COMBINATIONS OF ANTIBODY CONSTRUCTS AND INHIBITORS OF CYTOKINE RELEASE SYNDROME AND USES THEREOF

Abstract

The present invention relates to medical combination products comprising (i) at least one antibody construct comprising at least one domain which binds to a target antigen expressed on the surface of a cell and at least one other domain which binds to CD3 as well as (ii) at least one molecule that is an antagonist of/an inhibitor of signaling, which is based on an interaction of TNF with its cognate receptor (TNFR), wherein the antagonisation or the inhibition of TNF or its cognate receptor prevents, reduces, or blocks TNF/TNFR mediated signalling. Furthermore, the invention provides therapeutic and preventive methods and medical uses of said combination products, as well as a kit comprising said at least one antibody construct and at least one antagonist/inhibitor of TNF or its cognate receptor, wherein the interaction of said antagonist/inhibitor of TNF with its cognate receptor reduces, mitigates, prevents, or treats cytokine release syndrome.

Claims

1. A method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein said method comprises (a) administering an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, (b) administering an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling, wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling (b) is administered to a patient in need thereof prior to administration of said antibody construct (a), wherein the patient is a human being or a non-human primate.

2. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to claim 1, wherein said method comprises (a) administering an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, (b) administering an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling, (c) administering a corticosteroid, particularly dexamethasone, wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling in step (b) and said corticosteroid in step (c) are administered to a patient in need thereof prior to administration of said antibody construct (a), wherein the patient is a human being or a non-human primate.

3. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to claim 1 or 2, wherein the adverse event is cytokine release syndrome (CRS).

4. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 3, wherein the second domain of said antibody construct binds to human CD3 epsilon and to Callithrix jacchus or Saimiri sciureus CD3 epsilon.

5. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 4, wherein a) the antibody construct is a single chain antibody construct, b) the first domain is in the format of an scFv, c) the second domain is in the format of an scFv, d) the first and the second domain are connected via a linker, and/or e) the antibody construct comprises a domain providing an extended serum half-life.

6. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 5, wherein the first domain binds to a target antigen selected from the group comprising tumor-associated antigens, viral antigens, bacterial antigens, peptide-MHC complexes presenting a peptide fragments derived from a tumor-associated antigen, viral antigen, bacterial antigen, or a disease-associated antigen.

7. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 6, wherein the first domain binds to a target antigen, wherein said target antigen is a tumor-associated antigen selected from the group comprising CD19, CD33, FLT3, PSMA, BCMA, and DLL3.

8. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 7, wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling is selected from the group comprising small molecules, aptamers, biological molecules, antibodies and derivatives thereof.

9. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 8, wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling is selected from the group comprising etanercept, infliximab, adalimumab, certolizumab Pergol, and golimumab, particularly etanercept.

10. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell of a disease according to any one of claims 1 to 9, wherein said disease is either a solid tumor or a hematological cancer.

11. The method for the prevention or reduction of adverse events associated with immunotherapeutic treatment of cancer with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell according to any one of claims 1 to 10, preferably for immunotherapy of a neoplastic disease, wherein said corticosteroid is dexamethasone provided said patient is neither at risk of developing adverse events nor has an intolerance to dexamethasone, and particularly wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling etanercept is particularly preferred.

12. A method for the immunotherapeutic treatment of cancer in a patient, wherein said method comprises (a) administering an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, (b) administering an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling, wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling (b) is administered to a patient in need thereof prior to administration of said antibody construct (a), wherein the patient is a human being or a non-human primate.

13. A method for the immunotherapeutic treatment of cancer in a patient, wherein said method comprises (a) administering an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, (b) administering an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling, (c) administering a corticosteroid, particularly dexamethasone, wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling in step (b) and the corticosteroid in step (c) administered to a patient in need thereof prior to administration of said antibody construct (a), wherein the patient is a human being or a non-human primate.

14. The method for the immunotherapeutic treatment of cancer in a patient according to claims 12 and 13, wherein the second domain of said antibody construct binds to human CD3 epsilon and to Callithrix jacchus or Saimiri sciureus CD3 epsilon.

15. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 14, wherein a) the antibody construct is a single chain antibody construct, b) the first domain is in the format of an scFv, c) the second domain is in the format of an scFv, d) the first and the second domain are connected via a linker, and/or e) the antibody construct comprises a domain providing an extended serum half-life.

16. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 15, wherein the first domain binds to a target antigen selected from the group comprising tumor-associated antigens, viral antigens, bacterial antigens, peptide-MHC complexes presenting a peptide fragments derived from a tumor-associated antigen, viral antigen, bacterial antigen, or a disease-associated antigen.

17. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 16, wherein the first domain binds to a target antigen, wherein said target antigen is a tumor-associated antigen selected from the group comprising CD19, CD33, FLT3, PSMA, BCMA, and DLL3.

18. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 17, wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling is selected from the group comprising small molecules, biological molecules, aptamers, antibodies and derivatives thereof.

19. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 18, wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling is selected from the group comprising etanercept, infliximab, adalimumab, certolizumab Pergol, and golimumab, particularly etanercept.

20. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 19, wherein the cancer is selected from a solid tumor or a hematological cancer.

21. The method for the immunotherapeutic treatment of cancer in a patient according to any one of claims 12 to 20, wherein said patient is at risk of developing adverse events, or wherein the patient has an intolerance to IL-6R-antagonists, wherein the IL-6R-antagonist is tocilizumab.

22. A combination product for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell comprising (a) an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, (b) an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling, wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling (b) is for administration to a patient in need thereof prior to administration of said antibody construct (a), wherein said patient is either a human being or a non-human primate.

23. A combination product for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell comprising (a) an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, (b) an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling, (c) a corticosteroid, particularly dexamethasone, wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling (b) and the corticosteroid (c) are for administration to a patient in need thereof prior to administration of said antibody construct (a), wherein said patient is either a human being or a non-human primate.

24. The combination product according to claims 22 and 23 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the adverse event associated with immunotherapy is increased cytokine release of TNF, MCP-1, IL-1, and/or IL-6, particularly wherein the adverse event is CRS.

25. The combination product according to any one of claims 22 to 24 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the second domain of said antibody construct binds to human CD3 epsilon and to Callithrix jacchus or Saimiri sciureus CD3 epsilon.

26. The combination product according to any one of claims 22 to 24 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein a) the antibody construct is a single chain antibody construct, b) the first domain is in the format of an scFv, c) the second domain is in the format of an scFv, d) the first and the second domain are connected via a linker, and/or e) the antibody construct comprises a domain providing an extended serum half-life.

27. The combination product according to any one of the preceding claims 22 to 25 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the first domain binds to a target antigen selected from the group comprising tumor-associated antigens, viral antigens, bacterial antigens, peptide-MHC complexes presenting a peptide fragment derived from a tumor-associated antigen, viral antigen, bacterial antigen, or a disease-associated antigen.

