYTNYADSVKGRFTITTDKSTS TAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPG ERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQ WSSNPLTFGGGTKVEIKGSHHHHHHHHSEQ ID NO: 488 diL2K_H3 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYSGLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGE RATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQW SSNPLTFGGGTKVEIKGSHHHHHHHHSEQ ID NO: 489 diL2K_L1 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRSGGSGNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQ WSSNPLTFGGGTKVEIKGSHHHHHHHHSEQ ID NO: 490 dil_2K_L2 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSL SPGERATLSCRASQSVSYMNWYQQKPGKAPKRWISGGASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQ WSSNPLTFGGGTKVEIKGSHHHHHHHHSEQ ID NO: 491 diL2K_L3 DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDK STSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATLSL SPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYC SGFGGGTKVEIKGSHHHHHHHHSEQ ID NO: 492 Fc_hole_CD38 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGSGGSQVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSSGGGGSGGGGSGGG GSDIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVWIYGDNNRPSGIPERFSGSNSGNTATLT ISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLGQGSHHHHHHSEQ ID NO: 493 Fc_hole_Her2 DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGSGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQR FKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSDIQMTQSPSSLSASVGDR VTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYIY PYTFGQGTKVEIKRGSHHHHHHSEQ ID NO: 494 Fc_knop SFV01 (diL2K)_WT_VH / VL GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYT NYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVS SGGGGSGGGGSGGGGSDIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPK RWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVESEQ ID NO: 495 Fc_knop SFV01 (diL2K)_WT_VL / VH GADIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPK RWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATYYCQQWSSNPLTFGGGTKVE IKGGGGSGGGGSGGGGS DVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYT NYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVS SGSGGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFIIWYVDGVEV HNAKTKPREEQYASTYRVVSVLTVLHQDWLflGKEYKCKVSflKALAAPIEKTISKAKGQPREPQVYTLPPCRDELT KNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGKSEQ ID NO: 496 Fc_knop SFV0102 (UCHT1)_WT_VH / VL GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVS TYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLV TVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQG TKVEIKGSGGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVD GVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCR DELTKNQVSLWCLVKGFYPSDI AVEWESI IGQPEI IMYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGKSEQ ID NO: 497 Fc_knop SFV0102 (UCHT1)_WT_VL / VH GADIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPG KAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQG TKVEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALI NPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLV TVSSGSGGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLMGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCRD ELTKNQVSLWCLVKGFYPSDIAVEWESMGQPENIIYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGKSEQ ID NO: 498 Fc_knop SFV01 (diL2K)_N54A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYI jPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSGGGGGS ■ . AA ■ . . ■ . ■ ■ ■ VSHEDPEVKFNWYVDGVEVHIIAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKASEQ ID NO: 499 Fc_knop SFV01 (dil_2K)_N54l GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYl|PSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSGGGGGS ■ . AA ■ . . ■ . ■ ■ ■ VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPEI INYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 500 Fc_knop SFV01 diL2K)_S56A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPARGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSGGGGGS ■ . AA ■ . . ■ . ■ ■ ■ VSHEDPEVKFNWYVDGVEVHIIAKTKPREEQYASTYRVVSVLTVLHQDWLIIGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPEI INYKTTPPVLDSDGSFFLYSKLTVD KSR -A / Q QG P IVFSCSVMHEALHt IHYTQKSLSLSPGKSEQ ID NO: 501 Fc_knop SFV01 (diL2K)_Y167A GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSAMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSGGGGGS ■ . AA ■ . . ■ . ■ ■ ■ VSHEDPEVKFNWYVDGVEVHIIAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESI IGQPENI IY KTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 502 Fc_knop SFV01 (diL2K)_D185L GADVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITT DKSTSTAYMELSSLRSEDTATYYCARYYDDHYCLDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIVLTQSPATL SLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYLTSKVASGVPARFSGSGSGTDYSLTINSLEAEDAATY YCQQWSSNPLTFGGGTKVEIKGSGGGGGS"VSHEDPEVKFNWYVDGVEVHI1AKTKPREEQYASTYRVVSVLTVLHQDWLI1GKEYKCKVSNKALAAPIEKTISKA KGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESI1GQPEI1NYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGI1VFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 503 Fc_knop SFV0102 (UCHT1)_S30L GAEVQLVESGGGLVQPGGSLRLSCAASGYLFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSGGGC ■■ AA ■ " ■ ■ CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEK TISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPEIINYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGI IVFSCSVMHEALHI IHYTQKSLSLSPGKSEQ ID NO: 504 Fc_knop SFV0102 (UCHT1)_G33R GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTRYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSGGGC ■■ AA ■ " ■ ■ CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSIIKALAAPIEK TISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGI IVFSCSVMHEALHI IHYTQKSLSLSPGKSEQ ID NO: 505 Fc_knop SFV0102 (UCHT1)_L52R GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVARINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSGGGC ■■ AA ■ " ■ ■ CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSIIKALAAPIEK TISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGI IVFSCSVMHEALHI IHYTQKSLSLSPGKSEQ ID NO: 506 Fc_knop SFV0102 (UCHT1)_Y171A GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNALNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSGGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSIIKALAAPIEK TISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESIIGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGI IVFSCSVMHEALHI IHYTQKSLSLSPGKSEQ ID NO: 507 Fc_knop SFV0102 (UCHT1)_Y171 FGAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMT QSPSSLSASVGDRVTITCRASQDIRNFLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPE DFATYYCQQGNTLPWTFGQGTKVEIKGSGGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALAAPIEK TISKAKGQPREPQVYTLPPCRDELTKI1QVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGflVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 508 split_KeyLock SFV0102 (UCHT1) VH_WT_aHer2 VLA / H_aEpCAM VL / VH GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTI SSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWV KQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQ GTTVTVSSGSHHHHHHSEQ ID NO: 509 split_KeyLock SFV0102 (UCHT1) VH_S30L_ aHer2 VL / VH_aEpCAM VL / VH GAEVQLVESGGGLVQPGGSLRLSCAASGYLFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTI SSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWV KQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQ GTTVTVSSGSHHHHHHSEQ ID NO: 510 split_KeyLock SFV0102 (UCHT1) VH_G33R_ aHer2 VLA / H_aEpCAM VLA / H GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTRYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTI SSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWV KQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQ GTTVTVSSGSHHHHHHSEQ ID NO: 511 split_KeyLock SFV0102 (UCHT1) VH_K57S_ aHer2 VL / VH_aEpCAM VL / VH GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYSGVSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTI SSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWV KQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQ GTTVTVSSGSHHHHHHSEQ ID NO: 512 split_KeyLock SFV0102 (UCHT1) VH_V59S_ aHer2 VLA / H_aEpCAM VL / VH GAEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGSSTYNQKFKDRFTIS VDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGG SDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTI SSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRL SCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYY CSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKS SQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYS YPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWV KQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQ GTTVTVSSGSHHHHHHSEQ ID NO: 513 split_KeyLock SFV0102 (UCHT1) VH_H1_ aHer2 VLA / H_aEpCAM VL / VH GAEVQLVESGGGLVQPGGSLRLSCAASSGGSGTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISS LQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSC AASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCS RWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSCKSSQ SLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYP LTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLGWVKQ RPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYWGQGT TVTVSSGSHHHHHHSEQ ID NO: 514 split_KeyLock SFV0102 (UCHT1) aHer2 VL / VH_aEpCAM VLA / H_VL_WT GADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTL TISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAV YYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLG WVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYW GQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGK APKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 515 split_KeyLock SFV0102 (UCHT1) aHer2 VL / VH_aEpCAM VLA / H_VL_Y171A GADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTL TISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAV YYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQND YSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLG WVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYW GQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNALNWYQQKPGK APKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 516 split_KeyLock SFV0102 (UCHT1) aHer2 VL / VH_aEpCAM VL / VH_VL_N231A GADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTL TISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAV YYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQND YSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLG WVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYW GQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGK APKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGATLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 517 split_KeyLock SFV0102 (UCHT1) aHer2 VL / VH_aEpCAM VLA / H_VL_L3 GADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTL TISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAV YYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQND YSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLG WVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYW GQGTTVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGK APKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQSGFGQGTKVEIKGSHHHHHHSEQ ID NO: 518 KeyLock T05VH (empty back bone) > aHer2 VL / VH_aEpCAM VL / 'GGGGSGGGGSGGGGADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQL VESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTA YLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPS SLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISC KASGYAFTNYWLGWVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFC ARLRNWDEPMDYWGQGTTVTVSSGSHHHHHHSEQ ID NO: 519 KeyLock T05VL (empty back bone) oHer2 VLA / H_oEpCAM VLA / H_ GADIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTL TISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSL RLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAV YYCSRWGGDGFYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSELVMTQSPSSLTVTAGEKVTMSC KSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQND YSYPLTFGAGTKLEIKGGGGSGGGGSGGGGSGGGGSEVQLLEQSGAELVRPGTSVKISCKASGYAFTNYWLG WVKQRPGHGLEWIGDIFPGSGNIHYNEKFKGKATLTADKSSSTAYMQLSSLTFEDSAVYFCARLRNWDEPMDYW GQGTTVTVSSGGGGSGGGGSGGGGSSEQ ID NO: 520 Fc_knop empty back bone GSGGGGGSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFIIWYVDGVEVH IIAKTKPREEQYASTYRVVSVLTVLHQDWLfIGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPCRDELTK NQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGIIVFSCSVMHEALHSEQ ID NO: 521 Fc_hole empty back bone DKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYASTYRWSVLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKGSGGSEQ ID NO: 522 SFV01 (diL2K)_WT_VL / VH GADIVLTQSPATLSLSPGERATLSCRASQSVSYMNWYQQKPGKAPKRWIYDTSKVASGVPARFSGSGSGTDYSL TINSLEAEDAATYYCQQWSSNPLTFGGGTKVEIKGGGGSGGGGSGGGGSDVQLVQSGAEVKKPGASVKVSCKA SGYTFTRYTMHWVRQAPGQGLEWIGYINPSRGYTNYADSVKGRFTITTDKSTSTAYMELSSLRSEDTATYYCARY YDDHYCLDYWGQGTTVTVSSGSHHHHHHSEQ ID NO: 523 SFV0102 (UCHT1)_WT_VLA / H GADIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTL TISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCA ASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCA RSGYYGDSDWYFDVWGQGTLVTVSSGSHHHHHHSEQ ID NO: 524 KeyLock wild-type = VH(UCHT1)-WT_VL(UCHT1)-WT EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISS LQ PEDFATYYCQ QHYTTPPTFG QGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQL VESGGGLVQP GGSLRLSCAASGFNIKDTYI HWVRQAPGKG LEWVARIYPT NGYTRYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCSRWGGDGF YAMDYWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSE L V M T Q S P S S L T V T A G E K V T M S C K S S Q S L L N S G N Q K N Y L T W Y Q Q K P G Q P P K L L I Y W A S T R E S G V P D R F T G S G S G T D F T L T I S S V Q A E D L A V Y Y C Q N D Y S Y P L T F G A G T K L E I K GGGGSGGGGSGGGGSGGGGS E V Q L L E Q S G A E L V R P G T S V K I S C K A S G Y A F T N Y W L G W V K Q R P G H G L E W I G D I F P G S G N I H Y N E K F K G K A T L T A D K S S S T A Y M Q L S S L T F E D S A V Y F C A R L R N W D E P M D Y W G Q G T T V T V S SGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTS RLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 525 KeyLock mutant = VH(UCHT1)-WT_VL(UCHT1)-R169E EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISS LQ PEDFATYYCQ QHYTTPPTFG QGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQL VESGGGLVQP GGSLRLSCAASGFNIKDTYI HWVRQAPGKG LEWVARIYPT NGYTRYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCSRWGGDGF YAMDYWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSE L V M T Q S P S S L T V T A G E K V T M S C K S S Q S L L N S G N Q K N Y L T W Y Q Q K P G Q P P K L L I Y W A S T R E S G V P D R F T G S G S G T D F T L T I S S V Q A E D L A V Y Y C Q N D Y S Y P L T F G A G T K L E I K GGGGSGGGGSGGGGSGGGGS E V Q L L E Q S G A E L V R P G T S V K I S C K A S G Y A F T N Y W L G W V K Q R P G H G L E W I G D I F P G S G N I H Y N E K F K G K A T L T A D K S S S T A Y M Q L S S L T F E D S A V Y F C A R L R N W D E P M D Y W G Q G T T V T V S SGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIENYLNWYQQKPGKAPKLLIYYTS RLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 526 KeyLock mutant = VH(UCHT1)-WT_VL(UCHT1)-Y171A EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYKGVSTYNQKFKDRFTISVD KSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDI QMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISS LQ PEDFATYYCQ QHYTTPPTFG QGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQL VESGGGLVQP GGSLRLSCAASGFNIKDTYI HWVRQAPGKG LEWVARIYPT NGYTRYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCSRWGGDGF YAMDYWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSE L V M T Q S P S S L T V T A G E K V T M S C K S S Q S L L N S G N Q K N Y L T W Y Q Q K P G Q P P K L L I Y W A S T R E S G V P D R F T G S G S G T D F T L T I S S V Q A E D L A V Y Y C Q N D Y S Y P L T F G A G T K L E I K GGGGSGGGGSGGGGSGGGGS E V Q L L E Q S G A E L V R P G T S V K I S C K A S G Y A F T N Y W L G W V K Q R P G H G L E W I G D I F P G S G N I H Y N E K F K G K A T L T A D K S S S T A Y M Q L S S L T F E D S A V Y F C A R L R N W D E P M D Y W G Q G T T V T V S SGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNALNWYQQKPGKAPKLLIYYTS RLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHSEQ ID NO: 527 KeyLock mutant = VH(diL2K)-WT_VL(UCHT1)-Y171AGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSAS FLYSGVPSRFSGSRSGTDFTLTISSLQ PEDFATYYCQ QHYTTPPTFG QGTKVEIK GGGGSGGGGSGGGGSGGGGS EVQL VESGGGLVQP GGSLRLSCAASGFNIKDTYI HWVRQAPGKG LEWVARIYPT NGYTRYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCSRWGGDGF YAMDYWGQGT LVTVSSGGGGSGGGGSGGGGSGGGGSE L V M T Q S P S S L T V T A G E K V T M S C K S S Q S L L N S G N Q K N Y L T W Y Q Q K P G Q P P K L L I Y W A S T R E S G V P D R F T G S G S G T D F T L T I S S V Q A E D L A V Y Y C Q N D Y S Y P L T F G A G T K L E I K GGGGSGGGGSGGGGSGGGGS E V Q L L E Q S G A E L V R P G T S V K I S C K A S G Y A F T N Y W L G W V K Q R P G H G L E W I G D I F P G S G N I H Y N E K F K G K A T L T A D K S S S T A Y M Q L S S L T F E D S A V Y F C A R L R N W D E P M D Y W G Q G T T V T V SSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDIRNALNWYQQKPGKAPKLLIYYT SRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIKGSHHHHHHPreparation of Compositions of the InventionCompositions in accordance with the present invention are prepared in accordance with known standards for the preparation of pharmaceutical compositions.For instance, the compositions are prepared in a way that they can be stored and administered appropriately, e.g. by using pharmaceutically acceptable components such as carriers, excipients or stabilizers.Such pharmaceutically acceptable components are not toxic in the amounts used when administering the pharmaceutical composition to a patient. The pharmaceutical acceptable components added to the pharmaceutical compositions may depend, for instance, on the particular intended use of the pharmaceutical compositions and the route of administration.In general, the pharmaceutically acceptable components used in connection with the present invention are used in accordance with knowledge available in the art, e.g. from Remington's Pharmaceutical Sciences, Ed. AR Gennaro, 20th edition, 2000, Williams & Wilkins, PA, USA.Further development of KeyLock antibodies (antibody constructs of the invention)Different reasons for the variability in patient response to cancer immunotherapies have been proposed (Ventola CL). This includes the lack of single antigens only expressed on the tumor cells, the large tumor heterogeneity with clones expressing different antigens, and the overactive T cells response after construct activation possible ausing a cytokine release syndrome (CRS). The CRS is a large problem for constructs, like BiTE antibodies and CAR Tcells with a finale scFv domain able to bind to ttarget and to activate CD3 positive T cells. Treatments that target single molecular mutations or single antigens on cancer cells have only modestly affected survival in some cancers. This approach, which has been described as "reductionist,” might be improved by administering drug combinations that target multiple mutations and cancer pathways (Zugazagoitia J,). A major challenge for T cell mediated cancer immunotherapies is the need to develop agents that are effective against a dual- or multi-antigen signature on the tumor cell surface, while sparing single antigen positive bystander cells. Therefore, in order to gain on tumor specificity, different Boolean logic-gated strategies for dual-antigen restricted immunotherapy are reported and under development

