Multivalent trap-antibody fusions

Abstract

The present disclosure relates to multivalent antibody fusions, methods of making the same, and methods of using the same. In particular, aspects of the present disclosure relate to trap-based bispecific molecules, as well as methods of making trap-based bispecific molecules, useful for the effective treatment of diseases with a variety of potential signaling pathways.

Description

[0001] INCORPORATION BY REFERENCE OF ANY PRIORITY APPLICATION

[0002] This application claims the benefit of U.S. Provisional Serial No. 63 / 487,606, filed February 28, 2023, which is incorporated by reference herein in its entirety.

[0003] REFERENCE TO A SEQUENCE LISTING

[0004] This application is filed with an electronic sequence listing. The sequence listing is provided in a file named KDIAK191WOSEQLIST.XML, which was created on February 9, 2024, and last modified on February 9, 2024, and is 85,255 bytes in size. The information contained in the electronic sequence listing is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0005] The present disclosure relates to multivalent antibody fusions, methods of making the same, and methods of using the same. BACKGROUND

[0006] Multivalent molecules can bind to more than one target, or more than one portion of a target molecule. SUMMARY

[0007] Some embodiments provided herein are described by the embodiments provided below, and are also provided as possible combinations or overlapping embodiments:

[0008] Multivalent trap-antibody and / or trap-Fab fusions comprising: a trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the trap and the antibody are linked in tandem through a linker; the trap-antibody fusion comprises both an interleukin (IL) binding site and an antigen binding site; and wherein the IL binding site and the antigen binding site are located at different positions on the trap-antibody fusion. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0009] A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor and an IL accessory protein; wherein the IL trap and the antibody are linked in tandem by a linker; the IL trap-antibody fusion comprises both an IL binding site and an antigen binding site; and wherein the IL binding site and the antigen binding site are located at different locations on the trap-antibody fusion. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0010] A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap; wherein; wherein the IL trap comprises an IL receptor and an IL accessory protein; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and the antibody are linked in tandem by a linker; the interleukin trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and wherein binding of the IL trap-antibody fusion to an antigen inhibits antigen activity. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0011] Multivalent interleukin (IL) trap-Fab fusions comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein the IL trap comprises an IL receptor and an IL accessory protein; the IL trap and the Fab fragment are connected in tandem by a linker; the IL trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein the IL binding site and the antigen binding site are located at different positions on the trap-antibody fusion. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusions are bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0012] Multivalent interleukin (IL) trap-Fab fusions comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein the IL trap and the antibody are connected in tandem by a linker. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusions are bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0013] A method of inhibiting interleukin signaling in a subject comprising administering an interleukin trap-antibody fusion, the fusion comprising: an IL trap; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein; the IL trap-antibody fusion comprises an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and binding of the IL trap-antibody fusion to an antigen inhibits antigen activity. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecule comprises a TNFa inhibitor. In some embodiments, the TNFa inhibitor comprises a TNFa trap. In some embodiments, the TNFa inhibitor comprises a TNFa VHH. In some embodiments, the bispecific molecule comprises a TNFa trap fused to an IL-6 antibody. In some embodiments, the bispecific molecule comprises a TNFa VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecule comprises a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0014] A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor and an IL co-receptor; wherein the IL trap and the antibody are linked in tandem by a linker; the IL trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein the IL binding site and the antigen binding site are located at different positions on the trap-antibody fusion; and wherein the multivalent IL trap-antibody fusion is conjugated to a polymer. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0015] A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap; wherein; wherein the IL trap comprises an IL receptor and an IL accessory protein; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and the antibody are linked in tandem by a linker; the interleukin trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and wherein binding of the IL trap-antibody fusion to an antigen inhibits antigen activity; and wherein the multivalent IL trap-antibody fusion is conjugated to a polymer. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0016] A multivalent interleukin (IL) trap-Fab fusion comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein the IL trap comprises an IL receptor and an IL accessory protein; the IL trap and the Fab fragment are connected in tandem by a linker; the IL trap-Fab fusion comprises both an IL binding site and an antigen binding site; wherein the IL binding site and the antigen binding site are located at different positions on the trap-Fab fusion; wherein the multivalent IL trap-antibody fusion is conjugated to a polymer. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH. In some embodiments, the bispecific molecules comprise a TNFα trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFα VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap.

[0017] A multivalent interleukin (IL) trap-Fab fusion comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein the IL trap and the Fab are connected in tandem by a linker; and wherein the multivalent IL trap-Fab fusion is conjugated to a polymer.

[0018] A method of inhibiting cytokine, such as but not limited to interleukin signaling, in a subject comprising administering an interleukin trap-antibody fusion comprising: an IL trap; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein; the IL trap-antibody fusion comprises an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and binding of the IL trap-antibody fusion to an antigen inhibits antigen activity; and wherein the multivalent IL trap-antibody fusion is conjugated to a polymer. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules comprise an IL-1 trap fused to an anti-IL-6 or anti-HTRA1 antibody, an IL-6 trap fused to an anti-HTRA1 antibody, and an IL-33 trap fused to an anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFa inhibitor. In some embodiments, the TNFa inhibitor comprises a TNFa trap. In some embodiments, the TNFa inhibitor comprises a TNFa VHH. In some embodiments, the bispecific molecules comprise a TNFa trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFa VHH fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a VEGF trap. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 is a representative illustration of some embodiments of a multivalent interleukin (IL) trap-antibody fusion.

[0020] Figure 2 is a representative illustration of some embodiments of a multivalent interleukin (IL) trap-antibody fusion that binds to IL and an antigen.

[0021] Figure 3 is a flowchart and representative illustration of some embodiments of a method of inhibiting interleukin signaling.

[0022] Figure 4 is a schematic of some embodiments illustrating IL-1 trap and IgG fusion construct configurations. Dark crescent represents IL1R1 or IL1R2. Light crescent represents IL1RAcP.

[0023] Figure 5 is a superimposition of SPR sensorgrams showing that IL-1 trap anti-HTRA1 (TA97) can bind both IL-1 beta and HTRA1. SPR of injection of IL-1 beta after injection of HTRA1 (upper sensorgram) or injection of HTRA1 after injection of IL-1 beta (lower sensorgram).

[0024] Figure 6 Actual / expected SPR responses of injection of HTRA1 then IL-1 beta (left) or IL-1 beta then HTRA1 (right) to surfaces captured with IL-1 trap anti-HTRA1 (TA97 and TA98) and anti-HTRA1 antibody (aHTRA1.36) of two configurations are illustrated.

[0025] Figure 7 It is shown that IL-1 trap anti-HTRA1 (TA97) effectively inhibits HTRA1 activity even when it is bound to IL-1 beta. HTRA1 activity measured in H2-Opt assay is plotted against log scale of trap-antibody concentration (M). Open squares indicate that HTRA1 activity is inhibited even in the presence of excess IL-1 beta.

[0026] Figure 8 It is demonstrated that the mass of IL-1 trap anti-HTRA1 (TA105) shifts accordingly when bound to HTRA1 and / or IL-1 beta as measured by mass photometry.

[0027] Figure 9 It is shown that the pH dependence (upper panel) and NaCl concentration dependence (lower panel) thermal stability of IL-1 trap x anti-HTRA1 (TA97). Each point represents the average Tm of three replicates measured in DSF.

[0028] Figure 10 SDS-PAGE of IL-1 trap anti-HTRA1 (TA105) before and after biopolymer conjugation is shown.

[0029] Figure 11 It is demonstrated that biopolymer conjugated IL-1 trap anti-HTRA1 (TA105) binds to IL-1 beta in IL-1 beta Lumit assay.

[0030] Figure 12 It is demonstrated that biopolymer conjugated IL-1 trap anti-HTRA1 (TA105) inhibits the proteolytic activity of HTRA1 as measured in H2-opt assay.

[0031] Figure 13SDS-PAGE of IL-1 trap anti-IL-6 Fab (TF2) before and after bioconjugation is shown.

[0032] Figure 14 Bioconjugated IL-1 trap anti-IL-6 Fab (TF2) was shown to compete with IL-1 beta binding in an IL-1 beta sandwich ELISA.

[0033] Figure 15 Bioconjugated IL-1 trap anti-IL-6 Fab (TF2) was shown to inhibit IL-6 binding to IL-6R alpha in an IL-6 / IL-6R alpha DuoSet ELISA.

[0034] Figure 16 are graphical representations of some multivalent interleukin (IL) trap-antibody fusions conjugated to polymers.

[0035] Figure 17 Representative embodiments of full length and regions of IL-1, IL-6, IL-33, and VEGF receptor sequences are shown.

[0036] Figure 18 Some representative embodiments of IgG constant and variable region sequences are shown.

[0037] Figure 19 Some representative embodiments of linkers suitable for linking IL receptor proteins to antibody variable domains are shown.

[0038] Figure 20 Some representative embodiments of signal peptide sequences suitable for trap-antibody fusions disclosed herein are shown.

[0039] Figure 21 Some representative embodiments of full length heavy chain sequences suitable for trap-antibody fusions disclosed herein are shown.

[0040] Figure 22 Some representative embodiments of full length light chain sequences suitable for trap-antibody fusions disclosed herein are shown.

[0041] Figure 23 Some representative embodiments of full length heavy chain sequences suitable for trap-Fab fusions disclosed herein are shown.

[0042] Figure 24 Some representative embodiments of full length light chain sequences suitable for trap-Fab fusions disclosed herein are shown.

[0043] Figure 25Table 1 is a table listing embodiments of medical indications for which administration of a trap-antibody or trap-Fab fusion can be applicable.

[0044] Figure 26 OG1786 is shown.

[0045] Figure 27 OG1801 is shown.

[0046] Figure 28 OG1802 is shown.

[0047] Figure 29 It was demonstrated that IL-1 trap anti-IL-6 knob-in-hole antibodies compete with IL-1 β for binding in an IL-1 β sandwich ELISA.

[0048] Figure 30 Figure 1 is a graph showing some embodiments demonstrating that IL-1 trap anti-IL-6 knob-in-hole antibodies inhibit the binding of IL-6 to IL-6Rα in an IL-6 / IL-6Rα DuoSet ELISA, even in the presence of excess IL-1 β.

[0049] Figure 31A Figure 2 is a graph showing some embodiments of experimental / expected SPR responses when injecting IL-6 then IL-1 β into a surface captured with IL-1 trap anti-IL-6 knob-in-hole antibodies.

[0050] Figure 31B Figure 3 is a graph showing some embodiments of experimental / expected SPR responses when injecting IL-1 β then IL-6 into a surface captured with IL-1 trap anti-IL-6 knob-in-hole antibodies.

[0051] Figure 32A Figure 4 illustrates experimental / expected SPR responses when injecting IL-6 then TNFα into a surface captured with TNFα trap anti-IL-6 antibodies.

[0052] Figure 32B Figure 5 illustrates experimental / expected SPR responses when injecting TNFα then IL-6 into a surface captured with TNFα trap anti-IL-6 antibodies.

[0053] Figure 33 Figure 6 is a graph showing some embodiments demonstrating that the mass of anti-TNFα VHH anti-IL-6 antibody (TA189) shifts accordingly when bound to TNFα and / or IL-6, as measured by mass photometry.

[0054] Figure 34AFigure 6 is a graph showing experimental / expected SPR responses when injecting IL-6 then TNFa to a surface captured with anti-TNFa VHH anti-IL-6 antibody, according to some embodiments.

[0055] Figure 34B Figure 7 is a graph showing experimental / expected SPR responses when injecting TNFa then IL-6 to a surface captured with anti-TNFa VHH anti-IL-6 antibody, according to some embodiments. DETAILED DESCRIPTION

[0056] Provided herein are multivalent antibody fusions, methods of making the same, and methods of using the same. Some aspects of the disclosure relate to trap-based bispecific molecules, and methods of making trap-based bispecific molecules. In some embodiments, one or more multivalent antibody fusions and / or trap-based bispecific molecules can be used to effectively treat diseases having multiple potential signaling pathways. In some embodiments, the diseases include ocular inflammation or inflammation of the eye.

[0057] Growth factors (GFs) and cytokines mediate critical intercellular communication in endocrine, paracrine, and autocrine manners. They regulate cellular activities, including proliferation, differentiation, and migration, ultimately leading to various biological responses, such as tissue development, tissue homeostasis, and immune function; Kany S, Vollrath JT, Relja B. 2019. “Cytokines in Inflammatory Disease.” Int. J. Mol. Sci. 20: 6008–; Apte RS, Chen DS, Ferrara N. 2019. “VEGF in Signaling and Disease: Beyond Discovery and Development.” Cell 176: 1248–1264; Ren X, Zhao M, Lash B, Martino MM, Julier Z. 2020. “Growth Factor Engineering Strategies for Regenerative Medicine Applications.” Front. Bioeng. Biotechnol. 7. A common signaling mechanism used by GFs and cytokines involves homomultimerization or heteromultimerization of cognate receptors on the cell surface in response to ligand binding, which triggers activation and downstream intracellular signaling; Atanasova M, Whitty A. 2012. “Understanding cytokine and growth factor receptor activation mechanisms.” Crit. Rev. Biochem. Mol. Biol. 47: 502–530.Receptors are transmembrane proteins; the extracellular domain (ECD) region recognizes and binds ligands, while the intracellular portion exhibits intrinsic kinase activity or contains a "pocket" domain that interacts with kinases; Grozinger J. 2002. "Molecular mechanisms of cytokine receptor activation." Biochim. Biophys. Acta. Mol. Cell. Res. 1592: 215-223; Wang X, Lupardus P, LaPorte SL, Garcia KC. 2009. Structural Biology of Shared Cytokine Receptors. Annu. Rev. Anal. Chem. (Palo Alto. Calif). 27: 29-60.

[0058] Cytokine dysregulation is associated with a variety of health problems, including inflammatory diseases, age-related diseases, and cancer; Turner MD, Nedjai B, Hurst T, Pennington DJ. 2014. “Cytokines and chemokines: At the crossroads of cell signaling and inflammatory disease.” Biochim. Biophys. Acta. Mol. Cell. Res. 1843: 2563-2582; Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. 2018. “Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines.” Front. Immunol. 9; Morris RM, Mortimer TO, O’Neill KL. 2022. “Cytokines: Can Cancer Get the Message?” Cancers 14: 2178-The molecular design of several drugs is based on the Fc-fusion format, in which a native ECD domain is fused to a fragment crystallizable (Fc) region of immunoglobulin G (IgG); Economides AN, Carpenter LR, Rudge JS, Wong V, Koehler-Stec EM, Hartnett C, Pyles EA, Xu X, Daly TJ, Young MR, et al. 2002. "Cytokine traps: multi-component, high-affinity blockers of cytokine action." Nat. Med. 9: 47-52; Scott LJ. 2014. "Etanercept: A Review of Its Use in Autoimmune Inflammatory Diseases." Drugs 74: 1379-1410; Sophie R, Akhtar A, Sepah YJ, Ibrahim M, Bittencourt M, Do DV, Nguyen QD. 2012. "Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases." Biol. Ther. 2. The Fc portion forms a dimer through interdomain interactions, which are further stabilized by an interchain disulfide bond. This in turn places the receptors in close proximity in a manner that allows the ECD domains to dimerize and bind to their targets with high affinity (trap mechanism).

[0059] Bispecific antibodies have shown to be a promising strategy to overcome some of the fundamental limitations of monospecific antibody therapy that cannot address multiple cross-talking signaling pathways underlying the target disease. Despite efforts to address immunogenicity, chain mispairing issues and production scale-up associated with multivalent molecules, there remains a need to develop bispecific formats that effectively address these issues; Brinkmann U, Kontermann RE. 2017. "The making of bispecific antibodies." mAbs 9: 182-212; Godar et Godar M, deHaard H, Blanchetot C, Rasser J. 2018. "Therapeutic bispecific antibody formats: a patent applications review" (1994-2017). Expert. Opin. Ther. Pat. 28: 251-276. Accordingly, some aspects of the present disclosure are relevant to multivalent antibody fusions, methods of making the same, and methods of using the same.

[0060] Some aspects of the present disclosure relate to trap-based bispecific molecules that exploit the natural dimeric interface of variable heavy (VH) and variable light (VL) regions found in antibodies. In this format, the receptor domains are linked in tandem with the VH and VL regions. This configuration places the ECD in a direction that is favorable for ligand binding. The heterodimeric nature of the VH:VL pair allows for the design of homodimeric or heterodimeric-based traps without the need for further engineering (e.g., Fc knob-in-hole structure), and the complementarity determining regions (CDRs) allow for binding of a second target of interest.