28. The combination product according to any one of the preceding claims 22 to 27 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the first domain binds to a target antigen, wherein said target antigen is a tumor-associated antigen selected from the group comprising CD19, CD33, FLT3, PSMA, BCMA, and DLL3.

29. The combination product according to any one of the preceding claims 22 to 28 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling is selected from the group comprising small molecules, biological molecules, aptamers, antibodies and derivatives thereof.

30. The combination product according to any one of the preceding claims 22 to 29 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling is selected from the group comprising etanercept, infliximab, adalimumab, certolizumab Pergol, and golimumab, particularly etanercept.

31. The combination product according to any of the preceding claims 22 to 30 for the prevention or reduction of adverse events associated with immunotherapy of a disease with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein the disease is a neoplastic disease, particularly a solid tumor or a hematological cancer.

32. The combination product according to any of the preceding claims 22 to 31 for the prevention or reduction of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, wherein said combination product is for administration to a patient at risk of developing adverse events, or having an intolerance, to IL-6-antagonists or IL-6R-antagonists, particularly wherein the IL-6R-antagonist is tocilizumab.

33. A kit comprising a combination product according to any of the preceding claims 22 to 32 in a package, wherein the combination product is present in a single container, or the components of said combination product are present individually, said kit optionally further comprising at least one of instructions for use, a device for administration of said combination product or components thereof, at least one separately packed medium for reconstitution, a pharmaceutical carrier for at least one of said combination products or components thereof.

34. An inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling as defined in any of the foregoing claims 22 to 33 for use in a method for the prevention of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell in a patient suffering from a neoplastic disease, particularly from solid tumor or a hematological cancer.

35. The inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling as defined in any of the foregoing claims 22 to 34 for use in a method for the prevention of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell in a patient suffering from a neoplastic disease as defined in the preceding claim 34, wherein said patient is at risk of developing CRS.

36. The inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling as defined in any of the foregoing claims 22 to 35 for use in a method for the prevention of CRS in a patient suffering from a neoplastic disease who is at risk of developing CRS as defined in the preceding claims 47 and 48, wherein said patient is a person subjected to therapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell as defined in any of the preceding claims.

37. Use of an inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling as defined in any of the foregoing claims wherein said inhibitor/antagonist of TNF/TNFR that reduces TNF/TNFR signalling in the preparation of a medicament for the prevention of adverse events associated with immunotherapy with an antibody construct comprising a first domain which binds to a target antigen on the surface of a target cell, and a second domain which binds to human CD3 on the surface of a T cell, particularly for the prevention of CRS in a patient suffering from a neoplastic disease as defined in any of the preceding claims.

Description

DESCRIPTION OF THE FIGURES

[0389] FIG. 1—Pretreatment with TNFα blockade did not affect BiTE® molecule efficacy: Human CD3c knock-in mice were pretreated with either a control antibody, TNFα blockade agents (anti-TNFα antibody or a TNFRII-Fc) administered once per day for two days prior to dosing either a negative control BiTE® molecule (1000 μg/kg) or a mouse CD19 BiTE® molecule (100 μg/kg or 1000 μg/kg) that recognizes CD19 on B cells (n=5 animals per group). At 72 hours post-BiTE® dose, animals were euthanized, and spleens were harvested for analysis. B cells were enumerated by flow cytometry as described in Methods. The engagement of T cells in vivo using a murine CD19 targeted BiTE® molecule resulted in depletion of B cells in the spleen, and administration of TNFα blocking reagents prior to BiTE® administration did not affect the ability of the BiTE® molecule to mediate depletion of splenic B cells. Significance values: ns, p>0.05; * p≤0.05, ** p≤0.01, *** p≤0.001, **** p≤0.0001 (one-way ANOVA with Tukey's test); TNFα=tumor necrosis factor alpha, BiTE®=bispecific T cell engager, anti-TNFα Ab=TNFα blocking antibody, TNFRII-Fc=tumor necrosis factor receptor II-Fc fusion protein.

[0390] FIG. 1. BiTE® molecule-induced serum IFNγ and IL-2 were not significantly reduced by TNFα blockade prior to BiTE® molecule administration: Human CD3c knock-in mice were pretreated with either a control antibody, TNFα blockade agents (anti-TNFα antibody or a TNFRII-Fc) for two days prior to dosing with either a negative control BiTE® molecule (1000 μg/kg) or a mouse CD19 BiTE® molecule (100 μg/kg and 1000 μg/kg) that recognizes CD19 on B cells (n=5 animals per group). Serum IFNγ and IL-2 were measured four hours after BiTE® treatment. Mean (A) IFNγ, (B) IL-2 levels in groups pretreated with both TNFα blocking agents were not significantly lower after administration of CD19 BiTE® at both doses compared to control antibody pretreatment groups (one-way ANOVA with Tukey's test). Significance values: ns, p>0.05; * p≤0.05, ** p≤0.01, *** p≤0.001, **** p≤0.0001; IFNγ=interferon gamma, IL-2=interleukin 2, BiTE®=bispecific T cell engager, TNFα=tumor necrosis factor alpha, anti-TNFα Ab=TNFα blocking antibody, TNFRII-Fc=TNF receptor II Fc-fusion protein, ULOD=upper limit of detection.

[0391] FIG. 3. BiTE® molecule-induced Serum IL-6 was significantly reduced by TNFα blockade prior to BiTE® administration: Human CD3c knock-in mice were pretreated with either a control antibody, TNFα blockade agents (anti-TNFα antibody or a TNFRII-Fc) for two days prior to dosing with either a negative control BiTE® molecule (1000 μg/kg) or a mouse CD19 BiTE® molecule (100 μg/kg and 1000 μg/kg) that recognizes CD19 on B cells (n=5 animals per group). Serum IL-6 was measured four hours after BiTE® treatment. Mean IL-6 levels in groups pretreated with both TNFα blocking agents were significantly lower after administration of CD19 BiTE® at both doses compared to control antibody pretreatment groups (one-way ANOVA with Tukey's test). Significance values: ns, p>0.05; * p≤0.05, ** p≤0.01, *** p≤0.001, **** p≤0.0001; IL-6=interleukin 6, BiTE®=bispecific T cell engager, TNFα=tumor necrosis factor alpha, anti-TNFα Ab=TNFα blocking antibody, TNFRII-Fc=TNF receptor II Fc-fusion protein, ULOD=upper limit of detection.

[0392] FIG. 4. Cytokine measurement in Example 2: Blood samples of 5 animals were collected 4 and 24 hours after each vehicle and muS110 administration, respectively and TNF, IL-6 and MCP1 serum concentrations were determined using the BD™ CBA Mouse Flex Set System (BD) in accordance to the manufactures instructions.

[0393] FIG. 5. Impact of TNF Blockage on AMG 110 Bioactivity

[0394] FIG. 6. AMG 103-mediated MCP-1 Secretion: MCP-1 concentrations in cell culture supernatants were quantified by the BD Cytometric CBA human MCP-1 Flex Set. Error bars in both graphs indicate the standard error of the mean of duplicate measurements.