[0102] , Boolean logic is a branch of mathematics that defines logic gates as integrators of binary inputs represented by 1 and 0 into a variety of outputs. These logic gates, as applied for immunotherapies, have been classified into broad categories termed 'OR', and 'AND' which integrate the presence or absence of two tumor antigens (TAs) at the cell surface. This allows for T cell immunotherapies, a dual-antigen restricted cytotoxic output. In addition, different strategies have also exploited non-binary and continuous variables of the tumor and the tumor micro-environment, such as TAs density, tumor-secreted proteases, immunosuppressive cytokines, low pH, low oxygen, and extracellular ATP to enhance the tumor-selectivity of targeted therapies, thereby implementing a variation of the 'AND' gate [103, 104], The major drawback for most of these Boolean OR-gated strategies is, they are using an irreversible activation step, like for example antibody-domain exchange reaction, protease cleaving of a blocking peptide, a dimerization domain or pH-sensitive encapsulation. After the final activation step in the tumor tissue, the dual-antigen restricted targeting is lost and the constructs can also bind single antigen positive cells, causing possible "on-target off tumor” site effects.In contrast, the Boolean AND-gated strategies retain their dual-antigen restricted cytotoxic function even after activation in the tumor tissue. The most advanced Boolean AND-gated immunotherapies are the Hemibodies, the Precision Guided Antibody Tumor Engagers (PrecisionGATE™), the Format Chain Exchange technology (FORCE), the CYCAT® Halfbody molecules, and the artificial latching orthogonal cage-key proteins (LOCKR) in combination with specific CAR T cells [85, 102, 105, 106, 109, 110], All of these Boolean AND-gated immunotherapies, which are the direct competitors of the KeyLock antibody technology of this invention, are in early preclinical development and face major hurdles because of drawbacks of their design. All are using two or more separate binders. They are bipartite, tripartite or multipartite constructs and each part must be recombinant produced separately, given separately to the patient, and find themselves independently on the surface of the tumor cells. For clinical use, if there are negative side effects reported, it will be difficult to clearly distinguish what construct caused it. In addition, any degrading or reducing effects on only one of the constructs, like thru proteases in the serum or tissue, renal filtration, internalization and catabolic clearance in the liver, antibody-bound immune complexes, or binding to non-target tissue expressing high one of the antigens (a phenomenon known as antigen sink), will compromise the combinatorial nature of the entire strategy. There is another major drawback for these competitive Boolean AND-gated immunotherapies using two or more separate binders. For manufacturing this will increase the work and GMP ("Good Manufacturing Practice") productions cost and the carbon foodprint. In recent years a major concern for new T cell redirected immunotherapies came up, the economic sustainability for theworldwide health care systems (Leech AA). In a systematic literature review for economic evaluations for treating advanced and metastatic gastric cancer with novel therapies, the authors found the interventions under consideration were not cost effective, presenting challenges to sustainability and affordability. The authors highlight a requirement for cost-effectiveness evaluations and for second-line or later-line treatments of advanced and metastatic cancer that consider all relevant comparators and that are compliant with reporting-completeness and methodological-quality requirements (Sharma S, ). A large part of the high cost for new clinical trials and medications are the manufacturing cost after the required high standards of good manufacturing practice (GMP) (Schaft N,). In addition, the carbon foodprint and environmental impact of the drug development is getting more attention (Erl Amasawa). For future immunotherapy strategies, the expenses for GMP production must be limited, as well as the CO2 levels, the energy amount and the necessary consumables for production, storage, transport and administration. While safety must be maintained with an improved cost-benefit ratio.In order to circumvent some of these limitations of the current Boolean AND-gated immunotherapeutic strategies, the inventors developed the KeyLock antibody technology