[0061] Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. It is a complex disease with diverse etiological factors and no effective treatment; Fleckenstein M, Keenan TDL, Guymer RH, Chakravarthy U, Schmitz-Valckenberg S, Klaver CC, Wong WT, Chew EY. 2021; “Age-related macular degeneration.” Nat. Rev. Dis. Primers. 7. Studies have shown that GFs and cytokines are involved in the onset and progression of AMD. Inhibition of VEGF-A has been shown to effectively treat neovascularization and slow disease progression; Song D, Liu P, Shang K, Ma Y. 2022. “Application and mechanism of anti-VEGF drugs in age-related macular degeneration.” Front. Bioeng. Biotechnol. 10, however, it does not address the underlying immune component potentially associated with anti-VEGF therapy resistance. Currently, there is no effective treatment for the predominant form of AMD (dry AMD), also known as geographic atrophy (which accounts for approximately 90% of cases). Genetic risk factors and dysregulated inflammatory responses form a complex interplay of signaling pathways that can hinder the development of effective monospecific therapies.

[0062] Overall, cytokines have been shown to play a key role in the development of retinal diseases. Elevated serum levels of the pro-inflammatory cytokine interleukin 6 (IL-6) have been reported in AMD patients. IL-6 has been observed to stimulate defective angiogenesis, possibly as an indirect consequence of IL-6-mediated upregulation of VEGF expression. Moreover, more direct functions of IL-6 such as endothelial cell proliferation and migration have been reported in the presence of VEGF inhibitors, suggesting that its angiogenic signaling occurs independently of VEGF. Other studies show that retinal pigment epithelial (RPE) cells release IL-1a under conditions of death or stress, which can contribute to the recruitment of immune cells. Thus, IL-1b produced by activated microglia and macrophages can promote further recruitment of macrophages to the areas affected by the tissue, leading to photoreceptor and RPE cell death, Wooff Y, Man SM, Aggio-Bruce R, Natoli R, Fernando N. 2019. “IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases.” Front. Immunol. 10.

[0063] Genome-wide association studies (GWAS) identified loci on human chromosome 10q26 associated with AMD risk, two of which, ARMS2 and HTRA1, are adjacent to each other. These studies demonstrated an association between disease progression and single nucleotide polymorphisms (SNPs) in the HTRA1 promoter region, which leads to increased expression, DeWan A, Liu M, Hartman S, Zhang SS-M, Liu DTL, Zhao C, Tam POS, Chan WM, Lam DSC, Snyder M et al., 2006. “HTRA1 Promoter Polymorphism in Wet Age-Related Macular Degeneration.” Science 314:989-992; Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X et al., 2006. "A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration." Science 314:992-993; Fritsche LG, Igl W, Bailey JNC, Grassmann F, Sengupta S, Bragg-Gresham JL, Burdon KP, Hebbring SJ, Wen C, Gorski M et al., 2015. "A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants." Nat. Genet. 48: 134-143.High temperature requirement factor Al (HTRA1) is a serine protease known to cleave excess extracellular matrix (ECM) proteins and members of the TGF-beta family; Lu Z-G, May A, Dinh B, Lin V, Su F, Tran C, Adivikolanu H, Ehlen R, Che B, Wang Z-H, et al. 2021. “The interplay of oxidative stress and ARMS2-HTRA1 genetic risk in neovascular AMD.” Vessel. Plus. 2021. It has been hypothesized that cleavage of certain ECM proteins contributes to the accumulation of extracellular debris, which in turn sensitizes cells to inflammatory stimuli; Beguier F, Housset M, Roubeix C, Augustin S, Zagar Y, Nous C, Mathis T, Eandi C, Benchaboune M, Drame-Maigne A, et al. 2020. “The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.” Immunity 53: 429-441.e8; Lin MK, Yang J, Hsu CW, Gore A, Bassuk AG, Brown LM, Colligan R, Sengillo JD, Mahajan VB, Tsang SH. 2018. “HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1. Aging. Cell. 17: e12710-.” It was also shown that HTRA1 induces expression of inflammatory cytokines and VEGF, and overexpression of HTRA1 in the mouse retina recapitulates key physiological markers of AMD. These data confirm the observation that HTRA1 risk alleles show strong and nearly equal association with both wet and dry forms of AMD.

[0064] In some embodiments, the present disclosure relates to reducing concurrent inflammation and defective angiogenesis that drive the pathogenesis of AMD.

[0065] In some embodiments, the present disclosure relates to reducing ocular inflammation or inflammation of the eye.

[0066] Some aspects of the present disclosure relate to bispecific molecules. Some aspects of the present disclosure relate to bispecific molecules that simultaneously block a combination of cytokines, GF, and HTRA1 for reducing concurrent inflammation and defective angiogenesis that drive the pathogenesis of AMD.

[0067] In some embodiments, these bispecific molecules include IL-1 trap fused to anti-IL-6 or anti-HTRA1 antibodies, IL-6 trap fused to anti-HTRA1 antibodies, and IL-33 trap fused to anti-IL-6 antibodies. Bispecifics are constructed in the design of a heterodimeric trap fused to VH and VL regions. In addition, a Fab version of anti-IL-6 was generated in tandem with IL-1 trap (heterodimer) and VEGF trap (homodimer). Each of these dual inhibitor molecules can be optionally equipped with unpaired cysteines in their C-terminal regions, which can be conjugated with a phosphorylcholine-based biopolymer for half-life extension. In some embodiments, the bispecific molecules comprise a TNFα inhibitor. In some embodiments, the TNFα inhibitor comprises a TNFα trap. In some embodiments, the TNFα inhibitor comprises a TNFα VHH.

[0068] Definitions

[0069] As used herein, the term "interleukin" (IL) refers to one or more of a group of related proteins produced by white blood cells (leukocytes) and other cells in the body. Interleukins regulate immune responses. Interleukins are a type of cytokine.

[0070] As used herein, the term "cytokine" refers to a small protein, polypeptide, or peptide involved in inflammatory signaling, or a protein released by one cell population to act as an intercellular mediator on another cell or to have autocrine effects on the protein-producing cell. Cytokines include, but are not limited to, chemokines, interferons, interleukins, lymphokines, monokines, tumor necrosis factors, CCL1, CCl2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, XCL1, XCL2, INFa, INFb, INFg, IL-1, IL-1a, IL-1b, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A-F, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36Ra, IL-36a, IL-36b, IL-36g, IL-37, IL-38, GM-CSF, TNFa, TNFb, TNFg, TGF-I-3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15, TNFSF18, or TNFSF19, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), CNTF-like cytokine (CLC), cardiotrophin (CT), Kit ligand (KL), or any combination thereof.

[0071] As used herein, the terms "valence," "valency," or "valent" refer to the relative ability of a substance (e.g., an antibody) to act on, or react with, or bind to a biological substrate (e.g., an antigen); the number of antigen binding sites an antibody has, or the number of antigenic determinants an antigen has. In some embodiments, valence refers to the number of binding sites on a molecule. In some embodiments, valence refers to the property of an atom or group, indicating its combining power, especially in terms of the number of hydrogen atoms. In some embodiments, a substance or molecule is zerovalent, nonvalent, monovalent, univalent, divalent, bivalent, trivalent, tervalent, tetravalent, quadrivalent, pentavalent, quinquivalent, quinquivalent, hexavalent, sexivalent, heptavalent, septivalent, octavalent, nonavalent, decavalent, dodecavalent, polyvalent, or multivalent.

[0072] The term "antibody" includes intact antibodies and binding fragments thereof. Binding fragments refer to molecules other than intact antibodies that comprise a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of binding fragments include Fv, Fab, Fab-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. ScFv antibodies are described in Houston JS. 1991. Methods in Enzymol. 203:46-96. In addition, an antibody fragment comprises a single chain polypeptide having the characteristics of a VH domain or region (i.e., is capable of assembling with a VL domain or region) or a VL domain or region (i.e., is capable of assembling with a VH domain or region) to form a functional antigen binding site, thereby providing the antigen binding properties of a full-length antibody. The terms "domain" and "region" are used interchangeably.

[0073] As used herein, the term "antigen binding fragment (Fab fragment)" refers to an antibody fragment that binds an antigen. A Fab fragment comprises one constant and one variable domain of each of a heavy chain and a light chain.

[0074] The term "VHH domain", also known as VHH, VHH domain, VHH antibody fragment, and VHH antibody, was originally described as the antigen-binding immunoglobulin (Ig) (variable) domain of "heavy chain antibodies" (i.e., "antibodies devoid of light chains"; Hamers-Casterman et al. (1993) Nature 363: 446-448). The term "VHH domain" was chosen to distinguish these variable domains from the heavy chain variable domains present in conventional 4-chain antibodies (referred to herein as "VH domains") and the light chain variable domains present in conventional 4-chain antibodies (referred to herein as "VL domains"). For further description of VHHs and Nanobodies, reference is made to the review article by Muyldermans (Reviews in Molecular Biotechnology 74:277-302, 2001).

[0075] Specific binding of an antibody to its target antigen means an affinity of at least 10 6 , 10 7 , 10 8 , 10 9 , or 10 10 M -1 . Specific binding is detectably higher in magnitude and distinguishable from non-specific binding that occurs to at least one unrelated target. Specific binding can be the result of a bond formation between specific functional groups or a specific spatial fit (e.g., lock-and-key type), whereas non-specific binding is usually the result of van der Waals forces. However, specific binding does not necessarily mean that the antibody or fusion protein binds one and only one target.

[0076] The basic antibody structural unit is a tetramer of subunits. Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The term "domain" and "region" are used interchangeably. This variable region is followed by a constant region. The variable region of each chain is primarily defined by a single variable domain or region. The variable regions of the two chains define a single antigen-binding site of the antibody. The carboxy-terminal portion of each chain defines a constant region. The light chain of an antibody typically has one constant region domain. The heavy chain has a variable region of a size similar to that of the light chain and a constant region that is typically larger than that of the light chain. The variable regions of the heavy and light chains are joined by a "J" segment of about 12 or more amino acids. The heavy chain also includes a "D" segment of about 10 or more amino acids. (See generally, Fundamental Immunology (Paul, W., ed., 2nd ed., Raven Press, N.Y., 1989), Chapter 7) (incorporated by reference in its entirety for all purposes).

[0077] The light chains of an antibody can be classified as kappa (kappa) or lambda (lambda). The heavy chains of an antibody can be classified as gamma (gamma), mu (mu), alpha (alpha), delta (delta), or epsilon (epsilon), and define the antibody's isotype as IgG, IgM, IgA, IgD, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" segment of about 12 or more amino acids. The heavy chain also includes a "D" segment of about 10 or more amino acids. (See generally, Fundamental Immunology (Paul, W., ed., 2nd ed., Raven Press, N.Y., 1989), Chapter 7) (incorporated by reference in its entirety for all purposes).

[0078] The mature variable regions of each light / heavy chain pair form the antibody binding site. Thus, intact antibodies have two binding sites, i.e., are bivalent. In native antibodies, the binding sites are identical. However, bispecific antibodies can be generated in which the two binding sites are different (see, e.g., Songsivilai S, Lachmann PC. 1990. Bispecific antibody: a tool for diagnosis and treatment of disease. Clin Exp Immunol. 79:315-321; Kostelny SA, Cole MS, Tso JY. 1992. Formation of bispecific antibody by the use of leucine zippers. J Immunol. 148: 1547-1553). The variable regions all display the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N- to C-terminus, both light and heavy chains contain the domains FRl, CDRl, FR2, CDR2, FR3, CDR3, and FR4. For convenience, the variable heavy chain CDRs can be referred to as CDRHl, CDRH2, and CDRH3; and the variable light chain CDRs can be referred to as CDRLl, CDRL2, and CDRL3. H 1, CDR H 2, and CDR H 3; the variable light chain CDRs can be referred to as CDR L 1, CDR L 2, and CDR L3. The assignment of amino acids to each domain is consistent with the definitions in Kabat EA et al. 1987 and 1991. Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD) or Chothia C, Lesk AM. 1987. Canonical Structures for the Hypervariable Regions of Immunoglobulins. J Mol Biol 196:901-917; Chothia C et al. 1989. Conformations of Immunoglobulin Hypervariable Regions. Nature 342:877-883. Kabat also provides a numbering convention (Kabat Numbering) that is widely used in which corresponding residues between different heavy chain variable regions or between different light chain variable regions are assigned the same number. Although Kabat Numbering can be used for antibody constant regions, more commonly EU Numbering is used, as is the case in this application. Although specific sequences of the exemplary antibodies disclosed herein are provided, it is understood that one to several amino acids at the amino or carboxy terminus of the light and / or heavy chain, particularly the heavy chain C-terminal lysine residue, can be missing or derivatized in some or all molecules following expression of the protein chain.

[0079] The term "epitope" refers to a site on an antigen that binds to an antibody or extracellular trap segment. Epitopes on proteins can be formed both by contiguous amino acids or noncontiguous amino acids juxtaposed on the protein as a result of tertiary folding of the protein(s). Epitopes formed from contiguous amino acids (also known as linear epitopes) are usually retained when exposed to denaturing solvents, whereas epitopes formed by tertiary folding (also known as conformational epitopes) are usually lost under denaturing conditions. An epitope typically comprises at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Methods of determining the spatial conformation of an epitope include, for example, x-ray crystallography and two-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols, in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, ed. (1996).

[0080] Antibodies that recognize the same or overlapping epitopes can be identified in a simple immunoassay that displays the ability of one antibody to compete with another antibody for binding to a target antigen. The epitope of an antibody can also be determined by X-ray crystallography of the antibody (or Fab fragment) bound to its antigen to identify the contacting residues.

[0081] Alternatively, two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody.

[0082] Competition between antibodies is determined by an assay in which a test antibody inhibits specific binding of a reference antibody to a common antigen (see, e.g., Junghans et al., Cancer Res. 50: 1495, 1990). A test antibody competes with a reference antibody if an excess of the test antibody (e.g., at least 2x, 5x, 10x, 20x, or 100x) inhibits binding of the reference antibody by at least 50%. In some embodiments, a test antibody inhibits binding of a reference antibody by 75%, 90%, or 99%, as measured in a competitive binding assay. Antibodies identified by competition assays (competing antibodies) include antibodies that bind the same epitope as the reference antibody, as well as antibodies that bind to a proximal epitope that is close enough to the epitope bound by the reference antibody to produce steric hindrance.

[0083] As used herein, the term “Trap” or like terms refers to a molecule comprising a binding domain or fragment thereof, allowing the molecule to work as a trap, preventing a protein or other molecule from binding to a receptor or other binding partner expressed by a cell. Various embodiments of Trap proteins are known in the art and can be found, for example, in U.S. Pub. No. 20150376271, the entire contents of which regarding various Trap embodiments and fusions thereof are incorporated herein by reference. In some embodiments, the term “Trap” or like terms refers to a molecule comprising a full-length extracellular region or any portion thereof, or a combination of portions from different molecules that antagonize signaling between at least one molecule and another molecule.

[0084] As used herein, "HTRA1" refers to HtrA serine protease. HTRA1 can refer to, but is not limited to, human HTRA1 (Gene ID: 5654), mouse HTRA1 (Gene ID: 56213), rat HTRA1 (Gene ID: 65164), canine HTRA1 (Gene ID: 477852), chicken HTRA1 (Gene ID: 100857572), bovine HTRA1 (Gene ID: 282326). In some embodiments, HTRA1 is human HTRA1 ("HuHTRA1").

[0085] "aHTRA1" and "anti-HTRA1 antibody" are used interchangeably herein to refer to an antibody that binds HTRA1 as provided herein.

[0086] As used herein, "potency" with respect to an anti-HTRA1 antibody refers to the ability or degree of inhibition of HTRA1 activity (e.g., HTRA1 proteolytic activity) when the antibody binds to HTRA1.

[0087] As used herein, "IL-6 antibody-HTRA1 Trap fusion," "IL-6 antibody-HTRA1 Trap," "Ab IL-6-HTRA1 Trap," "anti-IL-6-HTRA1 Trap," "HTRA-antiIL6," "HTRA-antiIL-6," "HTRA1 Trap-antiIL6 antibody fusion (TAF)," "HTRA1 Trap-IL6," "HTRA1 IL-6," "IL6-HTRA," or similar terms or reverse terms (e.g., "HTRA1 Trap-IL-6 Ab," "HTRA1 Trap-IL-6 antibody fusion," etc.) refer to a fusion between an IL-6 antibody and a HTRA1 Trap. When used generally, the order of the two terms can be switched. When used specifically, the order of the two terms indicates the relative position of the components in the construct. The terms "IL-6 Ab-HTRA1 Trap," "Ab IL-6 HTRA1 Trap," or "anti-IL-6 HTRA1 Trap," "Trap-Ab," anti-IL-6-HTRA, anti-IL6-HTRA1, or other similar terms or reverse terms (e.g., "HTRA1 Trap-IL-6 Ab," "HTRA1 Trap-IL-6 antibody fusion," etc.) refer to the arrangement of the Ab fused to the relevant domain of the HTRA1 binding protein, thereby providing a HTRA1 trap.