[0395] FIG. 7. VCAM-1 Expression on HUVEC in AMG 103 Co-culture Assays: VCAM-1 expression by flow cytometry. ICAM-1 expression levels are expressed as Median Fluorescence Intensity (MFI). VCAM-1 expressing HUVEC are expressed as percentage of CD31+HUVEC. Error bars indicate the standard error of the mean of duplicate measurements. Two PBMC donors were used in this experiment.

EXAMPLE 1

[0396] Immunocompetent C57BL/6 mice engineered to express human CD3 (huCD3 knock-in) were pretreated with either a control antibody or two different TNFα blocking agents, an anti-TNFα blocking antibody (anti-TNFα Ab) or a tumor necrosis factor receptor II-Fc fusion protein (TNFRII-Fc). These agents were administered once per day for two days prior to dosing with either an anti-mouse CD19 BiTE® molecule (100 μg/kg or 1000 μg/kg) that recognizes CD19 on B cells, or a negative control BiTE® molecule (n=5 animals per group). Serum cytokines were measured four hours after BiTE® treatment and B cell depletion was measured at 72 hours after BiTE® treatment. The engagement of T cells in vivo using the anti-mouse CD19-targeted BiTE® molecule resulted in activation of T cells, production of cytokines that could be measured in the serum, and depletion of B cells in the spleen. Administration of TNFα blocking reagents prior to BiTE® administration did not affect the ability of the BiTE® molecule to deplete B cells in the spleen (FIG. 1), nor did it impair the release of IFN-γ (FIG. 2), which is important for continued to T cell cytotoxicity, or IL-2 (FIG. 2), which is important for T cell proliferation. However, TNFα blockade did decrease the expression of IL-6 in the serum of animals post-BiTE® administration (FIG. 3). These results show that TNFα blockade can reduce circulating IL-6, which has been implicated in immunotherapy-induced CRS, without affecting BiTE®-mediated cytotoxicity.

Cytokine Measurements

[0397] Milliplex Mouse Cytokine/Chemokine kits (EMD Millipore) were used on Curiox 96w DropArray microplates per both manufacturers' protocols to test the cytokine levels in the original samples collected. Assays were performed such that contents of one EMD Millipore Milliplex kit was used in smaller amounts on 4 Curiox microplates. The lots of the Curiox plates and all items included in the Millipore kits were as shown in Table 1 below.

TABLE-US-00002 TABLE 1 Description Cat# Kit lot# Exp date Pre-mixed blend MCYPMX32 3136598 Nov-20 of analytes Standard MXM8070-2 SC7N807-8K May-20 QC1 MXM6070-2 MCY-108 May-20 QC2 MXM6070-2 MCY-208 May-20 Serum Matrix MXMSM 3075213 May-20 Detection MXM1070-3 3207309 May-21 Antibodies Streptavidin- L-SAPE10 3216830 Apr-21 Phycoerythrin Assay Buffer L-AB 3231126 May-21 Curiox 96w #96-CC-BD-05 C96C2219135-B May-20 dropArray plates Curiox Wash — 1x PBS, 0.1% BSA, Buffer 0.05% Tween20 (PBS 14190-136, lot 17765965)

Preparation of Curiox Items

[0398] All samples were run on four Curiox microplates. [0399] Two Curiox Humid Boxes were prepared with 8 paper towels and 100 mL PBS. [0400] Lid sponges on each of two Curiox plates were wetted with 12 mL PBS. [0401] Plates were blocked with 20 μL/well 1% BSA/PBS [0402] Plates were left inside humid box on a Titramax 1000 Shaker (Heidolph Instruments) at ˜400 rpm for 30 minutes

Preparation of Milliplex Reagents

[0403] Beads:

[0404] A premix of beads was used in this assay. Analytes IFNγ, IL-2, IL-6 and TNFα were read by the software and subsequently analyzed.

[0405] Quality Controls:

[0406] One vial of each Quality Control 1 and 2 was reconstituted with 250 μL ddH2O per vial, vortexed lightly (5 seconds), and allowed to sit at room temp for at least 10 minutes before being used.

[0407] Wash Buffer:

[0408] Curiox Wash Buffer (1×PBS, 0.1% BSA, 0.05% Tween20) was created by mixing. Each liter contains: [0409] 900 mL 1×PBS [0410] 100 mL 1% BSA in PBS [0411] 500 μL 10% Tween20 in PBS

[0412] Serum Matrix:

[0413] One vial of lyophilized serum matrix was freshly reconstituted with 2 mL Assay Buffer, left to sit at room temp for 10 minutes and then used according to protocol 5 μL per well in standards, quality control, and blank wells.

[0414] Serum Dilutions:

[0415] Each serum sample was assessed in duplicate and neat only with no dilutions.

[0416] Standard Reconstitution and Dilution:

[0417] One vial of cytokine standard was freshly reconstituted with 250 μL ddH2O, vortexed lightly (5 seconds), and allowed to sit at room temperature for at least 10 minutes before being diluted and readied for the assay. Standard dilutions were then made at 1:2 such that 100 μL of higher concentrated standard was serially diluted into 100 μL assay buffer to create 13 total dilutions; highest concentration being 10,000 pg/mL, and lowest concentration at 2.4 pg/mL, for all analytes.

Immunoassay Procedure

[0418] The Curiox plates (currently in Block) were each washed 1× using the Curiox DropArray plate washer. Using reverse pipetting (for more accurate dispensing of pipet contents), the following were added to the plates using the plate layouts captured in ELN 20191022-00064. 5 μL bead mix was added per well to all wells. 5 μL Serum Matrix was added to Standards and Quality Control wells. 5 μL Assay Buffer was added to the sample wells. 5 μL Standards and QC controls were added to the appropriate wells. 5 μL sample was added to the appropriate wells. The plates were each mixed 10 seconds using a Vortex Genie plate mixer at 1000 rpm and then left to incubate in the Humid Boxes on a Titramax Shaker, with the magnet array, at ˜400 rpm overnight at 4° C. The following day, plates were washed 3× using the Curiox DropArray plate washer. 5 μL of biotinylated Detection Antibody was added to each well, plates were mixed 10 seconds using a Vortex Genie plate mixer at 1000 rpm, and then were left to incubate in the Humid Boxes, without magnet array, on a Titramax Shaker at ˜400 rpm for 1 hour at room temperature. 5 μL of Streptavidin-PE-labeled detection antibody was added to each well, plates were mixed 10 seconds using a Vortex Genie plate mixer at 1000 rpm and then were left to incubate in the Humid Boxes, without the magnet array, at ˜400 rpm shaking for 30 minutes at room temperature. The plates were again washed 3× using the Curiox DropArray plate washer. 20 μL of sheath fluid was added to each of the wells, plates were mixed 10 seconds using a Vortex Genie plate mixer at 1000 rpm and then were left to incubate in the Humid Boxes, without the magnet array, on a Titramax Shaker at ˜400 rpm for at least 5 minutes at room temperature. Individual well contents from each of the Curiox microplates were then mixed by pipetting up and down at least 10 times and transferred to the wells in a quadrant of a 384-well plate. After all Curiox plates' contents were transferred, 50 μL/well sheath fluid was added to each 384-well plate (now 70 μL/well), and the 384-well plates were mixed 30 seconds using a Vortex Genie plate mixer at 1000 rpm. The 384-well plate was read on a Luminex FlexMap 3D reader using xPONENT software.