[0111] , A multivalent single-partite antibody format for dual- or multi-antigen restricted immunotherapy (Figure 36). In a KeyLock construct the anti-CD3 binding variable heavy (VH) and variable light (VL) chain domains are split / separated from each other, by the target antigen scFv domains. For an optimal KeyLock antibody function the binding affinities of the individual VH and VL chains are crucial (Figure 36A). For a basic KeyLock antibody constructe, targeting two different target antigens and one on the effector cell, there are four (i-iv) crucial affinities: (I) the affinity against their respective antigen on the target cell, (ii) the affinity against the respective antigen on the effector cell, (ill) the interface-affinity of the VH and VL chains to each other (from the same antibody clone), and (iv) the interface-affinity of the VH and VL chains, from different antibody clones, connected to each other. These different affinities combine for the total avidity of the KeyLock construct. The flexibility, length and composition of the linkers used to connect the individual VH and VL chains to each other are important, because of the apparently weaker VH and VL interactions, they allow in the absence of target antigen for a transient separation ("breathing”) and swaping of the VH and VL domains with different connected VH / VL domains. This prevents or reduces the pairing of the split / separated anti-CD3 VH and VL chains to bind and activate T cells if not both target antigens are present.Because of the single-chain format of the KeyLock antibodies, one possible shortcoming is the pairing of the split / separated anti-CD3 VH and VL chains at high antibody concentrations, especially in the presence of single antigen positive cells. This is observed when wild type antibody sequences, using anti-CD3 scFv sequences, are used. The high affinity of wild type antibodies is due to the maturation process they undergo for positive selection of high binding clones. This high affinity of wild type anti-CD3 VH and VL chains leads to disadvantages for their use in the KeyLock antibody format, like a reduced therapeutic dose range and possible unwanted cytotoxicity against single antigen positive cells if constructs accumulate in specific organs or body fluids.The affinity of antibody variable domains (VH and VL) against their target antigens is mostly mediated by the complementarity determining regions (CDRs) and to minor part by the framework (FR) regions. In contrast, the interface-affinity of an antibody variable VH and VL chains to each other, is mostly mediated by the FR and to minor part by the CDRs. These different parts of an antibody variable domain, the CDRs and FRs, are often mutated in the clinical development process to improve target specificity, antibody stability, antibody manufacturing, reduced the immunogenicity, or to introduce novel functionality (Miller NL,).In contrast, the inventors use for this invention in a single antibody construct different amino acid mutations in the CDR, the FR and both regions, for two different anti-CD3fi chain directed VH and VL domains (from the UCHT1 and di L2K antibody clones) for a decrease in affinity against effector T cells in the absence of target antigens, but with sustained functional complementation and T cell activation when all antigen binding domains are bound to the target cell. This makes it different from all other reported, single or dual-antigen restricted antibody formats. Accordingly, the inventors found that it is possible to advantageously use mutants of the anti-CD3 VH and VL chains to provide the new recombinant proteinaceous binding molecules of the present invention. Therefore, in the present invention the binding moieties specific for different tumor target antigens and the spli t / separated anti-CD3 VH and VL chains, carrying different amino acid mutations, were linked. Four different antibody formats were created (Figure 37), targeting as scFv a single antigen (Figure 37 A), targeting as BITE antibody two antigens (Figure 2B), targeting as split-KeyLock fragment three antigens in a bipartite format (Figure 37C), and targeting as a KeyLock antibody three antigens in a single-partite format (Figure 37D).To generate specific mutants of two different antibody clones (UCHT 1 and diL2K) targeting human CD3E chain, in silico based methods using affinity modulation by rational design and molecular docking and interaction analysis were used. The antibody sequences of the UCHT1 and diL2K clones are humanized versions of original murine antibody clones [78, 90], The diL2K clone is a humanized version of the original OKT3 clone. For this purpose the inventors made use of the published crystal structure data for the murine antibody-CD3 complexes OKT3 (PDB: 1SY6, 2.1 A, complex with CD3-gamma / epsilon dimer) and the UCHT1 (PDB: 1XIW, 1.9 A, complex with CD3-epsilon / delta dimer) (Figures 38, 42, 44 and 45). In silico methods were used to modulate different point mutations (Figures 39 and 40) and different CDR deletions (Figures 41 and 46) predicted to affect the binding of the respective scFv with the CD3E chain.The use of different amino acid point mutations and the wild-type sequences in the anti-CD3fi scFv format showed as expected, a decrease in target binding affinity (Kd) for all mutants compared to the wild-type scFv using the VH-VL orientation (from the NH2-terminus to COCH terminus) (Figure 48). The wild-type scFv in the VL-VH orientation was still able to bind antigen, but with decrease in affinity. For antibodies it is not able to predict what orientation of the variable domains (VH-VL or VL-VH) is better for binding. This also depends on the linkers used to connect the VH and VL domains, affecting their correct pairing. Because the CD3E chain is expressed on T cells as a dimer with the CD3delta or CD3gamma chain, both target antigens were used for affinity measuring. The inventors found, that different scFv mutants affect the binding to the CD3ED or CD3EG complex differently. For example the scFvmutants V59S and G33R (of the UCHT1 clone), show high affinity against the CD3ED complex similar to the wildtype scFv (Figure 48B). In contrast against CD3EG complex both mutations V59S and G33R (of the UCHT1 clone), show significant drop in affinity compared to the wild-type scFv. This is an intriguing observation, allowing different anti-CD3 mutant scFv to bind and activate different chains of the T cell receptor complex, with possible different stimulatory or inhibitory effect on different T cell sub-population. When testing different CDR deletion mutants it was surprising to see binding of some to the CD3 complex. The CDR regions are known for the stability of the individual VH and VL domains, and CDR deletions abrogates binding to their respective antigens.To analyze, if the changes in affinity of the different anti-CD3s scFv mutants correlates with reduced or changed T cell activation and target cell killing, the most promising mutants were transferred into the known bispecific T cell engager (BiTE) format using Fc antibody constant domains (Fc_knop into hole) (Figure 50). This format was selected because the mutated anti-CD3s scFv domains connected at the N-terminus of the Fc_knop chain, are fare away from the anti-CD38 target antigen binding scFv domain connected at the C-terminus of the FC_hole chain. This distance of the two scFv domains allows to investigate the differences in T cell activation for the mutant scFv, without interaction with the VH-VL domains of the targeting scFv. For the wild-type control BiTES targeting CD38, for both antibody clones (UCHT 1 and di L2K) showed excellent cytotoxicity for the VH-VL scFv. In contrast for the VL-VH orientation only the wild-type scFv for the UCHT1 showed good cytotoxicity while this was gone for the diL2K clone (Figure 51 A and B).To our surprise, some of the anti-CD3s scFv mutants with no detectable binding against their respective target antigen in the ELISA assays (Figures 48A to 49D), show good or excellent cytotoxicity in the BiTE format (Figure 51 A to C). For example, the mutant Y171 A (of the UCHT1 clone), with no detectable Kd in the ELISA, show 90% target cell killing. The mutant D185L (of the diL2K clone), with no detectable Kd in the ELISA, also reached 90% target cell killing, and the mutant Y167A (of the diL2K clone), with no detectable Kd in the ELISA, reached 50% target cell killing. This is an important observation for this invention, showing it is not possible to select a new mutant antibody for modulating effector cell activation in, by using the mutant antibody Kd against its target as a surrogate for a functional T cell activating antibody. In this BiTE format the mutant binders were used in a scFv format, connecting the VH and VL chains.To further investigate, if the mutants also work if their VH and VL chains are split / separated from each other, the most promising mutants were cloned into spli t-Key Lock fragments (Figure 37C) and recombinant produced (Figure 52A to C). This format was chosen because of two advantages: (i) It is possible to pair different mutants and wild type sequences in a large scale format, (ii) And to investigate different ratios of mutant or wild-type VH and VL chains to each other. These combination studies with split-Key...