[0088] As noted above, this portion of the HTRA1 binding protein is the portion that prevents HTRA1 from binding to a substrate. As described herein, the arrangement (ordering) of the Trap and antibody portions can vary. Thus, unless otherwise explicitly stated or otherwise apparent from context, the phrase as used herein with respect to Ab-Traps (or HTRA1 / IL-1 traps, IL-6 / IL-1 traps, etc.) fusion proteins refers to all disclosed embodiments of antibody and Trap positioning. If a direction is specifically indicated, then it can be indicated by, for example, stating that the "arrangement" can be one of the following: Trap-Ab, Trap IL-1 Ab, Trap IL-6 Ab, VEGF Trap Ab IL-6. Similarly, it will be understood that some context-specific molecular orientation or arrangement of embodiments of the present disclosure, as indicated by the context of the embodiments. For all discussion of fusion proteins provided herein, both arrangements (alternative and combined) are expressly contemplated. Further, it will be understood that the phrase IL-6 Ab, when used in the context of a fusion protein, includes both options due to ordering, where the antibody is continuous (left side), and where the TRAP is inside the Ab. Likewise, unless otherwise stated, the term "Ab" or "antibody" when used in the context of a fusion protein (or other similar terms) includes all three options. In some embodiments, the IL-1 Trap is fused to IL-6 or HTRA1 in one of the following ways: to the N-terminus of the heavy chain comprising the IL-6 or HTRA1 VH; or between the hinge region and the CH1 domain of the heavy chain comprising the IL-6 or IL-1 VH. There is no distinction between the nomenclature using Ab, antibody, "anti" or other similar terms to refer to an antibody or fragment thereof. There is no distinction between the nomenclature "Il-6" or "IL6" or "IL-6". There is no distinction between the nomenclature "Il-1" or "IL1" or "IL-1".

[0089] As used herein, the term "vascular endothelial growth factor (VEGF)" refers to a signaling protein belonging to the VEGF / PDGF (platelet-derived growth factor) group of the cysteine-knot superfamily of signaling molecules that have eight conserved cysteine residues that form a cysteine knot structure. The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, PlGF (placenta growth factor), VEGF-E (Orf-VEGF), and prototypical Trimeresurus flavoviridis svVEGF. In addition to the last two members, the five genes of the VEGF family are present in the mammalian genome, including humans.

[0090] “aVEGF” and “anti-VEGF antibody” are used interchangeably herein to refer to an antibody that binds VEGF as provided herein.

[0091] As used herein, “VEGF Trap” or like terms refer to VEGF binding domains (VEGFR1 domain 2, VEGFR2 domain 3). These fragments make the protein work as a VEGF trap, preventing VEGF from binding to cell-expressed VEGF receptors. In some embodiments, the VEGF Trap includes only VEGFR1 domain 2, VEGFR2 domain 3. Various embodiments of trap proteins are known in the art and can be found, for example, in U.S. Pub. No. 20150376271, the entire contents of which regarding various VEGF Trap embodiments (which are VEGFR proteins or fragments thereof) and fusions thereof are incorporated herein by reference. In some embodiments, the term “VEGF Trap” or like terms refer to the full-length extracellular region or any portion thereof, or a combination of portions from different VEGF receptors that can antagonize signaling between at least one VEGF and VEGFR.

[0092] As used herein, the term “IL trap” or like terms refer to interleukin binding domains of interleukin receptor proteins and accessory proteins. In some embodiments, this refers only to the extracellular domains or portions thereof of interleukin receptor proteins and accessory proteins. These fragments make the protein work as an IL trap, preventing IL from binding to cell-expressed IL receptors. For example, but not limited to, the term “IL-1 trap” refers to the three IG-like domains (D1-D3) of the extracellular domain of the IL1R1 receptor protein and the three IG-like domains (D1-D3) of the extracellular IL1-R1A accessory protein. The transmembrane and intracellular Toll / IL-1R (TIR) domains are not required for IL-1 trap function. These fragments make the protein work as an IL-1 trap, preventing I-1L from binding to cell-expressed IL-1 receptors.

[0093] As used herein, the term “TNFα trap” or like terms refer to interleukin binding domains of TNFR1 and / or TNFR2. In some embodiments, this refers to the extracellular domains of TNFR1 and / or TNFR2. These fragments make the protein work as a TNFα trap, preventing TNFα from binding to cell-expressed TNFα receptors.

[0094] As used herein, "IL-6 antibody-VEGF Trap fusion," "IL-6 antibody-VEGF Trap," "Ab IL-6-VEGF Trap," "anti-IL-6-VEGF Trap," "VEGFR-anti-IL6," "VEGFR-anti-IL-6," "VEGF Trap-anti-IL6 antibody fusion (TAF)," "VEGF Trap-IL6," "VEGFR IL-6," "IL6-VEGFR," or similar terms or reverse terms (e.g., "VEGF Trap-IL-6 Ab," "VEGF Trap-IL-6 antibody fusion," etc.) refer to a fusion between an IL-6 antibody and a VEGF Trap. When used generally, the order of the two terms can be switched. When used specifically, the order of the two terms indicates the relative position of the components in the construct. The term "IL-6 Ab-VEGF Trap," "Ab IL-6 VEGF Trap," or "Ab IL-6-Trap" or "anti-IL-6 VEGF Trap," anti-IL-6-VEGFR, anti-IL6-VEGFR, or other similar terms or reverse terms (e.g., "VEGF Trap-IL-6 Ab," "VEGF Trap-IL-6 antibody fusion," etc.) refer to the arrangement of the Ab fused to the relevant domain of the VEGF binding protein, thereby providing a VEGF trap. As noted above, this portion of the VEGF binding protein is the portion that prevents VEGF from binding to the VEGF receptor. As described herein, the arrangement (ordering) of the Trap and antibody portions can vary. Thus, unless otherwise explicitly stated or otherwise clear from context, the phrase "Ab-Trap (or IL-6 / VEGF Trap, etc.) fusion" as used herein refers to all disclosed embodiments of the positioning of the antibody and Trap. If the orientation is specifically indicated, it can be indicated by, for example, stating the "arrangement" can be one of the following: Trap IL-6 Ab, VEGF Trap Ab IL-6, VEGF Trap Ab IL6.

[0095] The term "patient" includes human and other mammalian subjects that receive prophylactic or therapeutic treatment.

[0096] To classify an amino acid substitution as conservative or non-conservative, the amino acids are grouped as follows: Group I (amino acids with side chains having a negative charge): Asp, Glu; Group II (amino acids with side chains having a positive charge): Arg, His, Lys; Group III (amino acids with side chains having a polar uncharged charge): Ser, Thr, Cys, Pro, Asn, Gin; Group IV (amino acids with side chains having a nonpolar aliphatic character): Gly, Ala, Val, Leu, Met, He; and Group V (amino acids with side chains having a nonpolar aromatic character): Phe, Tyr, Trp.

[0097] Percent sequence identity is determined by maximizing alignment of antibody sequences by the Kabat numbering convention for variable regions or the EU numbering for constant regions. After alignment, if a region of a test antibody (e.g., the entire mature variable region of a heavy or light chain) is compared to the same region of a reference antibody, the percent sequence identity between the region of the test antibody and the region of the reference antibody is the number of positions for which the same amino acid occupies divided by the total number of positions in the two regions aligned (gaps not counted), multiplied by 100 to convert to a percentage. Sequence identity of other sequences can be determined by aligning the sequences using an algorithm such as BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, WI, with default gap parameters, or by inspection and optimal alignment (i.e., producing the highest percentage of sequence similarity over a comparison window). The percent sequence identity is calculated by comparing two optimally aligned sequences over a comparison window, determining the number of positions at which the same residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window (i.e., the window size), and multiplying the result by 100 to yield the percent sequence identity.

[0098] A composition or method that "comprises" or "comprising" one or more recited elements can include additional elements not specifically recited. For example, a composition comprising an antibody can include the antibody alone or the antibody in combination with other ingredients.

[0099] The term "antibody-dependent cellular cytotoxicity" or ADCC is a mechanism of inducing cell death that relies on the interaction of antibody-coated target cells (i.e., cells with bound antibody) with immune cells (also called effector cells) that have lytic activity. Such effector cells include natural killer cells, monocytes / macrophages, and neutrophils. ADCC is triggered by the interaction between the Fc region of a cell-bound antibody and Fcy receptors (particularly FcyRI and FcyRIII) on immune effector cells such as neutrophils, macrophages, and natural killer cells. Depending on the type of effector cells mediated, target cells are eliminated by phagocytosis or lysis. Death of antibody-coated target cells is the result of effector cell activity.

[0100] The term opsonization, also known as "antibody-dependent cellular phagocytosis," or ADCP, refers to the process by which antibody-coated cells are internalized, in whole or in part, by phagocytic immune cells (e.g., macrophages, neutrophils, and dendritic cells) that bind to the Fc region of immunoglobulins.

[0101] The term "complement-dependent cytotoxicity" or CDC refers to a mechanism of inducing cell death in which the Fc effector domain of target-bound antibodies activates a series of enzymatic reactions that ultimately form pores in the target cell membrane. Typically, antigen-antibody complexes (e.g., complexes on antibody-coated target cells) bind and activate complement component Clq, which in turn activates the complement cascade, leading to target cell death. Activation of complement can also result in deposition of complement components on the target cell surface, promoting ADCC by binding to complement receptors (e.g., CR3) on leukocytes.

[0102] A humanized antibody is a genetically engineered antibody in which CDRs from a non-human "donor" antibody are grafted into a human "acceptor" antibody sequence (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539, Carter, US 6,407,213, Adair, US 5,859,205 6,881,557, Foote, US 6,881,557). The acceptor antibody sequence can be, e.g., a sequence of a mature human antibody, a composite of such sequences, a consensus sequence or a germline region sequence of a human antibody. Thus, a humanized antibody is an antibody having some or all of the CDRs completely or substantially from a donor antibody, and variable region framework sequences and constant regions (if present) completely or substantially from a human antibody sequence. Similarly, a humanized heavy chain has at least one, two and usually all three CDRs completely or substantially from a donor antibody heavy chain, and heavy chain variable region framework sequences and heavy chain constant regions (if present) substantially from human heavy chain variable region framework and constant region sequences. Similarly, a humanized light chain has at least one, two and usually all three CDRs completely or substantially from a donor antibody light chain, and light chain variable region framework sequences and light chain constant regions (if present) substantially from human light chain variable region framework and constant region sequences. In addition to nanobodies and dAbs, a humanized antibody comprises a humanized heavy chain and a humanized light chain. CDRs in a humanized antibody are substantially from corresponding CDRs in a non-human antibody when at least 85%, 90%, 95% or 100% of the corresponding residues (as defined by Kabat) between the respective CDRs are identical. A variable region framework sequence of an antibody chain or a constant region of an antibody chain is substantially from a human variable region framework sequence or a human constant region, respectively, when at least 85, 90, 95 or 100% of the corresponding residues (as defined by Kabat) are identical.

[0103] Although humanized antibodies typically incorporate all six CDRs from the mouse antibody (as defined by Kabat), they can also be formed from less than all CDRs (e.g., at least 3, 4, or 5 CDRs from the mouse antibody) (e.g., De Pascalis R, Iwahashi M, Tamura M, et al. 2002. Grafting “Abbreviated” Complementary-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody. J Immunol. 169:3076-3084; Vajdos FF, Adams CW, Breece TN, Presta LG, de Vos AM, Sidhu, SS. 2002. Comprehensive functional maps of the antigen-binding site of an anti-ErbB2 antibody obtained with shotgun scanning mutagenesis. J Mol Biol. 320: 415-428; Iwahashi M, Milenic DE, Padlan EA, et al. 1999. CDR substitutions of a humanized monoclonal antibody (CC49): Contributions of individual CDRs to antigen binding and immunogenicity. Mol Immunol. 36:1079-1091; Tamura M, Milenic DE, Iwahashi M, et al. 2000. Structural correlates of an anticarcinoma antibody: Identification of specificity-determining regions (SDRs) and development of a minimally immunogenic antibody variant by retention of SDRs only.J Immunol. 164:1432-1441).

[0104] Chimeric antibodies are antibodies in which the mature variable regions of the light and heavy chains of a non-human antibody (e.g., mouse) are combined with human light and heavy chain constant regions. Such antibodies essentially or completely retain the binding specificity of the mouse antibody and are about two-thirds human sequence.

[0105] As used herein, the term "knob-in-hole" (KIH) can refer to a strategy that pairs the heavy chain portions of the constant region in antibodies and fragments thereof. The "knob" portion is designed by replacing a small amino acid with a larger one. For example, in some embodiments, the knob includes the knob in SEQ ID No. 65. It fits into the "hole," which is designed by replacing a large amino acid with a smaller one. For example, in some embodiments, the hole includes the hole in SEQ ID No. 66. Connecting the "knob" and the "hole" is a disulfide bond between each chain.

[0106] A veneered antibody is a type of humanized antibody that retains some, and usually all, of the CDRs and some of the non-human variable region framework residues of a non-human antibody, but has other variable region framework residues, e.g., exposed residues, replaced with residues from the corresponding positions of a human antibody sequence that can contribute to a B- or T-cell epitope (Padlan EA. 1991. A possible procedure for reducing the immunogenicity of antibody variable regions while preserving their ligand-binding properties. Mol Immunol. 28:489-98). The result is an antibody in which the CDRs are entirely or substantially from a non-human antibody, and the variable region framework of the non-human antibody is made more human by the substitutions. Human antibodies can be isolated from humans, or produced from expression of human immunoglobulin genes (e.g., in transgenic mice, in vitro, or by phage display).Methods of generating human antibodies include the trioma method of Ostberg L, Pursch E. 1983. Human x (mouse x human) hybridomas stably producing human antibodies. Hybridoma 2:361-367; Ostberg, U.S. Patent No. 4,634,664; and Engleman et al., U.S. Patent 4,634,666; the use of transgenic mice containing human immunoglobulin genes (see, e.g., Lonberg et al., WO 93 / 12227 (1993); US 5,877,397, US 5,874,299, US 5,814,318, US 5,789,650, US 5,770,429, US 5,661,016, US 5,633,425, US 5,625,126, US 5,569,825, US 5,545,806, Nature 148, 1547-1553 (1994), Nature Biotechnology 14, 826 (1996), Kucherlapati, WO 91 / 10741 (1991)) and phage display methods (see, e.g., Dower et al., WO 91 / 17271 and McCafferty et al., WO 92 / 01047, US 5,877,218, US 5,871,907, US 5,858,657, US 5,837,242, US 5,733,743 and US 5,565,332).

[0107] “Pharmaceutically acceptable excipient” refers to an excipient that can be included in the composition and that does not itself induce significant adverse toxicological effects on the patient and is approved or approvable by the FDA for use in treatment of patients (particularly humans). Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s solution, standard sucrose, standard glucose, and the like.

[0108] Therapeutic proteins are administered in an effective regimen, which refers to a dosage, route of administration, and frequency of administration that delays onset, reduces severity, inhibits further progression, and / or improves at least one sign or symptom of the disorder. If the patient already has the disorder, the regimen can be referred to as a therapeutically effective regimen. In some embodiments, the disorder comprises diabetic retinopathy, early, intermediate, late age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, ocular inflammation, HTRA1 -associated disorders and / or IL-1 -associated disorders, scleritis, diabetic macular edema, diabetic retinopathy, wet age-related macular degeneration, uveitis, non-infectious uveitis, uveitis macular edema, cytokine release syndrome following CAR-T or similar immuno-oncology therapies, and / or induction of IL-6 expression observed following blockade of anti-PD-1 / PD-L1 molecule therapy, cancer, brain edema in glioblastoma, IL-6-associated disorders, and / or VEGF-associated disorders. In some embodiments, the disorder is ocular inflammation. In some embodiments, the disorder is ocular inflammation. If the patient is at high risk for the disorder relative to the general population but has not yet presented symptoms, the regimen can be referred to as a prophylactically effective regimen. In some cases, the therapeutic or prophylactic effect can be observed for an individual patient relative to that patient's historical control or past experience. In other cases, the therapeutic or prophylactic effect can be demonstrated in a population of patients receiving treatment relative to a control population of patients not receiving treatment, in pre-clinical or clinical trials.

[0109] The "biological half-life" of a substance is a pharmacokinetic parameter that describes the time required for the amount of the substance to be reduced by one-half from its initial value after administration of the substance.

[0110] "BCVA" means best-corrected visual acuity.

[0111] "OCT-A" means OCT-angiography.

[0112] "SD-OCT" means spectral domain optical coherence tomography.

[0113] A "neovascular disorder" is a condition or disease state characterized by altered, dysregulated, or uncontrolled angiogenesis. Examples of neovascular disorders include neoplastic transformation (e.g., cancer), and ocular neovascular disorders, including diabetic retinopathy and age-related macular degeneration.