Spleen Flow Cytometry Analysis

[0419] At the end of the study, animals were euthanized by carbon dioxide asphyxiation followed by physical cervical dislocation. Spleens were removed and collected in RPMI into individual wells of a 24-well plate. Spleens were pulverized through a 100 μm filter, rinsed with PBS, and 100 μL counting beads (Invitrogen, cat: 01-2222-42, lot:2037700, Carlsbad, Calif.) were added. The disaggregated spleens were then centrifuged at 500 rpm for 5 minutes at 4° C. After decanting the supernatant, the cell pellet was lysed with 1 mL RBC lysis buffer (Unity Lab Services, Amgen, South San Francisco) and quenched with FACS buffer containing FBS (2%). Cells were centrifuged a second time at 500 rpm for 5 minutes at 4° C. After decanting the supernatant, the cell pellet was resuspended in 1 mL FBS-free media. 200 μL of cell suspension was transferred to a 96-well V-bottom plate, live/dead dye exclusion (Invitrogen, Eugene, Oreg.) was added (at a 1:500 dilution) and the cells were incubated for 45 minutes at room temperature in the dark. Cells were washed, centrifuged as previously, and resuspended in 50 μL of Fc block (BD Biosciences, San Jose, Calif.) prior to staining with the following antibodies: BUV395 anti-mouse CD4 clone GK1.5, BV650 anti-mouse CD44 clone IM7, BV421 anti-mouse CD8α clone 53-6.7, PE anti-mouse CD25 clone PC61, BV711 anti-mouse CD62L clone MEL-14 (all from BD Biosciences, San Jose, Calif.), BV510 anti-mouse CD45 clone 30-F11, BV605 anti-mouse Thy1.2 clone 53-2.1, FITC anti-mouse CD19 clone 1D3/CD19, APC anti-mouse CD20 clone SA275A11, AF700 anti-mouse CD69 clone H1.2F3 (all from Biolegend, San Diego, Calif.) and Pe-Cy7 anti-mouse PD1 clone J43 (Thermo Fisher, San Diego, Calif.). Cells were washed and resuspended prior to analysis on a FACSymphony flow cytometer (BD Biosciences, San Jose, Calif.).

Statistical Analysis

[0420] Graphs were generated, and data analysis was performed using GraphPad Prism software (version 7.04, Lo Jolla, Calif.). Mean serum cytokine levels and B cell counts (n=5 animals per group) were expressed as the mean±standard deviation. The p value of 0.05 was used to determine significant differences between all groups using a one-way ANOVA with Tukey's test (GraphPad Prism).

Example 2

[0421] Female BALB/cJ Rj mice (n=10/group) were treated with either vehicle or the BiTE® antibody construct muS110, directed against murine Epithelial Cell Adhesion Molecule for 2 days (Table 2) Animals in group 3 were pre-treated with etanercept (Enbrel) on days −2 and −1 as well as 1 hour before each muS110 administration. Animals in group 4 were administered an anti-IL6 monoclonal antibody (MP5-20F3, BD) on day −1 and one hour before each muS110 treatment. Blood samples were collected 4 and 24 hours after each vehicle and muS110 administration and serum concentrations of IL-6, TNF and MCP1 were determined using the BD™ CBA Mouse Enhanced Sensitivity Flex Set System (Becton Dickinson, BD) in accordance to the manufacturer's instructions (Table 2).

TABLE-US-00003 TABLE 2 Study Design Route of Treatment Group Compound Dosages Administration Schedule* 1 Vehicle — i.v. Days: 1, 2 2 muS110 0.05 i.v. Days: 1, 2 mg/kg/d 3 Enbrel + Enbrel: Enbrel: i.p. Enbrel: muS110 10 mg/kg/d muS110: i.v. days −2, −1, 1, 2 muS110: muS110: 0.05 mg/kg/d days 1, 2 4 Anti-IL6 + Anti-IL6: mAb: i.v. Anti-IL6: muS110 2.5 mg/kg/d muS110: i.v. days −1, 1 muS110: muS110: 0.05 mg/kg/d days 1, 2 *Etanercept (Enbrel) and the anti-IL6 monoclonal antibody were administered 1 hour before muS110 treatment on days 1 and 2.

In Vitro Anti-TNF Assay

[0422] Cytotoxicity, T-cell activation (CD69 upregulation) and cytokine release were determined in multiparametric cytotoxicity assays. Redirected T cell cytotoxicity was evaluated by flow cytometry using isolated human CD3+ T cells as effector cells and Epithelial Cell Adhesion Molecule (EpCAM)-expressing KatoIII tumor cells as target cells. Effector and target cells were co-cultured at an E:T cell ratio of 10:1 and serial dilutions of BiTE® antibody construct AMG110, directed against murine Epithelial Cell Adhesion Molecule in the absence or presence of an anti-TNF monoclonal antibody (BD) or the respective isotype control. AMG 110-mediated redirected target cell lysis was determined after 24, 48 and 72 hours. TNF and IL-6 concentrations in the cell culture supernatant were measured with the CBA human TH1/TH2 Kit in accordance to the manufacturer's instruction.

BiTE® Molecule Induced MCP-1 Release Blocked by Etanercept (Enbrel)

[0423] Human umbilical vein endothelial cells (HUVEC) were co-cultured with CD19-expressing NALM-6 cells and human PBMC and increasing concentrations of BiTE® antibody construct blinatumomab (AMG 103) against CD19 in the absence or presence of etanercept. MCP-1 concentrations were determined with the BD Cytometric CBA human MCP-1 Flex set system (BD, Germany after 2 and 5 hours, respectively according to the manufacturer's instructions and are shown in FIG. 6.

Blinatumumab VCAM Assay

[0424] The effect of blinatumomab (AMG 103) on T cell activation and the induction of VCAM-1 on endothelial cells was analyzed in co-cultures of HUVEC, isolated T cells and CD19-expressing NALM-6 target cells. VCAM-1 expression on CD31+HUVEC was analyzed by flow cytometry. The T cell activation marker VCAM-1 was up-regulated by AMG 103, which was sensitive to etanercept, indicating the potential role of TNF in BiTE® molecule-mediated endothelial activation (FIG. 7).

Example 3

Etanercept Prophylaxis for PSMA-Targeting BiTE-Related CRS in Humans

[0425] Etanercept premedication occurred within two days before BiTE administration to assess whether prophylaxis with the TNF-α inhibitor decreases the frequency and severity of CRS without compromising the efficacy of the BiTE. In an initial cohort of 6 to 8 subjects, the PSMA-targeting BiTE is administered. In addition to dexamethasone prophylaxis, subjects in the cohort received prophylaxis with etanercept (50 mg subcutaneously [SC]) two days prior to each dose of PSMA-targeting BiTE in the first administration cycle. This dose and timing was selected based on the PK properties of etanercept (slow absorption with mean±SD time of maximum concentration [tmax] of 69±34 hours; half-life of 102±30 hours) (Enbrel Package Insert, 2017; Zhou et al., 2011).