Claims

CLAIMS1. An antibody construct comprising(i) at least one variable heavy chain (VH) of an anti-CD3 antibody,(ii) at least one variable light chain (VL) of the anti-CD3 antibody, and(ill) at least two single chain variable fragments (scFvs),wherein the antibody construct comprises the same number of (I) variable heavy chain(s) (VH) of the anti- CD3 antibody and (ii) variable light chain(s) (VL) of the anti-CD3 antibody,wherein each of the variable heavy chain(s) (VH) and the variable light chain(s) (VL) of the anti-CD 3 antibody are connected to each other by a protein structure comprising at least one or more of the single chain variable fragments (scFvs), and wherein in the antibody construct, at least two of the single chain variable fragments (scFvs) are against different target epitopes of the same target antigen or against different target antigens.

2. The antibody construct according to claim 1 , wherein at least one VH and VL of the anti-CD3 antibody form an anti-CD3 binding domain in the presence of said different target epitopes or target antigens on a target cell surface.

3. The antibody construct according to claim 1 or 2, wherein the antibody construct is a single covalently linked construct.

4. The antibody construct according to any one of claims 1 to 3, wherein the antibody construct or the protein structure further comprises an immunoglobulin Fc region and / or an immunoglobulin constant region.

5. The antibody construct according to claim 4, wherein said immunoglobulin Fc region and / or immunoglobulin constant region are an immunoglobulin, preferably an IgG.

6. The antibody construct according to any one of claims 1 to 5, wherein the antibody construct or the protein structure further comprises albumin, single albumin-domains, albumin-binding domains, and / or other plasma / serum proteins such as part of membrane proteins cleaved and detected in the plasma / serum.

7. The antibody construct according to any one of claims 1 to 6, wherein said different target epitopes or target antigens are tumor and / or cancer epitopes or antigens.

8. The antibody construct according to any one of claims 1 to 7, wherein said different target epitopes or target antigens are prostate tissue epitopes or antigens.

9. The antibody construct according to any one of claims 1 to 8, wherein said different target epitopes or target antigens are cell type and / or cell lineage specific epitopes or antigens.

10. The antibody construct according to any one of claims 1 to 9, wherein said different target epitopes or target antigens are allergens and or auto-epitopes or auto-antigens.

11. The antibody construct according to claim any one of claims 1 to 10 wherein at least one, two, or all target epitopes or target antigens are selected from the group consisting of CD38, SLAMF7 / CS1 / CD319, ERBB2 / Her2 / NEU / CD340, FGFR1 / CD331, EGFR, EpCAM / CD326, ERBB3, ERBB4, MET, PDGFRA, PDGFRB, FGFR2, FGFR3, FGFR4, KIT, FLT3, IGF1 R, RET, R0S1 , ALK, TGFBR1 , TGFBR2, ACVR2A, ACVR1 B, LRP5, LRP6, E-Cadherin I CDH1, N-Cadherin I CDH2, AQP3, AQP1, AQP4, AQP5, AQP9, CD451 PTPRC, CD34, CD1381 SDC1, CD901 THY1, CD1231 IL3RA, IL1RAP, IL2RB I CD122, CD117 / Kit, CD244, CD49F I ITGA6, ABCG2, ESAM, CD10 I MME, CD81, GHR, PRLR, PSMA, PSCA, CD133, CD166, CD44v6 I CD44, CD29 I ITGB1, CD24, Lgr5, CEA / CEACAM5, VEGFR2 I KDR, CXCR4 / CD33, CD56 / NCAM1, CD19, CD20, B7H3 / CD276, L1CAM, CD37, LFA-1 / ITGB2 / CD18, R0R1, R0R2, CD70, CD123 / IL3RA, IGF1R / CD221, CCR7 I CD197, CCR4 I CD194, TNFRSF9 I 4-1BB, CTLA4 I CD152, GPC3 I Glypican-3, CADM1, CD4, B7-h4 I VTCN1, TYRP1, PDL1 / CD274, PDCD1 / PD-1, PDCD1LG2 / PD-L2, BTLA, DLL3, CEACAM1 / CD66a, LFA- 1 I ITGB2, CD22, NRP1 1 CD304, CHRNA1, GD2 I Disialoganglioside, CTAG1A / NY-ESO-1, CD70, CD30 I TNFRSF8, CD98hc I SLC3A2, CD52, CD64 I FCGR1A, CD46 I MCP, CD6, CD10 I MME, CD25 I IL2RA, CD40, CD47, CD49a I ITGA1 , CD49c I ITGA3, CD49e I ITGA5, CD51 1 ITGAV, CD55, CD571 B3GAT1 , CD59, CD61 I ITGB3, CDw75 I ST6GAL1, CD79a, CD82, CD95 I FAS, CD99, CD105 I ENG, CD107a I LAMP1, CD107b I LAMP2, CD131 I CSF2RB, CD147 I BSG, CD151, AGTR1, AGTR2, KRAS, NRAS, HRAS, and BRAF or combinations thereof.