[0114] A "ocular neovascular" disorder is a disorder characterized by altered, dysregulated, or uncontrolled angiogenesis in a patient's eye. Such disorders include optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidal neovascularization, corneal neovascularization, vitreous neovascularization, glaucoma, pannus, pterygium, macular edema, diabetic retinopathy, diabetic macular edema, vascular retinopathy, retinal degeneration, uveitis, non-infectious uveitis, retinal inflammatory disease, and proliferative vitreoretinopathy.

[0115] Multivalent interleukin (IL) trap-antibody fusion

[0116] Some embodiments herein relate to a multivalent interleukin (IL) trap-antibody or trap-Fab fusion comprising an IL trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor and an IL co-receptor; wherein the IL trap and the antibody are linked in tandem by a linker; the IL trap-antibody or trap-Fab fusion comprises both an IL binding site and an antigen binding site; and wherein the IL binding site and the antigen binding site are located at different locations on the trap-antibody or trap-Fab fusion.

[0117] Some embodiments herein relate to a multivalent interleukin (IL) trap-antibody or trap-Fab fusion. In some embodiments, the multivalent IL trap-antibody or trap-Fab fusion comprises an IL trap; wherein; wherein the IL trap comprises an IL receptor and an IL co-receptor; an antibody or Fab fragment; wherein the antibody or Fab fragment comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and the antibody are linked in tandem by a linker; the interleukin trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and wherein binding of the IL trap-antibody fusion to an antigen inhibits antigen activity.

[0118] Figure 1is a representative illustration of some embodiments of a multivalent interleukin (IL) trap-antibody fusion. In some embodiments, the IL trap-antibody fusion comprises a homodimeric receptor. In some embodiments, the IL trap-antibody fusion comprises a heterodimeric fusion. In some embodiments, the IL receptor protein and the accessory protein are linked to the heavy and light chains of the same antibody arm. In some embodiments, the IL receptor protein and the accessory protein.

[0119] In some embodiments, a multivalent interleukin (IL) trap-antibody 100 or trap-Fab fusion 106 is disclosed. In some embodiments, the multivalent IL trap-antibody fusion comprises an IL trap 101 and an antibody or fragment thereof 102. In some embodiments, the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3. In some embodiments, the antibody fragment comprises a Fab fragment. In some embodiments, the IL trap 104 comprises an IL receptor and an IL accessory protein. In some embodiments, the IL trap 101 and the antibody 102 or Fab fragment are linked in tandem by a linker 103. In some embodiments, the length of the linker is selected according to the ability of the linker to promote a desired function or property of the multivalent IL trap-antibody fusion. In some embodiments, the IL trap-antibody 100 or trap-Fab fusion 106 comprises both an IL binding site 104 and an antigen binding site 105. In some embodiments, the IL binding site and the antigen binding site are located at different locations on the trap-antibody or trap-Fab fusion. For example, in some embodiments, the IL binding site is located on the IL trap linked to the antibody or Fab fragment, while the antigen binding site is located on the antibody arm. In some embodiments, the IL binding site is linked to the same antibody arm as the antigen binding site. In some embodiments, the IL binding site is linked to the antibody arm opposite the antigen binding site. In some embodiments, the binding of the IL trap-antibody fusion to IL inhibits IL signaling. In some embodiments, the binding of the IL trap-antibody fusion to the antigen inhibits antigen activity. In some embodiments, the antigen binding site and the IL binding site are in tandem on the same antibody or Fab fragment arm. In some embodiments, the interleukin trap-antibody-heterodimer or trap-Fab fusion is multivalent.

[0120] Figure 2are representative illustrations of some embodiments of multivalent interleukin (IL) trap-antibody fusions or trap-Fabs that bind IL and an antigen. In some embodiments, the IL trap-antibody fusion comprises a homodimeric receptor. In some embodiments, the IL trap-antibody fusion comprises a heterodimeric fusion. In some embodiments, the IL receptor protein and the accessory protein are linked to the heavy and light chains of the same antibody arm. In some embodiments, the IL receptor protein and the accessory protein are linked in tandem to the heavy chain, light chain, or both, of one or both antibody arms.

[0121] In some embodiments, a multivalent interleukin (IL) trap-antibody 200 or trap-Fab fusion 208 is provided. In some embodiments, the multivalent IL trap-antibody 200 or trap-Fab 208 fusion comprises an IL trap 201 and an antibody or fragment thereof 202. In some embodiments, the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising three complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3. In some embodiments, the antibody fragment comprises a Fab fragment. In some embodiments, the IL trap 201 comprises an IL receptor and an IL co-receptor. In some embodiments, the IL trap 201 and the antibody 202 are connected in series by a linker 203. In some embodiments, the length of the linker is selected according to the ability of the linker to facilitate a desired function or property of the multivalent IL trap-antibody fusion. In some embodiments, the IL trap-antibody fusion 200 comprises both an IL binding site 204 and an antigen binding site 205. In some embodiments, the IL binding site and the antigen binding site are located at different locations on the trap-antibody or trap-Fab fusion. For example, in some embodiments, the IL binding site is located on the IL trap connected to the antibody, while the antigen binding site is located on the antibody arm. In some embodiments, the IL binding site is connected to the same antibody arm as the antigen binding site. In some embodiments, the IL binding site is connected to the antibody arm opposite the antigen binding site. In some embodiments, binding of the IL trap-antibody fusion to IL 206 inhibits IL signaling. In some embodiments, binding of the IL trap-antibody fusion to an antigen 207 inhibits antigen activity. In some embodiments, the antigen binding site and the IL binding site are in series on the same antibody arm. In some embodiments, binding of the IL trap-antibody fusion to IL inhibits IL signaling. In some embodiments, binding of the IL trap-antibody fusion to an antigen inhibits antigen activity. In some embodiments, the interleukin trap-antibody-heterodimer fusion is multivalent.

[0122] Figure 16 is a graphical representation of some embodiments of a multivalent interleukin (IL) trap-antibody fusion conjugated to a polymer.

[0123] In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody conjugate. In some embodiments, the antibody conjugate comprises an anti-HTRA1 antibody conjugate. In some embodiments, the trap-antibody fusion comprises an antibody conjugate and a homodimeric receptor. In some embodiments, the trap-antibody fusion comprises an antibody conjugate and a heterodimeric receptor.

[0124] Some aspects of the disclosure relate to methods of inhibiting interleukin signaling in a subject. In some embodiments, the methods comprise administering an interleukin trap-antibody-heterodimer fusion. In some embodiments, the heterodimeric fusion comprises an IL trap, an antibody, an IL binding site, and an antigen binding site; wherein binding of the IL trap-antibody-heterodimer fusion to the IL inhibits IL signaling; and binding of the IL trap-antibody-heterodimer fusion to the antigen inhibits antigen activity.

[0125] Some aspects of the disclosure relate to methods of inhibiting interleukin signaling in a subject. In some embodiments, the methods comprise administering an interleukin trap-antibody-heterodimer or trap-Fab fusion. In some embodiments, the heterodimeric fusion comprises an IL trap; an antibody or Fab fragment; wherein the antibody or Fab fragment comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein; the IL trap-antibody-heterodimer fusion comprises an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody-heterodimer or trap-Fab fusion to the IL inhibits IL signaling; and binding of the IL trap-antibody-heterodimer or trap-Fab fusion to the antigen inhibits antigen activity.

[0126] Figure 3 is a flowchart and representative illustration of some embodiments of methods of inhibiting interleukin signaling.

[0127] In some embodiments, a method 300 of inhibiting interleukin signaling in a subject is disclosed. In some embodiments, the method comprises administering an interleukin trap- antibody-heterodimer or trap-Fab fusion 301. In some embodiments, the heterodimer fusion comprises an IL trap 303. In some embodiments, the IL trap comprises a receptor protein. In some embodiments, the IL trap comprises an effector protein. In some embodiments, the interleukin trap-antibody-heterodimer or trap-Fab fusion comprises an antibody 304. In some embodiments, the IL trap comprises an effector protein. In some embodiments, the interleukin trap-antibody-heterodimer or trap-Fab fusion comprises a Fab fragment 309. In some embodiments, the antibody or Fab fragment comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3. In some embodiments, the IL trap-antibody-heterodimer or trap-Fab fusion comprises an IL binding site 306 and an antigen binding site 307. In some embodiments, binding of the IL trap-antibody-heterodimer or trap-Fab fusion to IL inhibits IL signaling. In some embodiments, binding of the IL trap-antibody-heterodimer or trap-Fab fusion to an antigen inhibits antigen activity. In some embodiments, the interleukin trap-antibody-heterodimer fusion is multivalent.

[0128] In some embodiments, the interleukin trap-antibody-heterodimer or trap-Fab fusion is multivalent. In some embodiments, the interleukin trap-antibody-heterodimer fusion or trap-Fab is monovalent, bivalent, trivalent, tetravalent, pentavalent, hexavalent, heptavalent, or octavalent.

[0129] In some embodiments, the interleukin trap-antibody-heterodimeric fusion comprises two IL traps and one antibody or two Fab fragments. In some embodiments, the trap-antibody fusion is bispecific. In some embodiments, the antibody comprises an anti-HTRA1 antibody or fragment thereof. In some embodiments, the IL trap comprises an IL1R1 receptor protein. In some embodiments, the IL trap comprises an IL1R1A accessory protein. In some embodiments, the IL trap comprises an IL1R1 receptor protein and an IL1R1A accessory protein. In some embodiments, the IL trap comprises an IL1R1 receptor protein and / or an IL1R1A accessory protein.

[0130] In some embodiments, the interleukin trap-antibody-heterodimeric or trap-Fab fusion is conjugated to a polymer. In some embodiments, the antibody conjugate has the structure of Formula (I):

[0131]

[0132] wherein: each heavy chain of the anti-HTRA1 antibody is represented by the letter H, each light chain of the anti-HTRA1 antibody is represented by the letter L; the polymer is bound to the anti-HTRA1 antibody through the thiol of C443 (EU numbering), which is depicted on one of the heavy chains; PC is, wherein the curve represents the point of attachment to the rest of the polymer; wherein X is a) -OR, wherein R is -H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including -Br, -Cl, or -I; and i) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different and are integers from 0 to 3000; or ii) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different, such that the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is 2500 plus or minus 20%. In some embodiments, the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is about 1500 to about 3500 plus or minus about 10% to about 20%. In some embodiments, X is -OR, wherein R is a sugar, an aminoalkyl, a mono- substituted, poly-substituted, or unsubstituted variant of the following residues: saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl or C2-C24 alkynyl, acyl, acyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxycarbonyl, alkoxycarbonylacyl, amino, aminocarbonyl, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, alkylthio, arylthio, oxysulfonyl, carboxyl, cyano, and haloalkyl (including polyhaloalkyl), -CO-O-R7, carbonyl-CCO-R7, -CO-NR8R9, -(CH2)n-COOR7, -CO-(CH)n-COOR7, -(CH2)n-NR8R9, ester, alkoxycarbonyl, aryloxycarbonyl, wherein n is an integer from 1 to 6, wherein each R7, R8, and R9 is independently selected from the group consisting of a hydrogen atom, a halogen atom, a mono-substituted, poly-substituted, or unsubstituted variant of the following residues: saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl or C2-C24 alkynyl, acyl, acyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxycarbonyl, alkoxycarbonylacyl, amino, aminocarbonyl, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, alkylthio, arylthio, oxysulfonyl, carboxyl, cyano, and haloalkyl (including polyhaloalkyl), 5-membered rings, and 6-membered rings.

[0133] In some embodiments, the antibody conjugate has the structure of Formula (II):

[0134]

[0135] wherein:

[0136] “n.” is an integer from 1 to 50, “n.i” is an integer from 1 to 50;

[0137] Each heavy chain of the anti-HTRA1 antibody is represented by the letter H, each light chain of the anti-HTRA1 antibody is represented by the letter L; the polymer is bound to the anti-HTRA1 antibody through the thiol of C443 (EU numbering), which is depicted on one of the heavy chains; PC is, where the curve represents the point of attachment to the rest of the polymer; where X is a) -OR, where R is -H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including -Br, -Cl, or -I; and i) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different and are an integer from 0 to 3000; or ii) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different, such that the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is 2500 plus or minus 20%.

[0138] In some embodiments, the half-life of the anti-HTRA1 antibody is extended by linking a “half-life extending moiety” or “half-life extending group.” Half-life extending moieties include peptides and proteins that can be expressed in frame with (or chemically conjugated to, as the case can be) the biologic drug under study, and various polymers that can be linked or conjugated to one or more amino acid side chains or terminal functional groups (e.g., -SH, -OH, -COOH, -CONH2, -NH2) or one or more N- and / or O-glycan structures. Half-life extending moieties are generally used to increase the in vivo circulating half-life of a biologic drug.

[0139] Suitable peptide / protein half-life extending moieties include, but are not limited to, Fc fusions, human serum albumin (HAS) fusions, carboxy-terminal peptide (CTP) fusions, X-tremeGen® XTEN gene fusion fusions, elastin-like peptide (ELPylation) (MCpherson DT, Morrow C, Minehan DS, et al. Production and purification of a recombinant elastomeric polypeptide, G-(VPGVG)19-VPGV, from Escheriachia coli), human transferrin fusions, proline-alanine-serine (PASylation), amino acid homopolymers (HAPylation), and gelatin-like protein (GLK) fusions.

[0140] Examples of polymer half-life extending moieties include polyethylene glycol (PEG), branched PEG, PEG® (Warwick Effect Polymers; Coventry, UK), polysialic acid (PSA), starch, hydroxyethyl starch (HES), hydroxyalkyl starch (HAS), carbohydrates, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl dextran, polyalkylene oxides (PAO), polyalkylene glycols (PAG), polypropylene glycol (PPG), polyoxazolines, polyacryloylmorpholines, polyvinyl alcohol (PVA), polycarboxylates, polyvinylpyrrolidone, polyphosphazenes, polyoxazolines, poly(ethylene-co-maleic anhydride), poly(styrene-co-maleic anhydride), poly(l-hydroxymethylethylene hydroxymethylformal) (PHF), zwitterionic polymers, phospholylcholine-containing polymers and polymers comprising MPC, poly(Gly x -Ser y ), hyaluronic acid (HA), heparosan polymers (HEP), Fleximers, dextran, and polysialic acid (PSA).

[0141] In one embodiment, the half-life extending moiety can be conjugated to the antibody using the free amino groups of the protein through N-hydroxysuccinimide (NHS) esters. Reagents that target binding amines can react with the e-amine of lysine, the a-amine of the N-terminal amino acid, and the d-amine of histidine, randomly.

[0142] In some embodiments, the half-life extending moiety is conjugated to one or more free SH groups using any suitable thiol-reactive chemistry, including but not limited to maleimide chemistry, or after prior oxidation, coupling of a polymer hydrazide or polymer amine to the carbohydrate moieties of the antibody. In some embodiments, maleimide conjugation is used. In some embodiments, conjugation occurs on a naturally occurring or genetically engineered cysteine.

[0143] In some embodiments, the polymer is covalently linked to a cysteine residue introduced into the anti-HTRA1 antibody by site-directed mutagenesis, or to a non-native cysteine. In some embodiments, the cysteine residue is in the Fc portion of the antibody. In some embodiments, the non-native cysteine residue is in the Fc portion of the antibody. In some embodiments, sites for introducing cysteine residues into the Fc region are provided in WO2013 / 093809, US 7,521,541, WO 2008 / 020827, US 8,008,453, US 8,455,622, and US2012 / 0213705, which are incorporated by reference herein for all purposes. In some embodiments, the cysteine mutations are Q347C (EU numbering) and L443C, referring to the human IgG heavy chain numbered by EU.

[0144] In some embodiments, conjugates of antibodies and high MW polymers used as half-life extenders are provided. In some embodiments, conjugates comprising an antibody coupled to a zwitterionic polymer are provided, wherein the polymer is formed from one or more monomeric units, and wherein at least one monomeric unit has a zwitterionic group. In some embodiments, the zwitterionic group is a phosphorylcholine.

[0145] In some embodiments, one of the monomeric units is HEMA-PC. In some embodiments, the polymer is synthesized from a single monomer, which is HEMA-PC.

[0146] In some embodiments, some antibody conjugates have 2, 3, or more polymer arms, wherein the monomer is HEMA-PC. In some embodiments, the conjugates have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 polymer arms, wherein the monomer is HEMA-PC. In some embodiments, the conjugates have 3, 6, or 9 arms. In some embodiments, the conjugates have 9 arms.

[0147] In some embodiments, the polymer-antibody conjugates have a polymer portion with a molecular weight between 100,000 and 1,500,000 Da. In some embodiments, the conjugates have a polymer portion with a molecular weight between 500,000 and 1,000,000 Da. In some embodiments, the conjugates have a polymer portion with a molecular weight between 600,000 and 800,000 Da. In some embodiments, the conjugates have a polymer portion with a molecular weight between 600,000 and 850,000 Da and have 9 arms. When a molecular weight is given for an antibody conjugated to a polymer, that molecular weight will be the sum of the molecular weight of the protein (including any carbohydrate moieties associated therewith) and the molecular weight of the polymer.