[0426] Subject incidence of safety events, including dose-limiting toxicities (DLTs), serious adverse events (SAEs), and adverse events leading to treatment discontinuation or dose reduction, will be reviewed when at least 3 DLT-evaluable subjects complete the DLT window. Subjects receiving three individual increasing doses of PSMA-targeting BiTE with etanercept prophylaxis experienced 1 DLT/SAE (grade 3 (G3) thrombocytopenia), 1 SAE (Grade 3 (G3) Afib), 0 dose reductions, 1 discontinuation (tolerability), CRS events in cycle 1: 4 grade 2 (G2), no grade 3/4 (G3/4). Etanercept prophylaxis improves CRS safety profile compared with no premedication or premedication with tocilizumab (8 mg/kg) given two hours before administration of the first dose of the PSMA-targeting BiTE. In the latter group 1 DLT/SAE (G3 Hypoacusis), 2 SAE (grade 3 (G3) Pruritus, grade 2/3 (G2/G3) CRS), 2 dose reductions, 2 discontinuations (disease progression), and CRS events in cycle 1: 4 grade 1 (G1), 7 grade 2 (G2), 4 grade 3 (G3) were observed. In the etanercept prophylaxis group the PSMA-targeting BiTE was administered at the same dosages and frequency as in the group without etanercept prophylaxis.