12. The antibody construct according to any one of claims 1 to 11, wherein the anti-CD3 antibody is a T cellactivating antibody.

13. The antibody construct according to any one of claims 1 to 12, wherein (i) the variable heavy chain (VH) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 274, 275, and 276, respectively, and wherein (ii) the variable light chain (VL) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 277, 278, and 279, respectively, or wherein (i) the variable heavy chain (VH) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 280, 281, and 282, respectively, and wherein (ii) the variable light chain (VL) of the anti-CD3 antibody comprises the complementarity determining regions (CDRs) 1, 2 and 3 comprising the amino acid sequences of SEQ ID NOs: 283, 284, and 285, respectively.

14. The antibody construct according to any one of claims 1 to 13, wherein (i) the variable heavy chain (VH) of the anti-CD3 antibody comprises the amino acid sequence of SEQ ID NO: 270 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto, and wherein (ii) the variable light chain (VL) of the anti- CD3 antibody comprises the amino acid sequence of SEQ ID NO: 271 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto, or wherein (i) the variable heavy chain (VH) of the anti- CD3 antibody comprises the amino acid sequence of SEQ ID NO: 272 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto, and wherein (ii) the variable light chain (VL) of the anti- CD3 antibody comprises the amino acid sequence of SEQ ID NO: 273 or an amino acid sequence at least 95%, at least 98% or at least 99% identical thereto.

15. The antibody construct according to any one of claims 1 to 14, wherein the anti-CD3 binding domain is capable of binding to CD3 on CD3 positive T cells and activating said cells.

16. The antibody construct according to any one of claims 1 to 15, wherein the antibody construct is a construct which forms a functional anti-CD3 binding domain in the presence of said different target antigens on a target cell surface at a concentration which is at least 10 fold (1 -log), at least 100 fold (2-log) or at least 1000 fold (3-log) lower than the concentration at which a functional anti-CD3 binding domain forms in the absence of one or more or all of said different target antigens from a target cell surface.

17. The antibody construct according to any one of claims 1 to 16, wherein the antibody construct comprises not more than one VH and not more than one VL of the anti-CD3 antibody and not more than two single chain variable fragments (scFvs) against different target antigens.

18. The antibody construct according to any one of claims 1 to 16, wherein the antibody construct comprises two VH and two VL, three VH and three VL, or four VH and four VL of the anti-CD3 antibody.

19. The antibody construct according to any one of claims 1 to 16, wherein the antibody construct comprises two, three or four single chain variable fragments (scFvs) against different target epitopes or target antigens.

20. The antibody construct according to any one of claims 1 to 16, wherein the antibody construct comprises two, three or four single chain variable fragments (scFvs) against different target antigens and comprises two, three or four single chain variable fragments (scFvs) as pairs or triplicates, direct connected to each other or separated at least by one single chain variable fragments (scFvs) against a different target.

21. The antibody construct according to any one of claims 1 to 20, wherein the target antigens are ERBB2 / Her2 / NEU / CD340 and EpCAM / CD326 or CD38 and SLAMF7 / CS1 / CD319.

22. The antibody construct according to any one of claims 1 to 21, wherein all of the at least one VH and at least one VL of the anti-CD3 antibody are linked to one of said single chain variable fragments (scFvs) comprised by the protein structure by a peptide linker.

23. The antibody construct according to any one of claims 1 to 22, wherein the peptide linker allows formation of an anti-CD3 binding domain from at least one VH and VL of the anti-CD3 antibody in the presence of said different target epitopes or target antigens.

24. The antibody construct according to any one of claims 1 to 23, wherein the antibody construct is selected from the following (a) to (q):(a) an antibody construct comprising the amino acid sequence of SEQ ID NO: 293 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 293,(b) an antibody construct comprising the amino acid sequence of SEQ ID NO: 294 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 294,(c) an antibody construct comprising the amino acid sequence of SEQ ID NO: 295 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 295,(d) an antibody construct comprising the amino acid sequence of SEQ ID NO: 296 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 296,(e) an antibody construct comprising the amino acid sequence of SEQ ID NO: 297 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 297,(f) an antibody construct comprising the amino acid sequence of SEQ ID NO: 298 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 298,(g) an antibody construct comprising the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 299,(h) an antibody construct comprising the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 300,(I) an antibody construct comprising the amino acid sequence of SEQ ID NO: 301 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 301,(j) an antibody construct comprising the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 302,(k) an antibody construct comprising the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 303,(l) an antibody construct comprising rises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 304,(m) an antibody construct comprising the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 305,(n) an antibody construct comprising the amino acid sequence of SEQ ID NO: 306 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 306,(o) an antibody construct comprising the amino acid sequence of SEQ ID NO: 307 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 307, and(p) an antibody construct comprising the amino acid sequence of SEQ ID NO: 308 or an amino acidsequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 308.

25. The antibody construct according to any one of claims 1 to 24, further comprising an additional proteinbinding group selected from a single-domain antibody (also known as a Nanobody or VHH), a monobody (derived from fibronectin type III), an anticalin (derived from lipocalins), an affibody (derived from immunoglobulin-binding protein A) and a DARPin (Designed Ankyrin Repeat Protein).

26. The antibody construct according to any one of claims 1 to 25, wherein (i) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270 or SEQ ID NO: 272, and / or wherein (ii) the at least one variable light chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271 or SEQ ID NO: 273.