[0148] In some embodiments, an anti-HTRA1 antibody having a HEMA-PC polymer is provided, the polymer having a molecular weight between about 100 kDa to 1650 kDa as measured by Mw. In some embodiments, the molecular weight of the polymer as measured by Mw is between about 500 kDa to 1000 kDa. In some embodiments, the molecular weight of the polymer as measured by Mw is between about 600 kDa to about 900 kDa. In some embodiments, the molecular weight of the polymer as measured by Mw is 750 kDa plus or minus 15%.

[0149] In some embodiments, the interleukin trap-antibody-heterodimer fusion further comprises a signal peptide. In some embodiments, the interleukin trap-antibody-heterodimer fusion further comprises a signal peptide that is the signal peptide of any one of SEQ ID NOs.: 16-23. In some embodiments, the signal peptide comprises the signal peptide of SEQ ID NO.: 16 (MYRMQLLSCIALSLALVTNS), SEQ ID NO.: 17 (MTLLWCVVSLYFYGILQSDA), SEQ ID NO.: 18 (MKVLLRLICFIALLISSLEAD), SEQ ID NO.: 19 (MLRLYVLVMGVSAFTLQPAA), SEQ ID NO.: 20 (METDTLLLWVLLLWVPGSTG), SEQ ID NO.: 21 (MGFWILAILTILMYSTAAKF), SEQ ID NO.: 22 (MLAVGCALLAALLAAPGAA), SEQ ID NO.: 23 (MLTLQTWLVQALFIFLTTESTG). In some embodiments, the interleukin trap-antibody-heterodimer fusion further comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the signal peptide of any one of SEQ ID NOs.: 16-23.

[0150] In some embodiments, the interleukin trap-antibody-heterodimer fusion simultaneously binds the IL and the antigen. In some embodiments, the interleukin trap-antibody-heterodimer fusion sequentially binds the IL and the antigen.

[0151] In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap having an IL binding affinity of about 0.01, 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM, or a binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap having an IL binding affinity of about or no more than about 0.01 to 100, 0.01 to 75, 0.01 to 50, 0.01 to 25, 0.01 to 10, 0.01 to 5, 0.01 to 1, 0.01 to 0.05, 0.05 to 100, 0.05 to 75, 0.05 to 50, 0.05 to 25, 0.05 to 10, 0.05 to 5, 0.05 to 0.1, 0.1 to 100, 0.1 to 75, 0.1 to 50, 0.1 to 25, 0.1 to 10, 0.1 to 5, 0.1 to 1, 0.1 to 0.5, 0.5 to 100, 0.5 to 75, 0.5 to 50, 0.5 to 25, 0.5 to 10, 0.5 to 5, 0.5 to 1, 1 to 100, 1 to 75, 1 to 50, 1 to 25, 1 to 10, 1 to 5, 5 to 100, 5 to 75, 5 to 50, 5 to 25, 5 to 10, 10 to 100, 10 to 75, 10 to 50, 10 to 25, 25 to 100, 25 to 75, 25 to 50, 50 to 100, 50 to 75, or 75 to 100 pM.

[0152] In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an antibody having an antigen binding affinity of about 50 to 500 pM. In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an antibody having an antigen binding affinity of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 pM, or a binding affinity within a range bounded by any two of the foregoing values or no more than any specified value. For example, in some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an antibody having an antigen binding affinity of between or no more than about 50 to 500, 50 to 450, 50 to 300, 50 to 250, 50 to 200, 50 to 150, 50 to 100, 100 to 500, 100 to 450, 100 to 400, 100 to 350, 100 to 300, 100 to 250, 100 to 200, 200 to 500, 200 to 400, 200 to 300, 250 to 500, 250 to 400, 300 to 500, 300 to 400, and 400 to 500 pM.

[0153] In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap having an IL binding affinity of about 0.01, 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM, or an IL binding affinity within a range defined by any two of the foregoing values, and an antibody having an antigen binding affinity of about 50 to 500 pM. For example, in some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap having an IL binding affinity of about or no more than 0.01, 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM, and an antibody having an antigen binding affinity of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 pM, or a binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the antibody has an antigen binding affinity of about or no more than 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-100, 100-500, 100-450, 100-400, 100-350, 100-300, 100-250, 100-200, 200-500, 200-450, 200-400, 200-350, 200-300, 300-500, 300-450, 300-400, or 400-500 pM.In some embodiments, the antibody has an antigen binding affinity of at least about 0.001 pM.

[0154] In some embodiments, the IL trap has an IL IC50of less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4 x 10 -9 In some embodiments, the IL trap has an IL IC50of less than about 0.1 to 4, 0.1 to 3.5, 0.1 to 3, 0.1 to 2.5, 0.1 to 2, 0.1 to 1.5, 0.1 to 1, 0.1 to 0.5, 0.5 to 4, 0.5 to 3.5, 0.5 to 3, 0.5 to 2.5, 0.5 to 2, 0.5 to 1.5, 0.5 to 1, 1 to 4, 1 to 3.5, 1 to 3, 1 to 2.5, 1 to 2, 2 to 4, 2 to 3.5, 2 to 3, or 3 to 4 x 10 -10 In some embodiments, the IL trap has an IL IC50of less than or equal to 2 nM.

[0155] In some embodiments, the IL trap is an IL-1, IL-1a, IL-1b, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-17A-F, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36Ra, IL-36a, IL-36b, IL-36g, IL-37, or IL-38 trap.

[0156] In some embodiments, the IL trap comprises a trap against an IL-1 family member (e.g., IL-1a, IL-1b, IL-1Ra, IL-18, IL-33, IL-36a, IL-36b, IL-36y, IL-36Ra, IL-37, or IL-38). In some embodiments, the IL trap comprises the same receptor accessory protein for binding IL-1a, IL-1b, IL-1Ra, IL-33, IL-36a, IL-36b, IL-36y.

[0157] In some embodiments, the IL trap comprises an IL receptor protein. In some embodiments, the IL trap receptor protein comprises IL-1R1, IL-2Rb, IL-2Ry, IL-3Ra, CSF2RB, IL-4R, IL-2Ry / IL-13Ra1, IL-5Ra, IL-6Ra, gpl30, IL-7Ra, IL-9R, IL-11Ra, IL-12Rb1, IL-12Rb2, IL-13Ra1, IL-13Ra2, IL-4R, IL-15Ra, CD4, CD9, IL-21R, IL-12Rb1, IL-23R, IL-27Ra, IL-31Ra, OSMR, CSF-1R, or ST2 receptor protein.

[0158] In some embodiments, the IL trap comprises a trap against an IL family member (e.g., IL-6, LIF, CNTF, CLCF1, OSM, IL-11, IL-27, IL-35, IL-39).

[0159] In some embodiments, the IL trap is a trap against an IL comprising a common cytokine receptor y chain (yc) (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, IL-21). In some embodiments, the IL trap is a trap against an IL comprising a common cytokine b receptor chain (b c) (e.g., IL-3, IL-5, GM-CSF).

[0160] In some embodiments, the IL accessory protein is IL1RacP. In some embodiments, the IL accessory protein is GP130 (IL6Rb).

[0161] In some embodiments, the antibody or fragment thereof is an anti-HTRA1 antibody or fragment thereof.

[0162] In some embodiments, the trap-antibody fusion or trap-Fab comprises an IL trap, which is an IL-1 trap, and an antibody or fragment thereof, which is an anti-HTRA1 antibody or fragment thereof.

[0163] In some embodiments, the trap-antibody fusion comprises an IL trap, which is an IL-1 trap. In some embodiments, the IL-1 trap comprises IL1R1 and IL1RacP. In some embodiments, the IL-1 trap has an IL-1 binding affinity of about 0.01 to 100 pM, and the antibody is an anti-HTRA1 antibody. For example, in some embodiments, the IL-1 trap has an IL-1 binding affinity of about 0.01, 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM, or an IL-1 binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the IL-1 trap has an IL-1 binding affinity of about or no more than about 0.01-100, 0.01-75, 0.01-50, 0.01-25, 0.01-10, 0.01-5, 0.01-1, 0.01-0.1, 0.1-100, 0.1-75, 0.1-50, 0.1-25, 0.1-10, 0.1-1, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-100, 5-75, 5-50, 5-25, 5-10, 10-100, 10-75, 10-50, 10-25, 25-100, 25-75, 25-50, 50-100, 50-75, or 75-100 pM. In some embodiments, the anti-HTRA1 antibody has a HTRA1 binding affinity of about or no more than 50-500 pM.For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of about or no more than 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 pM, or a HTRA1 binding affinity within a range defined by any two of the foregoing numerical limits. For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of between or no more than about 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-100, 100-500, 100-450, 100-400, 100-350, 100-300, 100-250, 100-200, 200-500, 200-450, 200-400, 200-350, 200-300, 300-500, 300-450, 300-400, or 400-500 pM. In some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of at least about 0.01 pM.

[0164] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-1 trap. In some embodiments, the IL-1 trap comprises IL1R1 and IL1RacP. In some embodiments, the IL-1 trap has an IL-1 binding affinity of less than about 1 nM. In some embodiments, the trap-antibody fusion comprises an antibody or fragment thereof, which is an anti-HTRA1 antibody or fragment thereof. In some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of less than about 1 nM.

[0165] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-33 trap, and an antibody or fragment thereof, which is an anti-HTRA1 antibody or fragment thereof.

[0166] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RacP; and an antibody or fragment thereof, which is an anti-HTRA1 antibody.

[0167] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RacP; wherein the IL-33 trap has an IL-33 binding affinity of less than about 1 nM; and an antibody or fragment thereof, which is an anti-HTRA1 antibody or fragment thereof; wherein the anti-HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of less than about 1 nM.

[0168] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-33 trap. In some embodiments, the IL-33 trap comprises ST2 and IL1RacP. In some embodiments, the IL-33 trap has an IL-33 binding affinity of about 0.01 to 100 pM. For example, in some embodiments, the IL-33 trap has an IL-33 binding affinity of about 0.01, 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM, or a binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the IL-33 trap has an IL-33 binding affinity of about 0.001-100, 0.001-75, 0.001-50, 0.001-25, 0.001-10, 0.001-5, 0.001-1, 0.001-0.1, 0.001-0.05, 0.001-0.01, 0.01-100, 0.01-75, 0.01-50, 0.01-25, 0.01-10, 0.01-5, 0.01-1, 0.01-0.1, 0.1-100, 0.1-75, 0.1-50, 0.1-25, 0.1-10, 0.1-1, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-100, 5-75, 5-50, 5-25, 5-10, 10-100, 10-75, 10-50, 10-25, 25-100, 25-75, 25-50, 50-100, 50-75, or 75-100 pM, or no more than about 0.001, 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM. In some embodiments, the IL-33 trap has an IL-33 binding affinity of at least about 0.01 pM. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody, which is an anti-HTRA1 antibody, or a fragment thereof. In some embodiments, the anti-HTRA1 antibody has a HTRA1 binding affinity of about 5 to 500 pM.For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of about or no more than 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 pM, or a binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the anti-HTRA1 antibody has a HTRA1 binding affinity of between or no more than about 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-100, 100-500, 100-450, 100-400, 100-350, 100-300, 100-250, 100-200, 200-500, 200-450, 200-400, 200-350, 200-300, 300-500, 300-450, 300-400, or 400-500 pM. In some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of at least about 0.01 pM.

[0169] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-6 trap, and an antibody, which is an anti-HTRA1 antibody, or fragment thereof.

[0170] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-6 trap. In some embodiments, the IL-6 trap comprises gpl30 (IL6Rβ) and IL-6Rα. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody, which is an anti-HTRA1 antibody, or fragment thereof.

[0171] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-6 trap. In some embodiments, the IL-6 trap comprises gpl30 (IL6Rβ) and IL-6Rα. In some embodiments, the IL-6 trap has an IL-6 binding affinity of less than about 1 nM. In some embodiments, the trap-antibody fusion comprises an antibody, which is an anti-HTRA1 antibody. In some embodiments, the anti-HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of less than about 1 nM.

[0172] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-6 trap. In some embodiments, the IL-6 trap comprises gpl30 (IL6Rβ) and IL-6Rα. In some embodiments, the IL-6 trap has an IL-6 binding affinity of about 0.01 to 100 pM. For example, in some embodiments, the IL-6 trap has an IL-6 binding affinity of about 0.01, 0.05, 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 75, 80, 90, 95, or 100 pM, or a binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the IL-33 trap has an IL-33 binding affinity of about 0.001-100, 0.001-75, 0.001-50, 0.001-25, 0.001-10, 0.001-5, 0.001-1, 0.001-0.1, 0.001-0.05, 0.001-0.01, 0.01-100, 0.01-75, 0.01-50, 0.01-25, 0.01-10, 0.01-5, 0.01-1, 0.01-0.1, 0.1-100, 0.1-75, 0.1-50, 0.1-25, 0.1-10, 0.1-1, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-100, 5-75, 5-50, 5-25, 5-10, 10-100, 10-75, 10-50, 10-25, 25-100, 25-75, 25-50, 50-100, 50-75, or 75-100 pM. In some embodiments, the IL-6 trap has an IL-6 binding affinity of at least about 0.01 pM. In some embodiments, the trap-antibody fusion comprises an antibody, which is an anti-HTRA1 antibody, or a fragment thereof. In some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of about 5 to 500 pM.For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has a HTRA1 binding affinity of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, or 500 pM, or a binding affinity within a range defined by any two of the foregoing values. For example, in some embodiments, the anti-HTRA1 antibody has a HTRA1 binding affinity of about 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-100, 100-500, 100-450, 100-400, 100-350, 100-300, 100-250, 100-200, 200-500, 200-450, 200-400, 200-350, 200-300, 300-500, 300-450, 300-400, or 400-500 pM.

[0173] Figure 17 Representative embodiments of the full length and regions of IL-1, IL-6, IL-33, and VEGF receptor sequences are shown.

[0174] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap comprising a receptor sequence that is Figure 17 the receptor sequence in Table 1.

[0175] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap comprising a receptor sequence that is the receptor sequence of any one of SEQ ID NO.: 1-15 or 67-71. In some embodiments, the trap-antibody fusion comprises a receptor sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the receptor sequence of any one of SEQ ID NO.: 1-15 or 67-71. In some embodiments, the trap-antibody fusion comprises a receptor sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the receptor sequence of any one of SEQ ID NO.: 1-15 or 67-71.

[0176] Table 1 lists some embodiments of the full length and regions of IL-1, IL-6, IL-33, VEGF, and TNFα receptor sequences.

[0177] Table 1:

[0178]

[0179]

[0180]

[0181]

[0182] Selected amino acid regions in the receptors are indicated in parentheses, where applicable.

[0183] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap comprising a receptor sequence that is the receptor sequence of any one of SEQ ID NO.: 1-15 or 67-71. In some embodiments, the trap-antibody fusion comprises a receptor sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the receptor sequence of any one of SEQ ID NO.: 1-15 or 67-71. In some embodiments, the trap-antibody fusion comprises a receptor sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the receptor sequence of any one of SEQ ID NO.: 1-15 or 67-71.

[0184] Figure 18 Some representative embodiments of IgG constant and variable region sequences are shown.

[0185] In some embodiments, the trap-antibody or trap-Fab fusion comprises IgG constant and variable region sequences that are the IgG constant and variable region sequences of Figure 18

[0186] ​In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is the variable domain sequence of any one of SEQ ID NO.: 30-44. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is a variable domain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the variable domain sequence of any one of SEQ ID NO.: 30-44. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is a variable domain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the variable domain sequence of any one of SEQ ID NO.: 30-44.

[0187] In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a constant domain sequence that is the constant domain sequence of any one of SEQ ID NO.: 28-29, 45-47, or 64-66. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a constant domain sequence that is a constant domain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the constant domain sequence of any one of SEQ ID NO.: 28-29, 45-47, or 64-66. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a constant domain sequence that is a constant domain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the constant domain sequence of any one of SEQ ID NO.: 28-29, 45-47, or 64-66.

[0188] Table 2 lists some embodiments of IgG constant region and variable region sequences.

[0189] Table 2:

[0190]

[0191]

[0192] In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is the variable domain sequence of any one of SEQ ID NO.: 30-44. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is a variable domain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the variable domain sequence of any one of SEQ ID NO.: 30-44. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is a variable domain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the variable domain sequence of any one of SEQ ID NO.: 30-44.

[0193] Figure 19Some representative embodiments of linkers suitable for linking IL receptor proteins to antibody variable domains are shown.

[0194] In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is Figure 19 the linkers in Table 3.