TABLE-US-00004 TABLE 3 Sequences SEQ ID Format/ NO Designation Source Amino acid sequence  1 CD3ϵ ECD human QDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLK EFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD  2 CD3ϵ ECD human QDGNEEMGGITQTPYKVSISGTTVILT pos. 1-27  3 CDR-L1 of H2C artificial GSSTGAVTSGYYPN  4 CDR-L2 of H2C artificial GTKFLAP  5 CDR-L3 of H2C artificial ALWYSNRWV  6 CDR-L1 of E2M artificial RSSTGAVTSGYYPN  7 CDR-L2 of E2M artificial ATDMRPS  8 CDR-L3 of E2M artificial ALWYSNRWV  9 CDR-L1 of F12Q artificial GSSTGAVTSGNYPN  10 CDR-L2 of F12Q artificial GTKFLAP  11 CDR-L3 of F12Q artificial VLWYSNRWV  12 CDR-H1 of F6A artificial IYAMN  13 CDR-H2 of F6A artificial RIRSKYNNYATYYADSVKS  14 CDR-H3 of F6A artificial HGNFGNSYVSFFAY  15 CDR-H1 of H2C artificial KYAMN  16 CDR-H2 of H2C artificial RIRSKYNNYATYYADSVKD  17 CDR-H3 of H2C artificial HGNFGNSYISYWAY  18 CDR-H1 of H1E artificial SYAMN  19 CDR-H2 of H1E artificial RIRSKYNNYATYYADSVKG  20 CDR-H3 of H1E artificial HGNFGNSYLSFWAY  21 CDR-H1 of G4H artificial RYAMN  22 CDR-H2 of G4H artificial RIRSKYNNYATYYADSVKG  23 CDR-H3 of G4H artificial HGNFGNSYLSYFAY  24 CDR-H1 of A2J artificial VYAMN  25 CDR-H2 of A2J artificial RIRSKYNNYATYYADSVKK  26 CDR-H3 of A2J artificial HGNFGNSYLSWWAY  27 CDR-H1 of ElL artificial KYAMN  28 CDR-H2 of ElL artificial RIRSKYNNYATYYADSVKS  29 CDR-H3 of ElL artificial HGNFGNSYTSYYAY  30 CDR-H1 of E2M artificial GYAMN  31 CDR-H2 of E2M artificial RIRSKYNNYATYYADSVKE  32 CDR-H3 of E2M artificial HRNFGNSYLSWFAY  33 CDR-H1 of F7O artificial VYAMN  34 CDR-H2 of F7O artificial RIRSKYNNYATYYADSVKK  35 CDR-H3 of F7O artificial HGNFGNSYISWWAY  36 CDR-H1 of F12Q artificial SYAMN  37 CDR-H2 of F12Q artificial RIRSKYNNYATYYADSVKG  38 CDR-H3 of F12Q artificial HGNFGNSYVSWWAY  39 CDR-H1 of I2C artificial KYAMN  40 CDR-H2 of I2C artificial RIRSKYNNYATYYADSVKD  41 CDR-H3 of I2C artificial HGNFGNSYISYWAY  42 CDR-L2 of H2C artificial GTKFLAP  43 CDR-L3 of H2C artificial ALWYSNRWV  44 CDR-H1 of H2C artificial KYAMN  45 CDR-L1 of H1E artificial GSSTGAVTSGYYPN  46 CDR-L2 of H1E artificial GTKFLAP  47 CDR-L3 of H1E artificial ALWYSNRWV  48 CDR-H1 of H1E artificial SYAMN  49 CDR-H2 of H1E artificial RIRSKYNNYATYYADSVKG  50 CDR-H3 of H1E artificial HGNFGNSYLSFWAY  51 CDR-L1 of G4H artificial GSSTGAVTSGYYPN  52 CDR-L2 of G4H artificial GTKFLAP  53 CDR-L3 of G4H artificial ALWYSNRWV  54 CDR-L1 of A2J artificial RSSTGAVTSGYYPN  55 CDR-L2 of A2J artificial ATDMRPS  56 CDR-L3 of A2J artificial ALWYSNRWV  57 CDR-L1 of ElL artificial GSSTGAVTSGYYPN  58 CDR-L2 of ElL artificial GTKFLAP  59 CDR-L3 of ElL artificial ALWYSNRWV  60 CDR-L1 of F7O artificial GSSTGAVTSGYYPN  61 CDR-L2 of F7O artificial GTKFLAP  62 CDR-L3 of F7O artificial ALWYSNRWV  63 CDR-L1 of I2C artificial GSSTGAVTSGNYPN  64 CDR-L2 of I2C artificial GTKFLAP  65 CDR-L3 of I2C artificial VLWYSNRWV  66 VL of H2C artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  67 VL of E2M artificial QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGATDMRPSGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  68 VL of F12Q artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL  69 VL variant artificial ELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF of H2C SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  70 VL variant artificial ELVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGATDMRPSGTPARF of A2J SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  71 VL variant artificial ELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF of F12Q SGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL  72 VH of F6A artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNIYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSFFAYWGQGTLVTVSS  73 VH of H2C artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSS  74 VH of H1E artificial EVQLVESGGGLEQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSFWAYWGQGTLVTVSS  75 VH of G4H artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNRYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSYFAYWGQGTLVTVSS  76 VH of A2J artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSWWAYWGQGTLVTVSS  77 VH of ElL artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYTSYYAYWGQGTLVTVSS  78 VH of E2M artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNGYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKERFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHRNFGNSYLSWFAYWGQGTLVTVSS  79 VH of F7O artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISWWAYWGQGTLVTVSS  80 VH of F12Q artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSS  81 VH of I2C artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSS  82 VH of F12q artificial EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSS  83 VH variant of F6A artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNIYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSFFAYWGQGTLVTVSS  84 VH variant of H2C artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSS  85 VH variant of H1E artificial EVQLLESGGGLEQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSFWAYWGQGTLVTVSS  86 VH variant of G4H artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNRYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSYFAYWGQGTLVTVSS  87 VH variant of A2J artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSWWAYWGQGTLVTVSS  88 VH variant of E1L artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYTSYYAYWGQGTLVTVSS  89 VH variant of E2M artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNGYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKERFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHRNFGNSYLSWFAYWGQGTLVTVSS  90 VH variant of F7O artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISWWAYWGQGTLVTVSS  91 VH variant of F12Q artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSS  92 VH variant of I2C artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSS  93 VL of F6A artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  94 VL of HlE artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  95 VL of G4H artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  96 VL of A2J artificial QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGATDMRPSGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  97 VL of E1L artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  98 VL of F7O artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL  99 VL of I2C artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 100 VL of F12q artificial QTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARF SGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 101 scFv of F6A artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNIYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSFFAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 102 scFv of H2C artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 103 scFv of H1E artificial EVQLVESGGGLEQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSFWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 104 scFv of G4H artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNRYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSYFAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 105 scFv of A2J artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGA TDMRPSGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 106 scFv of E1L artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYTSYYAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 107 scFv of E2M artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNGYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKERFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHRNFGNSYLSWFAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGA TDMRPSGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 108 scFv of F7O artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 109 scFv of F12Q artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 110 scFv of I2C artificial EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL ill scFv of F12q artificial EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD SVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 112 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNIYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of F6A SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSFFAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 113 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of H2C SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 114 scFv variant artificial EVQLLESGGGLEQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of H1E SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSFWAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 115 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNRYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of G4H SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSYFAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 116 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of A2J SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYLSWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGA TDMRPSGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 117 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of E1L SVKSRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYTSYYAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 118 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNGYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of E2M SVKERFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHRNFGNSYLSWFAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCRSSTGAVTSGYYPNWVQQKPGQAPRGLIGA TDMRPSGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 119 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNVYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of F7O SVKKRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGYYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCALWYSNRWVFGGGTKLTVL 120 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNSYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of F12Q SVKGRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYVSWWAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 121 scFv variant artificial EVQLLESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYAD of I2C SVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGG GSGGGGSGGGGSELVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGG TKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 122 20A2 VH CDR1 artificial NYGMH 123 20A2 VH CDR2 artificial LIWYDGSKKYYADSVKG 124 20A2 VH CDR3 artificial DPSSLTGSTGYYGMDV 125 20A2 VL CDR1 artificial SGDKLGDKYAC 