27. The antibody construct according to claim 26, wherein (i) the at least one variable heavy chain (VH) of the anti- CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270, and / or wherein (ii) the at least one variable light chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271.

28. The antibody construct according to claim 26, wherein (i) the at least one variable heavy chain (VH) of the anti- CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 272, and / or wherein (ii) the at least one variable light chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more but preferably not more than 5 amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 273.

29. The antibody construct according to any one of claims 26 to 28, wherein the amino acid substitutions or deletions decrease the affinity of the antibody construct against CD3 on CD3 positive T cells in the absence of one or more or all of the different target antigens from a target cell surface when compared to an antibody construct which lacks said substitutions or deletions but is otherwise identical, andwherein at least one VH and VL of the anti-CD3 antibody form an anti-CD3 binding domain in the presence of said different target antigens on a target cell surface.

30. The antibody construct according to any one of claims 26 to 29, wherein(A) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270 which are selected from Table 1, wherein the amino acid positions are determined based on Seq ID NO: 415 as a reference sequence but without counting the first two amino acids of Seq ID NO: 415, and / or(B) the at least one variable heavy chain (VH) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271which are selected from Table 2, wherein the amino acid positions are determined based on Seq ID NO: 415 as a reference sequence but without counting the first two amino acids of Seq ID NO: 415, and / or(C) the at least one variable heavy chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 272 which are selected from Table 3, wherein the amino acid positions are determined based on Seq ID NO: 419 as a reference sequence but without counting the first two amino acids of Seq ID NO: 419, and / or(D) the at least one variable heavy chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 273 which are selected from Table 4, wherein the amino acid positions are determined based on Seq ID NO: 419 as a reference sequence but without counting the first two amino acids of Seq ID NO: 419.

31. The antibody construct according to any one of claims 26 to 30, wherein the substitution is a substitution by flexible linkers to replace the deleted amino acids for variable domain stability, wherein optionally the flexible linkers are selected from the amino acid sequences of SGGSG, SGG or SG.

32. The antibody construct according to any one of claims 26 to 31, wherein (I) the variable heavy chain (VL) of the anti-CD3 antibody comprises an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 273 which are selected from R169E and Y171A, wherein the amino acid positions are determined based on Seq ID NO: 415 as a reference sequence but without counting the first two amino acids of Seq ID NO: 415.

33. The antibody construct according to any one of claims 26 to 32, wherein the antibody construct is selected from the following (a) to (c):(a) an antibody construct comprising the amino acid sequence of SEQ ID NO: 525 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 525,(b) an antibody construct comprising the amino acid sequence of SEQ ID NO: 526 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 526, and(c) an antibody construct comprising the amino acid sequence of SEQ ID NO: 527 or an amino acid sequence at least 90%, at least 95%, at least 98% or at least 99% identical thereto, wherein the antibody construct preferably has the CDRs of the amino acid sequence of SEQ ID NO: 527.

34. The antibody construct according to any one of claims 1 to 33, wherein the antibody construct further comprises one or more blocking domains to block formation of an anti-CD3 binding domain in the presence of said different target antigens in non-tumor tissue and / or to block formation of an anti-CD3 binding domain in the absence of one or more or all of said different target antigens from a target cell surface.

35. The antibody construct according to claim 34, wherein one or more of the blocking domains are connected to at least one of the variable heavy chain(s) (VH) of an anti-CD3 antibody (I), and / or one or more of the blocking domains are connected to at least one of the variable light chain(s) (VL) of the anti-CD3 antibody (ii), wherein the connection is optionally by a cleavable linker.

36. The antibody construct according to any one of claim 34 or 35, wherein the one or more blocking domain comprises a variable heavy chain (VH) of the anti-CD3 antibody comprising an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 270 or SEQ ID NO: 272 or a variable light chain (VL) of the anti-CD3 antibody comprising an amino acid sequence carrying one or more amino acid substitutions or deletions in the amino acid sequence of SEQ ID NO: 271 or SEQ ID NO: 273 wherein the substitutions or deletions reduce the formation of an anti-CD3 binding domain in the presence of said different target antigens on a target cell surface.

37. A nucleic acid molecule, or a set of nucleic acid molecules, encoding the antibody construct according to any one of claims 1 to 36.

38. A recombinant vector, or a set of recombinant vectors, comprising the nucleic acid molecule or set of nucleic acid molecules according to claim 37.

39. A recombinant host cell comprising the recombinant vector or set of recombinant vectors according to claim 38 and optionally expressing the antibody construct according to any one of claims 1 to 36.

40. A pharmaceutical composition comprising one or more antibody constructs according to any one of claims 1 to 36.

41. A kit comprising one or more antibody constructs according to any one of claims 1 to 36.

42. An antibody construct according to any one of claims 1 to 36 for use as a medicament.

43. An antibody construct according to any one of claims 1 to 36 for use in immunotherapy to treat cancer.

44. The antibody construct for use according to claim 42 or 43, wherein the antibody construct is to be administrated into the patient intra venous, sub cutaneous, intra thecal or intra peritoneal, via injections, short infusion (1 minute to 8 hours) or via a continuous infusion (> 8 hours).

45. The antibody construct for use according to any one of claims 42 to 44, wherein the antibody construct is to be administrated locally into a benign tumor or a cancer via injections, to increase local concentrations of the antibody construct and reduce systemic serum levels of the antibody construct.

46. The antibody construct for use according to any one of claims 42 to 45, wherein the antibody construct is to be administrated locally into a benign tumor or a cancer via injections, with the antibody construct embedded into a semi solid matrix to delay the antibody construct release over time and to reduce a wash out from the local injection site.

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