[0195] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL receptor protein linked to an antibody variable domain. In some embodiments, the trap-antibody fusion comprises a linker comprising one or more repeats. In some embodiments, the one or more repeats comprise repeats of GGGGS (SEQ ID NO.: 24). In some embodiments, the trap-antibody fusion comprises a linker comprising 1, 2, 3, 4, 5, 6, 7, or 8 repeats. In some embodiments, the trap-antibody fusion comprises a linker comprising 1, 2, 3, 4, 5, 6, 7, or 8 repeats of GGGGS (SEQ ID NO.: 24). In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker of any one of SEQ ID NOs.: 24-27. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker of any one of SEQ ID NO.: 24 (GGGGS). In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker of any one of SEQ ID NO.: 25 (GGGGSGGGGS). In some embodiments, the trap-antibody fusion comprises a linker that is a linker of any one of SEQ ID NO.: 26 (GGGGSGGGGSGGGGS). In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker of any one of SEQ ID NO.: 27 (GGGGSGGGGSGGGGS). In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to a linker of any one of SEQ ID NOs.: 24-27. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to a linker of any one of SEQ ID NOs.: 24-27.

[0196] Table 3 describes some embodiments of linkers suitable for linking IL receptor proteins to antibody variable domains.

[0197] Table 3.

[0198]

[0199] In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker in Table 3. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to a linker in Table 3. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to a linker in Table 3.

[0200] In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker of up to 20 amino acids. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids, or a linker of a number of amino acids within a range bounded by any two of the foregoing values. For example, in some embodiments, the trap-antibody or trap-Fab fusion comprises a linker of 1-20, 1-15, 1-10, 1-7, 1-5, 1-3, 3-20, 3-15, 3-10, 3-7, 3-5, 5-20, 5-15, 5-10, 5-7, 7-20, 7-15, 7-10, 10-20, 10-15, or 15-20 amino acids in length.

[0201] Figure 20 Some representative embodiments of signal peptide sequences suitable for use in the trap-antibody or trap-Fab fusions disclosed herein are shown.

[0202] In some embodiments, the trap-antibody fusion or trap-Fab comprises a signal peptide that is Figure 20 the signal peptide in Table 4.

[0203] Table 4 describes some embodiments of signal peptide sequences suitable for use in the trap-antibody or trap-Fab fusions disclosed herein.

[0204] Table 4:

[0205]

[0206] In some embodiments, the trap-antibody or trap-Fab fusion compound comprises a signal peptide, which is one of the signal peptides listed in Table 4. In some embodiments, the trap-antibody or trap-Fab fusion compound comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% homology to the signal peptides in Table 4. In some embodiments, the trap-antibody or trap-Fab fusion compound comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity to the signal peptides in Table 4.

[0207] In some embodiments, trap-antibody or trap-Fab fusion complexes are engineered by fusing the extracellular domains of heterodimeric human IL-1 receptors IL1RAcP, IL1R1, and IL1R2 to an anti-human IL-6 antibody. In some embodiments, the N-terminus of each receptor is fused to a VH or VL region. The HC / LC heterodimer places the IL-1 receptors nearby in a manner that allows them to mimic the native binding mechanism of IL-1. In some embodiments, IL1RAcP is tandemly linked to ILR1 or ILR2 and then fused to the heavy and / or light chains of the anti-IL-6 antibody. The fusion protein then binds to different signal peptides, driving extracellular secretion in mammalian cells.

[0208] Figure 4 This is a schematic diagram illustrating various embodiments of the IL-1 trap and IgG fusion structure. Dark crescent shapes represent IL1R1 or IL1R2. Light crescent shapes represent IL1RAcP. In some embodiments, IL1RAcP is tandemly linked to the heavy or light chain of either arm of the antibody along with IL1R1 or IL1R2. In some embodiments, IL1RAcP is tandemly linked to both the heavy and light chains of either arm of the antibody along with IL1R1 or IL1R2. In some embodiments, IL1R1 or IL1R2 and IL1RAcP are each respectively linked to the heavy and light chains of the two antibody arms. In some embodiments, IL1RAcP and IL1R1 or IL1R2 are each respectively linked to the heavy and light chains of the two antibody arms.

[0209] Table 5 lists some embodiments of the sequence composition of IL-1 trap anti-IL-6 antibody, IL-6 trap, IL-33 trap, IL-1 trap anti-IL-6 Fab, and double VEGF trap anti-IL-6 Fab. As listed in Table 5, the sequence composition represents SEQ IDs that can be covalently linked to each other, with heavy and light chains forming from left to right.

[0210] Table 5:

[0211]

[0212]

[0213]

[0214]

[0215] In some embodiments, the trap-antibody or trap-Fab fusion is a trap-antibody fusion in Table 5. In some embodiments, the trap-antibody fusion is a trap-antibody fusion that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to a trap-antibody fusion in Table 5.

[0216] In some embodiments, the trap-antibody or trap-Fab fusion comprises a combination of SEQ IDs disclosed herein. In some embodiments, the trap-antibody fusion comprises a combination of SEQ IDs disclosed in Table 5. In some embodiments, the trap-antibody fusion or trap-Fab is a trap-antibody fusion that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to a trap-antibody fusion comprising a combination of SEQ IDs disclosed in Table 5. In some embodiments, the trap-antibody or trap-Fab fusion comprises a heavy chain that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to a trap-antibody or trap-Fab fusion comprising a combination of SEQ IDs disclosed in Table 5.

[0217] In some embodiments, any of the constructs in Table 5 can be used to treat one or more conditions. In some embodiments, the conditions include diabetic retinopathy, early, intermediate, late age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, ocular inflammation, HTRA1 -associated conditions and / or IL-1 -associated conditions, scleritis, diabetic macular edema, diabetic retinopathy, wet age-related macular degeneration, uveitis, non-infectious uveitis, uveitis macular edema, cytokine release syndrome after CAR-T or similar immuno-oncology therapies, and / or induction of IL-6 expression observed after blockade of anti-PD-1 / PD-L1 molecules therapy, cancer, brain edema in glioblastoma, IL-6-associated conditions, and / or VEGF-associated conditions. In some embodiments, the condition is ocular inflammation. In some embodiments, the condition is eye inflammation. In some embodiments, any of the constructs in Table 5 can be used to treat one or more conditions in Figure 25 ​

[0218] Figure 21 Some representative embodiments of full length heavy chain sequences suitable for use in trap-antibody fusion disclosed herein are shown. In some embodiments, the trap-antibody fusion comprises a heavy chain in Figure 21 In some embodiments, the trap-antibody fusion comprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100% homology to a heavy chain in Figure 21 In some embodiments, the trap-antibody fusion comprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100% identity to a heavy chain in Figure 21 In some embodiments, the trap-antibody fusion comprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100% identity to a heavy chain in

[0219] Figure 22 Some representative embodiments of full length light chain sequences suitable for use in trap-antibody or trap-Fab fusion disclosed herein are shown. In some embodiments, the trap-antibody fusion comprises a light chain in Figure 22 In some embodiments, the trap-antibody fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100% homology to a light chain in Figure 22 In some embodiments, the trap-antibody fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100% identity to a light chain in Figure 22 In some embodiments, the trap-antibody fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100% identity to a light chain in

[0220] In some embodiments, the trap-antibody fusion comprises an IL-1 trap-anti-HTRA1. In some embodiments, the trap-antibody comprises an IL-33 trap-anti-HTRA1. In some embodiments, the trap-antibody comprises an IL-6 trap-anti-HTRA1.

[0221] Table 6 shows some embodiments of trap-antibody full length heavy chain sequences.

[0222] Table 6.

[0223]

[0224]

[0225]

[0226] Signal peptides are shown in bold. IL trap sequences are shown in italics. Linker sequences are underlined.

[0227] In some embodiments, the trap-antibody fusion comprises the heavy chains listed in Table 6. In some embodiments, the trap-antibody fusion comprises a heavy chain having approximately 70%, 75%, 80%, 90%, 95%, or 100% homology to the heavy chains listed in Table 6.

[0228] Table 7 shows some implementation schemes of the full-length light chain sequence of the trap-antibody fusion.

[0229] Table 7:

[0230]

[0231]

[0232] Signal peptides are shown in bold. IL trap sequences are shown in italics. Connector sequences are underlined.

[0233] In some embodiments, the trap-antibody fusion comprises the light chains listed in Table 7. In some embodiments, the trap-antibody fusion comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% homology to the light chains listed in Table 7. In some embodiments, the trap-antibody fusion comprises a light chain having approximately 70%, 75%, 80%, 90%, 95%, or 100% homology to the heavy chains listed in Table 7.

[0234] Figure 23 Some representative implementations of the full-length heavy chain sequence applicable to the trap-Fab fusion disclosed herein are shown.

[0235] In some implementations, the trap-Fab fusion contains Figure 23 The heavy chain in the structure. In some implementations, the trap-Fab fusion contains the heavy chain. Figure 23 The heavy chains in the complex have approximately 70%, 75%, 80%, 90%, 95%, or 100% homology. In some embodiments, the trap-Fab fusion contains heavy chains with... Figure 23 The heavy chains in the text have approximately 70%, 75%, 80%, 90%, 95%, or 100% identity.

[0236] Figure 24 Some representative implementations of the full-length light chain sequences applicable to the trap-Fab fusion disclosed herein are shown.

[0237] In some implementations, the trap-Fab fusion contains Figure 24the light chain in Table 8. In some embodiments, the trap-Fab fusion comprises a heavy chain that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the heavy chain in Table 8. Figure 24 the light chain in Table 8. In some embodiments, the trap-Fab fusion comprises a heavy chain that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the heavy chain in Table 8. Figure 24 the light chain in Table 8. In some embodiments, the trap-Fab fusion comprises a heavy chain that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the heavy chain in Table 8.

[0238] Table 8 shows some embodiments of trap-Fab fusion full length heavy chain sequences.

[0239] Table 8:

[0240]

[0241] The signal peptide is shown in bold. The IL trap sequence is shown in italics. The linker sequence is underlined.

[0242] In some embodiments, the trap-Fab fusion comprises a heavy chain in Table 8. In some embodiments, the trap-Fab fusion comprises a heavy chain that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the heavy chain in Table 8. In some embodiments, the trap-Fab fusion comprises a heavy chain that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the heavy chain in Table 8.

[0243] Table 9 shows some embodiments of trap-antibody fusion full length light chain sequences.

[0244] Table 9:

[0245]

[0246] The signal peptide is shown in bold. The IL trap sequence is shown in italics. The linker sequence is underlined.

[0247] In some embodiments, the trap-Fab fusion comprises a light chain in Table 9. In some embodiments, the trap-Fab fusion comprises a light chain that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to the light chain in Table 9. In some embodiments, the trap-Fab fusion comprises a light chain that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to the light chain in Table 9.

[0248] In some embodiments, Figure 10 , 11 or 12 can be used with the sequences shown in Figure 21 or 22. In some embodiments, Figure 13, 14 Or the conjugate shown in 15 can be with Figure 23 Alternatively, use the sequence shown in 24.

[0249] In some embodiments, the trap-antibody fusion is an IL-1 trap anti-HTRA1 antibody biopolymer conjugate. As used herein, the term “biopolymer” indicates that a polymer has been attached to a protein of interest. The term can also be described as a “conjugated” form of a protein. In some embodiments, the IL-1 trap anti-HTRA1 antibody biopolymer conjugate is TA105-OG1802. In some embodiments, the trap-antibody fusion comprises a heavy chain sequence of SEQ ID No.: 51. In some embodiments, the trap-antibody fusion comprises a heavy chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 51. In some embodiments, the trap-antibody fusion comprises a heavy chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 51. In some embodiments, the IL-1 trap anti-HTRA1 antibody biopolymer conjugate comprises a light chain sequence of SEQ ID No.: 57. In some embodiments, the trap-antibody fusion comprises a light chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 57. In some embodiments, the trap-antibody fusion comprises a light chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 57. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 38, a CH of SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 38, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 28.In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 38, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 44, a CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 44, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 44, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 29.In some embodiments, the IL-1 trap anti-HTRA1 fusion can be used to treat, or in conjunction with the treatment of, diabetic retinopathy, early, intermediate, late age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, ocular inflammation, HTRA1 -related disorders, and / or IL-1 -related disorders.

[0250] In some embodiments, the trap-Fab fusion is an IL-1 trap anti-IL-6 Fab biopolymer conjugate. In some embodiments, the trap-Fab fusion is TF2-OG1802. In some embodiments, the trap-Fab fusion comprises a heavy chain sequence of SEQ ID No.: 60. In some embodiments, the trap-Fab fusion comprises a heavy chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 60. In some embodiments, the trap-Fab fusion comprises a heavy chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 60. In some embodiments, the trap-Fab fusion comprises a light chain sequence of SEQ ID No.: 62. In some embodiments, the trap-Fab fusion comprises a light chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 62. In some embodiments, the trap-Fab fusion comprises a light chain sequence that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 62. In some embodiments, the trap-Fab fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 46. In some embodiments, the trap-Fab fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 46.In some embodiments, the trap-Fab fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 46. In some embodiments, the trap-Fab fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.: 29. In some embodiments, the trap-Fab fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 29.

[0251] In some embodiments, the trap-antibody fusion comprises an IL-1 trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66.In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 16, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 16, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 29.

[0252] In some embodiments, the trap-antibody fusion comprises an IL-1 trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66.In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 16, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 16, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 29.

[0253] In some embodiments, the trap-antibody fusion comprises an IL-1 trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 17, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 1, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 18, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 2, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 39, a CL that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 29.

[0254] In some embodiments, the trap-antibody fusion comprises a TNFa trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 72, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 67, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% homologous to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 72, a trap that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 67, a linker that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 25, a VH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 30, a CH that is about 70%, 75%, 80%, 90%, 95%, or 100% identical to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0255] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0256] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0257] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 28. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0258] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0259] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 67, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0260] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 68, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0261] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 28. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0262] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0263] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 68, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0264] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 69, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0265] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0266] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0267] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0268] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0269] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 28. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0270] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0271] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0272] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 70, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0273] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 70, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0274] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0275] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0276] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0277] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0278] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 28. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0279] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0280] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 70, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0281] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 71, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0282] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0283] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0284] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0285] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0286] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 64. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0287] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 28. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0288] In some embodiments, the trap-antibody fusion comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion body chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0289] In some embodiments, the trap-antibody fusion compound comprises a TNFα trap and an IL-6 antibody. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 65. In some embodiments, the trap-antibody fusion weight chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.: 66. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 66.In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 66. In some implementations, the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the adapter of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0290] In some embodiments, an anti-TFFα VHH anti-IL-6 antibody fusion complex is disclosed. In some embodiments, the fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VHH of SEQ ID No.: 74, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 28. In some embodiments, the trap fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion weight chain includes a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VHH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 74, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the fusion light chain comprises the signal peptide of SEQ ID No.: 16, VHH of SEQ ID No.: 74, the linker of SEQ ID No.: 25, VL of SEQ ID No.: 39, and CL of SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0291] In some embodiments, an anti-TFFα VHH anti-IL-6 antibody fusion complex is disclosed. In some embodiments, the fusion weight chain comprises the signal peptide of SEQ ID No.: 16, the VHH of SEQ ID No.: 74, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, and the CH of SEQ ID No.: 28. In some embodiments, the trap fusion weight chain includes a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VHH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 74, a linker having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having approximately 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology with SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0292] In some embodiments, an anti-TFFα VHH anti-IL-6 antibody fusion polymer is disclosed. In some embodiments, the fusion polymer chain comprises a signal peptide of SEQ ID No.: 16, VH of SEQ ID No.: 30, and CH of SEQ ID No.: 28. In some embodiments, the trap fusion polymer chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 30, and CH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 30, and a CH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 28. In some embodiments, the fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VHH of SEQ ID No.: 58, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, and the CL of SEQ ID No.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 58, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% homology to SEQ ID No.: 29.In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 58, a linker having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 39, and a CL having about 70%, 75%, 80%, 90%, 95%, or 100% identity with SEQ ID No.: 29.

[0293] Some embodiments of this document relate to nucleic acids encoding any trap-antibody or trap-Fab fusion complex disclosed herein. For example, in some embodiments, the nucleic acid encodes any trap-antibody or trap-Fab fusion complex in Table 5. Some embodiments of this document relate to vectors comprising nucleic acids encoding any trap-antibody or trap-Fab fusion complex disclosed herein. For example, in some embodiments, the vector comprises nucleic acids encoding any trap-antibody or trap-Fab fusion complex in Table 5. Some embodiments of this document relate to cells comprising vectors encoding any trap-antibody or trap-Fab fusion complex disclosed herein. For example, in some embodiments, the cells comprise vectors encoding any trap-antibody or trap-Fab fusion complex in Table 5.

[0294] In some implementations, receptor proteins and antibodies, such as Figure 4 The configuration shown.

[0295] In some embodiments, the binding of an IL trap to an IL reduces the activity of the IL. In some embodiments, the binding of an antibody to an antigen inhibits the activity of the antigen. In some embodiments, the simultaneous binding of an IL trap to an IL and the binding of an antibody to an antigen inhibit the activity of both the IL and the antigen.