126 20A2 VL CDR2 artificial QDRKRPS 127 20A2 VL CDR3 artificial QAWDSSTEV 128 20A2 light chain artificial MAWALLLLTLLTQGTGSWASYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVL VIYQDRKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSSTEVFGGGT KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 129 2OC1 VH CDR1 artificial SYDMS 130 20C1 VH CDR2 artificial LISGGGSNTYYADSVKG 131 20C1 VH CDR3 artificial PSGHYFYAMDV 132 20C1 VL CDR1 artificial RASQGISNWLA 133 20C1 VL CDR2 artificial AASSLQS 134 22D4 VH CDR1 artificial DYSMS 135 22D4 VH CDR2 artificial GINWNGGRTRYAD SVKG 136 22D4 VH CDR3 artificial EFNNFESNWFDP 137 22D4 VL CDR1 artificial SGDALPKKYAY 138 22D4 VL CDR2 artificial EDSKRPS 139 22D4 VL CDR3 artificial YSTDSSGNHRV 140 20C1.006 VH CDR1 artificial SYDMS 141 20C1.006 VH CDR2 artificial LISGGGSNTYYAESVKG 142 20C1.006 VH CDR3 artificial PSGHYFYAMDV 143 20C1.006 VL CDR1 artificial RASQGISNWLA 144 20C1.006 VL CDR2 artificial AASSLQS 145 20C1.006 VL CDR3 artificial QQAESFPHT 146 20C1.009 VH CDR1 artificial SYDMS 147 20C1.009 VH CDR2 artificial LISGGGSQTYYAESVKG 148 20C1.009 VH CDR3 artificial PSGHYFYAMDV 149 20C1.009 VL CDR1 artificial RASQGISNWLA 150 20C1.009 VL CDR2 artificial AASSLQS 151 20C1.009 VL CDR3 artificial QQAESFPHT 152 20A2.003 VH CDR1 artificial NYGMH 153 20A2.003 VH CDR2 artificial LIWYDASKKYYAESVKG 154 20A2.003 VH CDR3 artificial DPSSLTGSTGYYGMDV 155 20A2.003 VL CDR1 artificial SGDKLGDKYAS 156 20A2.003 VL CDR2 artificial QDRKRPS 157 20A2.003 VL CDR3 artificial QAFESSTEV 158 22D4.006 VH CDR1 artificial DYSMS 159 22D4.006 VH CDR2 artificial GINWNGGRTRYADAVKG 160 22D4.006 VH CDR3 artificial EFNNFESNWFDP 161 22D4.006 VL CDR1 artificial SGDALPKKYAY 162 22D4.006 VL CDR2 artificial EDAKRPS 163 22D4.006 VL CDR3 artificial YSTDASGNHRV 164 22D4.017 VH CDR1 artificial DYSMS 165 22D4.017 VH CDR2 artificial GINWNAGRTRYADAVKG 166 22D4.017 VH CDR3 artificial EFNNFESNWFDP 167 22D4.017 VL CDR1 artificial SGDALPKKYAY 168 22D4.017 VL CDR2 artificial EDAKRPS 169 22D4.017 VL CDR3 artificial YSTDASGNHRV 170 20A2 VH artificial QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVALIWYDGSKKYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCARDPSSLTGSTGYYGMDVWGQGTTVTVSS 171 20A2 VL artificial SYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDRKRPSGIPERFSGS NSGNTATLTISGTQAMDEADYYCQAWDSSTEVFGGGTKLTVL 172 20C1 VH artificial EVQLLESGGGLVQPGGALRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSLISGGGSNTYYADSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCASPSGHYFYAMDVWGQGTTVTVSS 173 20C1 VL artificial DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWYQQKPGKAPKLLIFAASSLQSGVPSRFGG SGSGTDFTFTISSLQPEDFATYYCQQADSFPHTFGGGTKVEIK 174 22D4 VH artificial EVQLVESGGSVVRPGGSLRLSCAASGFTVDDYSMSWVRQVPGKGLEWVSGINWNGGRTRYADSV KGRFTISRDSAKNSLYLQMNSLRAEDTALYYCAREFNNFESNWFDPWGQGTLVTVSS 175 22D4 VL artificial SYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKSGQAPVLVISEDSKRPSGIPERFSGS SSGTMATLTISGAQVEDEADYYCYSTDSSGNHRVFGGGTKLTVL 176 20C1.006 VH artificial EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSLISGGGSNTYYAESV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCASPSGHYFYAMDVWGQGTTVTVSS 177 20C1.006 VL artificial DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWYQQKPGKAPKLLIFAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQAESFPHTFGGGTKVEIK 178 20C1.009 VH artificial EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSLISGGGSQTYYAESV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCASPSGHYFYAMDVWGQGTTVTVSS 179 20C1.009 VL artificial DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWYQQKPGKAPKLLIFAASSLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYCQQAESFPHTFGGGTKVEIK 180 20A2.003 VH artificial QVQLVESGGGWQPGRSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVALIWYDASKKYYAESV KGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCARDPSSLTGSTGYYGMDVWGQGTTVTVSS 181 20A2.003 VL artificial SYELTQPPSVSVSPGQTASITCSGDKLGDKYASWYQQKPGQSPVLVIYQDRKRPSGIPERFSGS NSGNTATLTISGTQAMDEADYYCQAFESSTEVFGGGTKLTVL 182 22D4.006 VH artificial EVQLVESGGSVVRPGGSLRLSCAASGFTVDDYSMSWVRQVPGKGLEWVSGINWNGGRTRYADAV KGRFTISRDSAKNSLYLQMNSLRAEDTALYYCAREFNNFESNWFDPWGQGTLVTVSS 183 22D4.006 VL artificial SYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKPGQAPVLVISEDAKRPSGIPERFSGS SSGTMATLTISGAQVEDEADYYCYSTDASGNHRVFGGGTKLTVL 184 22D4.017 VH artificial EVQLVESGGSVVRPGGSLRLSCAASGFTVDDYSMSWVRQVPGKGLEWVSGINWNAGRTRYADAV KGRFTISRDSAKNSLYLQMNSLRAEDTALYYCAREFNNFESNWFDPWGQGTLVTVSS 185 22D4.017 VL artificial SYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKPGQAPVLVISEDAKRPSGIPERFSGS SSGTMATLTISGAQVEDEADYYCYSTDASGNHRVFGGGTKLTVL 186 20A2 heavy chain artificial MDMRVPAQLLGLLLLWLRGARCQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPG KGLEWVALIWYDGSKKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAR DPSSLTGSTGYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 187 20A2 light chain artificial MAWALLLLTLLTQGTGSWASYELTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVL VIYQDRKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDSSTEVFGGGT KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 188 20C1 heavy chain artificial MDMRVPAQLLGLLLLWLRGARCEVQLLESGGGLVQPGGALRLSCAASGFTFSSYDMSWVRQAPG KGLEWVSLISGGGSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAS PSGHYFYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 189 20C1 light chain artificial MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWYQQKPGK APKLLIFAASSLQSGVPSRFGGSGSGTDFTFTISSLQPEDFATYYCQQADSFPHTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 190 22D4 heavy chain artificial MDMRVPAQLLGLLLLWLRGARCEVQLVESGGSVVRPGGSLRLSCAASGFTVDDYSMSWVRQVPG KGLEWVSGINWNGGRTRYADSVKGRFTISRDSAKNSLYLQMNSLRAEDTALYYCAR EFNNFESNWFDPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 191 22D4 light chain artificial MAWALLLLTLLTQGTGSWASYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKSGQAPVL VISEDSKRPSGIPERFSGSSSGTMATLTISGAQVEDEADYYCYSTDSSGNHRVFGG GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 192 20C1. 006 artificial MDMRVPAQLLGLLLLWLRGARCEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPG heavy chain KGLEWVSLISGGGSNTYYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAS PSGHYFYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 193 20C1.006 artificial MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWYQQKPGK light chain APKLLIFAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAESFPHTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 194 20C1.009 artificial MDMRVPAQLLGLLLLWLRGARCEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPG heavy chain KGLEWVSLISGGGSQTYYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAS PSGHYFYAMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 195 20C1.009 artificial MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWYQQKPGK light chain APKLLIFAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAESFPHTF GGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 196 20A2.003 artificial MDMRVPAQLLGLLLLWLRGARCQVQLVESGGGVVQPGRSLRLSCAASGFTFSNYGMHWVRQAPG heavy chain KGLEWVALIWYDASKKYYAESVKGRFTISRDNSKNTLYLQMNSLRAEDTAAYYCAR DPSSLTGSTGYYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVK FNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 197 20A2.003 artificial MAWALLLLTLLTQGTGSWASYELTQPPSVSVSPGQTASITCSGDKLGDKYASWYQQKPGQSPVL light chain VIYQDRKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAFESSTEVFGGGT KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPS KQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 198 22D4.006 artificial MDMRVPAQLLGLLLLWLRGARCEVQLVESGGSVVRPGGSLRLSCAASGFTVDDYSMSWVRQVPG heavy chain KGLEWVSGINWNGGRTRYADAVKGRFTISRDSAKNSLYLQMNSLRAEDTALYYCAR EFNNFESNWFDPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 199 22D4.006 artificial MAWALLLLTLLTQGTGSWASYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKPGQAPVL light chain VISEDAKRPSGIPERFSGSSSGTMATLTISGAQVEDEADYYCYSTDASGNHRVFGG GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 200 22D4.017 artificial MDMRVPAQLLGLLLLWLRGARCEVQLVESGGSVVRPGGSLRLSCAASGFTVDDYSMSWVRQVPG heavy chain KGLEWVSGINWNAGRTRYADAVKGRFTISRDSAKNSLYLQMNSLRAEDTALYYCAR EFNNFESNWFDPWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 201 22D4.017 artificial MAWALLLLTLLTQGTGSWASYELTQPPSVSVSPGQTARITCSGDALPKKYAYWYQQKPGQAPVL light chain VISEDAKRPSGIPERFSGSSSGTMATLTISGAQVEDEADYYCYSTDASGNHRVFGG GTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTT PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 202 linker 1 artificial GGGG 203 linker 2 artificial GGGGS 204 linker 3 artificial GGGGQ 205 linker 4 artificial SGGGGS 206 linker 5 artificial PGGGGS 207 linker 6 artificial PGGDGS 208 linker 7 artificial GGGGSGGGS 209 linker 8 = (G.sub.4S).sub.2 artificial GGGGSGGGGS linker 210 linker 9 = (G.sub.4S).sub.3 artificial GGGGSGGGGSGGGGS linker 211 (G.sub.4S).sub.4 linker artificial GGGGSGGGGSGGGGSGGGGS 212 (G.sub.4S).sub.5 linker artificial GGGGSGGGGSGGGGSGGGGSGGGGS 213 (G.sub.4S) linker artificial GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 214 (G.sub.4S).sub.7 linker artificial GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 215 (G.sub.4S).sub.8 linker artificial GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 216 Ab156 artificial RDWDFDVFGGGTPVGG 217 linear FcRn BP artificial QRFVTGHFGGLXPANG 218 linear FcRn BP-Y artificial QRFVTGHFGGLYPANG 219 linear FcRn BP-H artificial QRFVTGHFGGLHPANG 220 core FcRn BP-H artificial TGHFGGLHP 221 cyclic FcRn BP-H artificial QRFCTGHFGGLHPCNG 222 HALB human DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLV AASQAALGL 223 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 1 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAGTFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAAMDDFAAFVEKCCKADDKETCFAEEGKKLV AASQAALGL 224 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 2 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 225 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 3 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPHLV AASKAALGL 226 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 4 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALGVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 227 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 5 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 228 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 6 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPHLV AASQAALGL 229 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 7 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPHLV AASKAALGL 230 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 8 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASKAALGL 231 