[0296] In some embodiments, the binding of the IL trap to IL reduces the activity of IL by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, 95, 99, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, or 1000%, or by a range defined by any two of the foregoing values. For example, in some embodiments, IL The binding of traps to ILs reduces IL activity by approximately 1-1000, 1-750, 1-500, 1-250, 1-150, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-150, 5-100, 5-75, 5-50, 5-25, 5-10, 10-1000, 10-750, 10-500, 10-250, 10-150, 10-100, 10-75, 10-5 0, 10-25, 25-1000, 25-750, 25-500, 25-250, 25-150, 25-100, 25-75, 25-50, 50-1000, 50-750, 50-500, 50-250, 50-150, 50-100, 100-1000, 100-750, 100-500, 100-250, 250-1000, 250-750, 250-500, 500-1000, 500-750 or 750-1000%.

[0297] In some implementations, the binding of the antibody to the antigen reduces the activity of the antigen by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, 95, 99, 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, or 1000%, or by a range defined by any two of the aforementioned values. For example, in some implementations, the binding of the antibody to the antigen reduces the antigen activity by approximately 1-1000, 1-750, 1-500, 1-250, 1-150, 1-100, 1-75, 1-50, 1-25, 1-10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-150, 5-100, 5-75, 5-50, 5-25, 5-10, 10-1000, 10-750, 10-500, 10-250, 10-150, 10-100, 10-75 10-50, 10-25, 25-1000, 25-750, 25-500, 25-250, 25-150, 25-100, 25-75, 25-50, 50-1000, 50-750, 50-500, 50-250, 50-150, 50-100, 100-1000, 100-750, 100-500, 100-250, 250-1000, 250-750, 250-500, 500-1000, 500-750 or 750-1000%.

[0298] In some implementations, the IL trap-antibody or trap-Fab fusion has approximately 1x10 4 2x10 4 3x10 4 4x10 4 5x10 4 6x10 4 7x10 4 8x10 4 9x10 4 1x10 5 2x10 5 3x10 5 4x10 5 5x10 5 6x10 5 7x10 5 8x10 5 9x10 5 1x10 6 2x10 6 3x10 6 4x10 6 5x106 6x10 6 7x10 6 8x10 6 9x10 6 1x10 7 2x10 7 3x10 7 4x10 7 5x10 7 6x10 7 7x10 7 8x10 7 9x10 7 1x10 8 2x10 8 3x10 8 4x10 8 5x10 8 6x10 8 7x10 8 8x10 8 9x10 8 1x10 9 2x10 9 3x10 9 4x10 9 5x10 9 6x10 9 7x10 9 8x10 9 Or 9x10 9 An IL binding rate constant (ka) of (1 / Ms), or an IL binding rate constant within a range defined by any two of the foregoing values. For example, in some embodiments, the IL trap-antibody or trap-Fab fusion has approximately 1 x 102 IL binding rate constants. 4 Up to 9x10 9 1x10 4 Up to 5x10 9 1x10 4 Up to 1x10 9 1x10 4 Up to 9x10 8 1x10 4 Up to 5x10 9 1x10 4 Up to 1x10 8 1x10 4 Up to 9x10 7 1x10 4 Up to 5x10 7 1x10 4 Up to 1x10 7 1x10 4 Up to 9x106 1x10 4 Up to 5x10 6 1x10 4 Up to 1x10 6 1x10 4 Up to 9x10 5 1x10 4 Up to 5x10 5 1x10 4 Up to 5x10 5 1x10 4 Up to 1x10 5 1x10 5 Up to 9x10 9 1x10 5 Up to 5x10 9 1x10 5 Up to 1x10 9 1x10 5 Up to 9x10 8 1x10 5 Up to 5x10 9 1x10 5 Up to 1x10 8 1x10 5 Up to 9x10 7 1x10 5 Up to 5x10 7 1x10 5 Up to 1x10 7 1x10 5 Up to 9x10 6 1x10 5 Up to 5x10 6 1x10 5 Up to 1x10 6 1x10 6 Up to 9x10 9 1x10 6 Up to 5x10 9 1x10 6 Up to 1x10 9 1x10 6 Up to 9x10 8 1x10 6 Up to 5x10 8 1x10 6 Up to 1x10 8 1x10 6 Up to 9x10 7 1x10 6 Up to 5x10 7 1x10 6 Up to 1x10 7 1x10 7Up to 9x10 9 1x10 7 Up to 5x10 9 1x10 7 Up to 1x10 9 1x10 7 Up to 9x10 8 1x10 7 Up to 5x10 9 1x10 7 Up to 1x10 8 1x10 8 Up to 9x10 9 1x10 8 Up to 5x10 9 1x10 8 Up to 1x10 9 1x10 8 Up to 9x10 8 Or 1x10 8 Up to 5x10 8 The IL binding rate constant is (1 / Ms).

[0299] In some implementations, the IL trap-antibody or trap-Fab fusion has approximately 1x10 -1 2x10 -1 3x10 -1 4x10 -1 5x10 -1 6x10 -1 7x10 -1 8x10 -1 9x10 -1 1x10 -2 2x10 -2 3x10 -2 4x10 -2 5x10 -2 6x10 -2 7x10 -2 8x10 -2 9x10 -2 1x10 -3 2x10 -3 3x10 -3 4x10 -3 5x10 -3 6x10 -3 7x10 -3 8x10 -3 9x10 -3 1x10 -4 2x10 -4 3x10 -4 4x10-4 5x10 -4 6x10 -4 7x10 -4 8x10 -4 9x10 -4 1x10 -5 2x10 -5 3x10 -5 4x10 -5 5x10 -5 6x10 -5 7x10 -5 8x10 -5 9x10 -5 1x10 -6 2x10 -6 3x10 -6 4x10 -6 5x10 -6 6x10 -6 7x10 -6 8x10 -6 9x10 -6 1x10 -7 2x10 -7 3x10 -7 4x10 -7 5x10 -7 6x10 -7 7x10 -7 8x10 -7 Or 9x10 -7 An IL dissociation rate constant (kd) of 1 / s, or an IL dissociation rate constant within the range defined by any two of the foregoing values. For example, in some embodiments, the IL trap-antibody or trap-Fab fusion has a rate constant of approximately 1 x 10⁻⁶ kDa. -1 Up to 9x10 -7 1x10 -1 Up to 5x10 -7 1x10 -1 Up to 1x10 -7 1x10 -1 Up to 9x10 -6 1x10 -1 Up to 5x10 -6 1x10 -1 Up to 1x10 -6 1x10 -1 Up to 9x10 -5 1x10 -1 Up to 5x10 -5 1x10 -1 Up to 1x10 -5 1x10-1 Up to 9x10 -4 1x10 -1 Up to 5x10 -4 1x10 -1 Up to 1x10 -4 1x10 -1 Up to 9x10 -3 1x10 -1 Up to 5x10 -3 1x10 -1 Up to 1x10 -3 1x10 -1 Up to 9x10 -2 1x10 -1 Up to 5x10 -2 1x10 -1 Up to 1x10 -2 1x10 -2 Up to 9x10 -7 1x10 -2 Up to 5x10 -7 1x10 -1 Up to 1x10 -7 1x10 -2 Up to 9x10 -6 1x10 -2 Up to 5x10 -6 1x10 -2 Up to 1x10 -6 1x10 -2 Up to 9x10 -5 1x10 -2 Up to 5x10 -5 1x10 -2 Up to 1x10 -5 1x10 -2 Up to 9x10 -4 1x10 -2 Up to 5x10 -4 1x10 -2 Up to 1x10 -4 1x10 -2 Up to 9x10 -3 1x10 -2 Up to 5x10 -3 1x10 -2 Up to 1x10 -3 1x10 -3 Up to 9x10 -7 1x10 -3 Up to 5x10 -7 1x10 -3 Up to 1x10 -7 1x10 -3 Up to 9x10 -61x10 -3 Up to 5x10 -6 1x10 -3 Up to 1x10 -6 1x10 -3 Up to 9x10 -5 1x10 -3 Up to 5x10 -5 1x10 -3 Up to 1x10 -5 1x10 -3 Up to 9x10 -5 1x10 -3 Up to 5x10 -4 1x10 -3 Up to 1x10 -4 1x10 -4 Up to 9x10 -7 1x10 -4 Up to 5x10 -7 1x10 -4 Up to 1x10 -7 1x10 -4 Up to 9x10 -6 1x10 -4 Up to 5x10 -6 1x10 -4 Up to 1x10 -6 1x10 -4 Up to 9x10 -5 1x10 -4 Up to 5x10 -5 1x10 -4 Up to 1x10 -5 1x10 -5 Up to 9x10 -7 1x10 -5 Up to 5x10 -7 1x10 -5 Up to 1x10 -7 1x10 -5 Up to 9x10 -6 1x10 -5 Up to 5x10 -6 1x10 -5 Up to 1x10 -6 1x10 -6 Up to 9x10 -7 1x10 -6 Up to 5x10 -7 1x10 -6 Up to 1x10 -7 1x10 -7 Up to 9x10 -7 Or 1x10 -7 Up to 5x10-7 The IL dissociation rate constant is (1 / s).

[0300] In some implementations, the IL trap-antibody or trap-Fab fusion has approximately 1x10 -8 2x10 -8 3x10 -8 4x10 -8 5x10 -8 6x10 -8 7x10 -8 8x10 -8 9x10 -8 1x10 -9 2x10 -9 3x10 -9 4x10 -9 5x10 -9 6x10 -9 7x10 -9 8x10 -9 9x10 -9 1x10 -10 2x10 -10 3x10 -10 4x10 -10 5x10 -10 6x10 -10 7x10 -10 8x10 -10 9x10 -10 1x10 -11 2x10 -11 3x10 -11 4x10 -11 5x10 -11 6x10 -11 7x10 -11 8x10 -11 9x10 -11 1x10 -12 2x10 -12 3x10 -12 4x10 -12 5x10 -12 6x10 -12 7x10 -12 8x10 -12 9x10 -12 1x10 -13 2x10 -13 3x10 -13 4x10 -13 5x10 -13 6x10-13 7x10 -13 8x10 -13 Or 9x10 -13 The IL equilibrium dissociation constant (KD) of M, or having an IL equilibrium dissociation constant within a range defined by any two of the foregoing values. For example, in some embodiments, the IL trap-antibody or trap-Fab fusion has approximately 1 x 10⁻⁶ KD. -8 Up to 9x10 -13 1x10 -8 Up to 5x10 -13 1x10 -8 Up to 1x10 -13 1x10 -8 Up to 9x10 -12 1x10 -8 Up to 5x10 -12 1x10 -8 Up to 1x10 -12 1x10 -8 Up to 9x10 -11 1x10 -8 Up to 5x10 -11 1x10 -8 Up to 1x10 -11 1x10 -8 Up to 9x10 -10 1x10 -8 Up to 5x10 -10 1x10 -8 Up to 1x10 -10 1x10 -8 Up to 9x10 -9 1x10 -8 Up to 5x10 -9 1x10 -8 Up to 1x10 -9 1x10 -8 Up to 9x10 -8 1x10 -8 Up to 5x10 -8 1x10 -9 Up to 9x10 -12 1x10 -9 Up to 5x10 -12 1x10 -9 Up to 1x10 -12 1x10 -9 Up to 9x10 -11 1x10 -9 Up to 5x10 -11 1x10 -9 Up to 1x10 -11 1x10 -9 Up to 9x10-10 1x10 -9 Up to 5x10 -10 1x10 -9 Up to 1x10 -10 1x10 -9 Up to 9x10 -9 1x10 -9 Up to 5x10 -9 1x10 -10 Up to 9x10 -12 1x10 -10 Up to 5x10 -12 1x10 -10 Up to 1x10 -12 1x10 -10 Up to 9x10 -11 1x10 -10 Up to 5x10 -11 1x10 -10 Up to 1x10 -11 1x10 -10 Up to 9x10 -10 1x10 -10 Up to 5x10 -10 1x10 -11 Up to 9x10 -12 1x10 -11 Up to 5x10 -12 1x10 -11 Up to 1x10 -12 1x10 -11 Up to 9x10 -11 1x10 -11 Up to 5x10 -11 1x10 -12 Up to 9x10 -12 Or 1x10 -12 Up to 5x10 -12 The equilibrium dissociation constant of M.

[0301] polymer:

[0302] A polymer is a molecule composed of many repeating subunits. These subunits (sometimes called "monomers") can be the same or different. There are natural and synthetic polymers. DNA, proteins, and complex carbohydrates are examples of natural polymers. Polystyrene and polyacrylamide are examples of synthetic polymers. A polymer composed of repeating units of a single monomer is called a homopolymer. A polymer composed of two or more monomers is called a copolymer, sometimes also called a heteropolymer. Copolymers in which certain types of monomers are aggregated together are sometimes called block copolymers. Polymers can be linear or branched. When a polymer is branched, polymer chains with a common origin are sometimes called polymer arms.

[0303] An "initiator" is a compound capable of serving as a matrix on which one or more polymerizations can be carried out using the monomers or comonomers described herein. The polymerization can be conventional free radical polymerization or preferred controlled / "living" free radical polymerization, such as atom transfer radical polymerization (ATRP), reversible addition-fracture termination (RAFT) polymerization, or nitride-mediated polymerization (NMP). The polymerization can be "pseudo" controlled polymerization, such as decay transfer. Initiators suitable for ATRP contain one or more unstable bonds that can be homolytically cleaved to form initiator fragment I, which is a free radical capable of initiating free radical polymerization, and a free radical scavenger I' that reacts with the free radicals of the growing polymer chains to reversibly terminate the polymerization. The free radical scavenger I' is typically halogenated, but can also be an organic moiety, such as a nitrile. In some embodiments of the invention, the initiator contains one or more 2-bromoisobutyrate groups as sites for polymerization via ATRP.

[0304] A “chemical linker” is a chemical part that connects two groups together, such as a half-life extension part and a protein. Linkers can be cleavable or non-cleavable. Cleavable linkers can be hydrolyzable, enzymatically cleavable, pH-sensitive, light-labile, or disulfide linkers, etc. Other linkers include homobifunctional and heterobifunctional linkers. A “linking group” is a functional group capable of forming a covalent bond consisting of one or more bonds connected to a bioactive agent. Non-limiting examples include those shown in Table 1 of WO2013059137 (incorporated by reference).

[0305] The term "reactive group" refers to a group that can react with another chemical group to form a covalent bond; that is, it exhibits covalent reactivity under suitable reaction conditions and usually represents a connection point with another substance. A reactive group is a part that can chemically react with functional groups on different parts to form a covalent bond, such as maleimide or succinimide esters. Reactive groups typically include nucleophiles, electrophiles, and photoactivators.

[0306] As used in this article, "phosphorylcholine," also known as "PC," refers to the following:

[0307]

[0308] The asterisk (*) indicates a junction. Phosphorylcholine is an amphoteric group, including salts (such as internal salts) and their protonated and deprotonated forms.

[0309] As used in this article, "phosphorylcholine-based polymers" refers to polymers containing phosphorylcholine. "Zwitterionic polymers" refers to polymers containing zwitterions.

[0310] Poly(acryloyloxyethyl phosphorylcholine) polymers refer to polymers containing 2-(acryloyloxy)ethyl-2-(trimethylammonium)ethyl phosphate as monomers.

[0311] Poly(methacryloyloxyethyl phosphorylcholine) polymers refer to polymers containing 2-(methacryloyloxy)ethyl-2-(trimethylammonium)ethyl phosphate as monomers.

[0312] As used herein, “molecular weight” in the context of polymers may refer to number-average molecular weight, weight-average molecular weight, or peak molecular weight. Unless otherwise stated, all references to molecular weight herein refer to peak molecular weight. These molecular weight determinations, namely number-average molecular weight (Mn), weight-average molecular weight (Mw), and peak molecular weight (Mp), can be measured using size exclusion chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values ​​may also be used to determine the number-average molecular weight, such as using end-group analysis or measuring colligative properties (e.g., freezing point depression, boiling point elevation, or osmotic pressure), or using light scattering techniques, ultracentrifugation, or viscometry to determine the weight-average molecular weight. In a preferred embodiment of the invention, molecular weight is measured by SEC-MALS (size exclusion chromatography-multi-angle light scattering). The polymerizing agents disclosed herein are generally polydisperse (i.e., the number-average molecular weight and weight-average molecular weight of the polymer are not equal). The polydispersity index (PDI) provides a measure of the dispersion of the polymer in a mixture. The PDI is given by the formula Mw / Mn. In this respect, homogeneous proteins will have a PDI of 1.0 (Mn is the same as Mw). Typically, the polydispersity index (PDI) of the polymer will be higher than 1.0. The polymer according to the invention preferably has a relatively low polydispersity index (PDI) value, for example, less than about 1.5, as determined by SEC-MALS, for example. In other embodiments, the polydispersity index (PDI) is more preferably in the range of about 1.4 to about 1.2, even more preferably less than about 1.15, even more preferably less than about 1.10, even more preferably less than about 1.05, and most preferably less than about 1.03.