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 9 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPKLV AASKAALGL 232 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 10 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLV AASQAALGL 233 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 11 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAGTFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAAMDDFAAFVEKCCKADDKETCFAEEGKKLV AASQAALGL 234 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 12 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 235 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 13 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPHLV AASKAALGL 236 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 14 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALGVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 237 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 15 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 238 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 16 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPHLV AASQAALGL 239 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 17 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPHLV AASKAALGL 240 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 18 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASKAALGL 241 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 19 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPKLV AASKAALGL 242 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 20 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLV AASQAALGL 243 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 21 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAGTFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAAMDDFAAFVEKCCKADDKETCFAEEGKKLV AASQAALGL 244 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 22 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 245 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 23 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPHLV AASKAALGL 246 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 24 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALGVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 247 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 25 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASQAALGL 248 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 26 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPHLV AASQAALGL 249 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 27 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPHLV AASKAALGL 250 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 28 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDKFAAFVEKCCKADDKETCFAEEGPKLV AASKAALGL 251 HALB artificial DAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQAPFEDHVKLVNEVTEFAKTCVADESAENCDK variant 29 SLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFH DNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKAS SAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADD RADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYA EAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEP QNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPC AEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALDVDETYVPKEFNAETFTFHAD ICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGPKLV AASKAALGL 252 Cross body 1 HC artificial ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK 253 Cross body 1 LC artificial GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNN KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSLTCLVK GFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN HYTQKSLSLSPGK 254 Cross body 2 HC artificial ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVEPKSSDKTHTCPPCPAPEAAGGPSVFLFPP KPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK 255 Cross body 2 LC artificial GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNN KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECSEPKSSDKTHTCPPCPAPEAAGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK 256 Hetero-Fc artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV binder Fc HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 257 Hetero-Fc artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV partner Fc HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 258 Maxi-body 1 artificial EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV target Fc DGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 259 Maxi-body 1 artificial EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV CD3 Fc DGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLY SDLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 260 Maxi-body 2 artificial EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV target Fc DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSRKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 261 Maxi-body 2 artificial EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV CD3 Fc DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLY SDLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 262 Mono Fc artificial APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVTTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDSDGSFFLYSDLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK 263 Fc monomer-1 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV +c/−g HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 264 Fc monomer-2 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV +c/−g/delGK HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 265 Fc monomer-3 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV −c/+g HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 266 Fc monomer-4 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV -d+d delGK HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 267 Fc monomer-5 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV −c/−g HNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 268 Fc monomer-6 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV −c/−g/ delGK HNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 269 Fc monomer-7 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV +c/+g HNAKTKPCEEQYNSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 270 Fc monomer-8 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV delGK HNAKTKPCEEQYNSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 271 scFc-l artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSGGGG SDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 272 scFc-2 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 273 scFc-3 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSGGGG SDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 274 scFc-4 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 275 scFc-5 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSGGGG SDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 276 scFc-6 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYGSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 277 scFc-7 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPCEEQYNSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSGGGGSGGGG SDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPCEEQYNSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 278 scFc-8 artificial DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPCEEQYNSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPCEEQYNSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 279 5x his-tag artificial HHHHH 280 6x his-tag artificial HHHHHH 281 CL-1 x I2C bispecific QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQCLEWMGWINPNSGGTKYAQKF molecule QGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDRITVAGTYYYYGMDVWGQGTTVTVSSGGG GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGVNNWLAWYQQKPGKAPKLLIYTAS SLQSGVPSRFSGSGSGTDFTLTIRSLQPEDFATYYCQQANSFPITFGCGTRLEIKSGGGGSEVQ LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVK DRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSG GGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKF LAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 282 CL-2 x I2C bispecific QVQMVQSGAEVKKHGASVKVSCKASGYTFTGYYMHWVRQAPGQCLEWMGWINPNSGGTKYAQKF molecule QGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDRITVAGTYYYYGMDVWGQGTTVTVSSGGG GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGVNNWLAWYQQKPGKAPKLLIYTAS SLQSGVPSRFSGSGSGTDFTLTIRSLQPEDFATYYCQQANSFPITFGCGTRLEIKSGGGGSEVQ LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVK DRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSG GGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKF LAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVL 283 CL-1 x I2C-6His bispecific QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQCLEWMGWINPNSGGTKYAQKF molecule - QGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDRITVAGTYYYYGMDVWGQGTTVTVSSGGG his tag GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGVNNWLAWYQQKPGKAPKLLIYTAS SLQSGVPSRFSGSGSGTDFTLTIRSLQPEDFATYYCQQANSFPITFGCGTRLEIKSGGGGSEVQ LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVK DRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSG GGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKF LAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVLHHHHHH 284 CL-2 x I2C-6His bispecific QVQMVQSGAEVKKHGASVKVSCKASGYTFTGYYMHWVRQAPGQCLEWMGWINPNSGGTKYAQKF molecule - QGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDRITVAGTYYYYGMDVWGQGTTVTVSSGGG his tag GSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCRASQGVNNWLAWYQQKPGKAPKLLIYTAS SLQSGVPSRFSGSGSGTDFTLTIRSLQPEDFATYYCQQANSFPITFGCGTRLEIKSGGGGSEVQ LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVK DRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSG GGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKF LAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVLHHHHHH 285 AUl epitope artificial DTYRYI 286 AU5 epitope artificial TDFYLK 287 T-7 tag artificial MASMTGGQQMG 288 V-5 tag artificial GKPIPNPLLGLDST 289 B-tag artificial QYPALT 290 E2 epitope artificial SSTSSDFRDR 291 FLAG tag artificial DYKDDDK 292 Glu-Glu tag 1 artificial EYMPME 293 Glu-Glu tag 2 artificial EFMPME 294 Histidine artificial KDHLIHNVHKEFHAHAHNK affinity tag 295 HSV epitope artificial QPELAPED 296 KT3 epitope artificial KPPTPPPEPET 297 Myc epitope artificial CEQKLISEEDL 298 7x his-tag artificial HHHHHHH 299 8x his-tag artificial HHHHHHHH 300 SI tag artificial NANNPDWDF 301 S-tag artificial KETAAAKFERQHMDS 302 Strep-tag 1 artificial WSHPQFEK 303 Strep-tag 2 artificial AWAHPQPGG 304 Universal tag artificial HTTPHH 305 VSV-G artificial YTDIEMNRLGK 306 Protein C artificial EDQVDPRLIDGK