[0313] As used herein, “protected,” “protected form,” “protecting group,” and “protective group” refer to groups (i.e., protecting groups) present under certain reaction conditions that prevent or block the reaction of specific chemically reactive functional groups in a molecule. Protecting groups vary depending on the type of chemically reactive group being protected, the reaction conditions used, and the presence (if any) of other reactive or protecting groups in the molecule. Suitable protecting groups include, for example, those found in Greene et al., “Protective Groups In Organic Synthesis,” 3rd ed., John Wiley and Sons, Inc., New York, 1999.

[0314] As used herein, "alkyl" refers to a straight-chain or branched saturated aliphatic group having an indicated number of carbon atoms. For example, C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, and decyl. Alkyl groups can include any number of carbons, such as 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6, and 5-6 carbons.

[0315] The term “lower” in relation to organic free radicals or compounds, as used above and below, defines a compound or free radical that may be branched or unbranched, having a maximum of seven carbon atoms, preferably a maximum of four carbon atoms, and (as unbranched) having one or two carbon atoms.

[0316] As used herein, "alkylene" refers to an alkyl group, i.e., a divalent hydrocarbon group, as defined above. The two parts attached to the alkylene group can be attached to the same or different atoms of the alkylene group. For example, a straight-chain alkylene group can be a divalent radical -(CH2)n, where n is 1, 2, 3, 4, 5, or 6. Alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, secondary butylene, pentylene, and hexylene.

[0317] The substituents of alkyl, alkenyl, alkylene, heteroalkyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups may be one or more selected from, but not limited to, the following groups: -OR', =O, =NR', =N-OR', -NR'R”, -SR', -halogen, -SiR'R”R”', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -OC(O)NR 'R”, -NR”C(O)R’, -NR’-C(O)NR”R”’, -NR”C(O)2R’, -NR-C(NR'R”R’”)=NR””, -NR-C(NR'R”)=NR’”, -S(O)R’, -S(O)2R’, -S(O)2NR'R”, -NRSO2R’, -CN and -NO2, in quantities ranging from 1 to (2m’+1), where m’ is the total number of carbon atoms in the group. R’, R”, R’” and R”” each independently represent hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. When R' and R” are attached to the same nitrogen atom, they can combine with the nitrogen atom to form 5, 6, or 7-membered rings. For example, -NR'R” means, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.

[0318] As used herein, "alkoxy" refers to an alkyl group attached to an oxygen atom to form a -OR group, where R is an alkyl group. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups can be further substituted by various substituents described herein. For example, alkoxy groups can be substituted with halogens to form "haloalkoxy" groups.

[0319] As used herein, “carboxyalkyl” means an alkyl group substituted with a carboxyl group (as defined herein). The term “carboxycycloalkyl” means a cycloalkyl group substituted with a carboxyl group (as defined herein). The term “alkoxyalkyl” means an alkyl group substituted with an alkoxy group (as defined herein). The term “carboxyl” as used herein refers to carboxylic acids and their esters.

[0320] As used herein, “halogenated alkyl” refers to an alkyl group as defined above, wherein some or all of the hydrogen atoms are replaced by halogen atoms. Halogen (halogenated) preferably means chlorinated or fluorinated, but can also be brominated or iodinated. For example, haloalkyl groups include trifluoromethyl, fluoromethyl, 1,2,3,4,5-pentafluorophenyl, etc. The term “perfluoro” defines all available compounds or groups in which hydrogen atoms are replaced by fluorine. For example, perfluorophenyl refers to 1,2,3,4,5-pentafluorophenyl, perfluoromethyl refers to 1,1,1-trifluoromethyl, and perfluoromethoxy refers to 1,1,1-trifluoromethoxy. Haloalkyl groups can also be referred to as halogen-substituted alkyl groups, such as fluorinated alkyl groups.

[0321] As used herein, in the context of this invention, "cytokine" is a member of a group of protein signaling molecules that can participate in cell-cell communication during immune and inflammatory responses. Cytokines are typically small, water-soluble glycoproteins with a mass of approximately 8–35 kDa.

[0322] As used herein, “cycloalkyl” refers to a saturated monocyclic or polycyclic aliphatic ring system containing about 3 to 12, 3 to 10, 3 to 7, or 3 to 6 carbon atoms. When a cycloalkyl group contains two or more rings, these rings can be linked together in a fused or spirocyclic structure. When a cycloalkyl group contains three or more rings, these rings can also be linked together to form a bridged ring structure. Monocyclic rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic and polycyclic rings include, for example, bicyclo[1.1.1]pentane, bicyclo[2.1.1]heptane, norbornane, decahydronaphthalene, and adamantane. For example, C3-8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane.

[0323] As used in this article, "within the ring" refers to the atoms or groups of atoms that make up part of the ring structure.

[0324] As used in this article, “outside the ring” refers to atoms or groups of atoms connected together, but not limited to a ring structure.

[0325] As used herein, “cycloalkyl ether” refers to a 4- or 5-membered cycloalkyl group having 3 or 4 carbon atoms in the ring and 1 oxygen or sulfur atom in the ring (e.g., oxetane, thione, tetrahydrofuran, tetrahydrothiophene); or a 6- or 7-membered cycloalkyl group having 1 or 2 oxygen or sulfur atoms in the ring (e.g., tetrahydropyran, 1,3-dioxane, 1,4-dioxane, tetrahydrothiophene, 1,3-dithiaran, 1,4-dithiaran, 1,4-oxetane).

[0326] As used herein, "alkenyl" refers to a straight-chain or branched hydrocarbon having 2 to 6 carbon atoms having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hextrienyl. Alkenyl groups may also have 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6, and 5 to 6 carbon atoms.

[0327] As used herein, "alkenyl" refers to an alkenyl group, i.e., a divalent hydrocarbon group, as defined above, that is, an alkenyl group attached to at least two other groups. The two parts attached to the alkenyl group can be attached to the same or different atoms of the alkenyl group. Alkenyl groups include, but are not limited to, vinylene, propene, isopropene, butene, isobutene, sec-butene, pentenene, and hexene.

[0328] As used herein, "alkynyl" refers to a straight-chain or branched hydrocarbon having 2 to 6 carbon atoms and having at least one triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butyrynyl, 1-pentynyl, 2-pentynyl, isopentenynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hextriynyl. Alynyl groups may also have 2 to 3, 2 to 4, 2 to 5, 3 to 4, 3 to 5, 3 to 6, 4 to 5, 4 to 6, and 5 to 6 carbon atoms.

[0329] As used herein, "ynynyl" refers to an ynyl group, i.e., a divalent hydrocarbon group, as defined above, that is, a group attached to at least two other groups. The two parts attached to the ynynyl group can be attached to the same or different atoms of the ynynyl group. Iynyl groups include, but are not limited to, ethynylene, propynylene, butynylene, secondary butynylene, pentyynylene, and hexynylene.

[0330] As used herein, "cycloalkylene" refers to a cycloalkyl group, i.e., a divalent hydrocarbon group, as defined above, that is, a cycloalkyl group attached to at least two other groups. The two parts attached to the cycloalkylene group may be attached to the same or different atoms of the cycloalkylene group. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene.

[0331] As used herein, “heterocyclic alkyl” refers to a cyclic system having 3 to about 20 ring members and 1 to about 5 heteroatoms (such as N, O, and S). Other heteroatoms may also be useful, including but not limited to B, Al, Si, and P. Heteroatoms may also be oxidized, for example, but not limited to -S(O)- and -S(O)2-. For example, heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, pyrrolyl, pyrrololinyl, imidazoalkyl, imidazolinyl, pyrazolyl, pyrazololinyl, piperazinyl, piperidinyl, indololinyl, quininecycloyl, and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl.

[0332] As used herein, "heterocycloalkylene" refers to a heterocycloalkylene group as defined above that is attached to at least two other groups. The two parts attached to the heterocycloalkylene group may be attached to the same or different atoms of the heterocycloalkylene group.

[0333] As used herein, “aryl” refers to a monocyclic or polycyclic aromatic ring assembly containing 6 to 16 carbon atoms (e.g., fused bicyclic, tricyclic, or more rings). For example, an aryl group can be phenyl, benzyl, or naphthyl, preferably phenyl. An aryl group can be monosubstituted, disubstituted, or trisubstituted by one, two, or three groups selected from the following: alkyl, alkoxy, aryl, hydroxyl, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy, and oxy-C2-C3-alkylene; all of these may optionally be further substituted, for example, as defined above; or 1- or 2-naphthyl; or 1- or 2-phenanthrene. Alkylenedioxy is a divalent substituent attached to two adjacent carbon atoms of a phenyl group, such as methylenedioxy or ethylenedioxy. Oxy-C2-C3-alkylene is also a divalent substituent attached to two adjacent carbon atoms of a phenyl group, such as oxyethylene or oxypropylene. An example of oxy-C2-C3-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.

[0334] Preferred aryl groups are naphthyl, phenyl, or phenyl monosubstituted or disubstituted with alkoxy, phenyl, halogen, alkyl, or trifluoromethyl, especially phenyl or phenyl monosubstituted or disubstituted with alkoxy, halogen, or trifluoromethyl, particularly phenyl.

[0335] Examples of substituted phenyl groups for R include: 4-chlorophenyl-1-yl, 3,4-dichlorophenyl-1-yl, 4-methoxyphenyl-1-yl, 4-methylphenyl-1-yl, 4-aminomethylphenyl-1-yl, 4-methoxyethylaminomethylphenyl-1-yl, 4-hydroxyethylaminomethylphenyl-1-yl, 4-hydroxyethyl-(methyl)-aminomethylphenyl-1-yl, 3-aminomethylphenyl-1-yl, 4-N-acetaminomethylphenyl-1-yl, 4-aminophenyl-1-yl, 3-aminophenyl-1-yl, 2-aminophenyl-1-yl, 4-phenylphenyl-1-yl, 4-( Imidazol-1-yl)-phenyl, 4-(imidazol-1-ylmethyl)-phenyl-1-yl, 4-(morpholin-1-yl)-phenyl-1-yl, 4-(morpholin-1-ylmethyl)-phenyl-1-yl, 4-(2-methoxyethylaminomethyl)-phenyl-1-yl and 4-(pyrrolidine-1-ylmethyl)-phenyl-1-yl, 4-(thiophenyl)-phenyl-1-yl, 4-(3-thiophenyl)-phenyl-1-yl, 4-(4-methylpiperazin-1-yl)-phenyl-1-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl, optionally substituted on the heterocycle.

[0336] As used herein, "arylene" refers to an aryl group as defined above that is attached to at least two other groups. The two parts attached to the arylene are attached to different atoms of the arylene. Arylene groups include, but are not limited to, phenylene.

[0337] As used herein, “arylene-oxy group” refers to an arylene group as defined above, wherein one of the portions attached to the arylene group is connected by an oxygen atom. Arylene-oxy groups include, but are not limited to, phenylene-oxy groups.

[0338] Similarly, the substituents of aryl and heteroaryl groups are diverse and selected from: -halogen, -OR', -OC(O)R', -NR'R”, -SR', -R', -CN, -NO2, -CO2R', -CONR'R”, -C(O)R', -OC(O)NR'R”, -NR”C(O)R', -NR”C(O)2R', -NR'-C(O)NR”R”', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C( NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R”, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, ranging from zero to the total number of open valences on the aromatic ring system; wherein R', R” and R”' are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C1-C4)alkyl and (unsubstituted aryl)oxy-(C1-C4)alkyl.

[0339] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -TC(O)-(CH2)qU-, where T and U are independently -NH-, -O-, -CH2-, or single bonds, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -A-(CH2)rB-, where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 3. One of the single bonds in the newly formed ring may optionally be substituted with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the formula -(CH2)sX-(CH2)t-, where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted (C1-C6) alkyl groups.

[0340] As used herein, "heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each heteroatom being N, O, or S. For example, heteroaryl includes pyridinyl, indolyl, indazole, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiopheneyl, benzofuranyl, furanyl, pyrroleyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiopheneyl, or any other group substituted with, for example, an alkyl, nitro, or halogen group, especially a monosubstituted or disubstituted group. Pyridinyl represents 2-, 3-, or 4-pyridinyl, advantageously 2- or 3-pyridinyl. Thiopheneyl represents 2- or 3-thiopheneyl. Quinolinyl preferably represents 2-, 3-, or 4-quinolinyl. The isoquinolinyl group preferably represents 1-, 3-, or 4-isoquinolinyl. The benzopyranyl and benzothiaranyl groups preferably represent 3-benzopyranyl or 3-benzothiaranyl, respectively. The thiazolyl group preferably represents 2- or 4-thiazolyl, with 4-thiazolyl being the most preferred. The triazolyl group is preferably 1-, 2-, or 5-(1,2,4-triazolyl). The tetrazolyl group is preferably 5-tetrazolyl.

[0341] Preferably, the heteroaryl group is pyridyl, indolyl, quinolinyl, pyrroleyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thiophenyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothiaphenyl, oxazolyl, indazoleyl or any substituted group, especially monosubstituted or disubstituted groups.

[0342] The term "heteroalkyl" refers to an alkyl group having one to three heteroatoms (such as N, O, and S). Other heteroatoms can also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can also be oxidized, for example, but not limited to -S(O)- and -S(O)2-. For example, heteroalkyl groups can include ethers, thioethers, alkyl-amines, and alkyl-thiols.

[0343] The term "heteroalkylene" refers to a heteroalkyl group as defined above that is attached to at least two other groups. The two parts attached to the heteroalkylene group can be attached to the same or different atoms of the heteroalkylene group.

[0344] As used in this article, an electrophile is an ion or atom or a collection of atoms, which may be ionic and has an electrophilic center, i.e., an electron-seeking center, capable of reacting with a nucleophile. An electrophile (or electrophilic reagent) is a reagent that forms a bond with its reaction partner (nucleophile) by accepting two bonded electrons from that reaction partner.

[0345] As used herein, a "nucleophile" refers to an ion, atom, or collection of atoms, which may be ionic and possess a nucleophilic center—that is, a center that seeks an electrophilic center or is capable of reacting with an electrophile. A nucleophile (or nucleophilic reagent) is a reagent that forms a bond with its reaction partner (electrophile) by donating two bonding electrons. A "nucleophilic group" refers to the nucleophile that has reacted with the reactive group. Non-limiting examples include amino, hydroxyl, alkoxy, haloalkoxy, etc.

[0346] As used herein, "maleimide group" refers to a pyrrole-2,5-dione-1-yl group having the following structure:

[0347]

[0348] When it reacts with a thiol group (e.g., a thioalkyl group), it forms a -S-maleimide group with the following structure.

[0349]

[0350] Where “•” represents the linking point of the maleimide group, and “ "" indicates the junction point between the sulfur atom of the thiol and the remaining part of the original mercapto-containing group.

[0351] As used herein, “linear” refers to a polymer having a single polymer arm in terms of its geometry, construction, or overall structure.

[0352] As used herein, "branching" refers to a polymer having two or more polymer "arms" extending from a core structure contained within the initiator, in relation to the polymer's geometry, construction, or overall structure. The initiator can be used in atom transfer radical polymerization (ATRP) reactions. Branched polymers can have 2 polymer chains (arms), 3 polymer arms, 4 polymer arms, 5 polymer arms, 6 polymer arms, 7 polymer arms, 8 polymer arms, 9 polymer arms, or more. Each polymer arm extends from a polymer initiation site. Each polymer initiation site can become a site for polymer chain growth by adding monomers. For example, but not limited to, using ATRP, the polymer initiation site on the initiator is typically an organohalide undergoing a reversible redox process catalyzed by a transition metal compound (e.g., cuprous halide). Preferably, the halide is bromine.

[0353] As used herein, “OG1786” is a 9-arm initiator for polymer synthesis, possessing… Figure 26 The structure shown depicts the salt form of OG1786 containing trifluoroacetic acid. According to the invention, OG1786 can be used in the form of other salts or a free base.

[0354] As used herein, “OG1801” is a polymer of approximately (+ / - 15%) 750 kDa (by Mn or Mp) prepared using OG1786 as an initiator in the ATRP synthesis of monomer HEMA-PC. The structure of OG1801 is as follows: Figure 27 As shown.

[0355] As used in this article, "OG1802" is OG1801 with added maleimide functionality, and it has Figure 28 The structure shown, where each of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is an integer (positive) (from 0 to about 3000), results in a total molecular weight (Mw) of 750,000 ± 15% Daltons for the polymer. When the term OG1802 is used to modify protein terms (such as trap-antibody fusion, trap-Fab fusion), it indicates that the protein is a conjugated protein.

[0356] Multi-angle light scattering (MALS) is a technique for analyzing macromolecules, in which a laser beam is irradiated onto the molecule, and the oscillating electric field of the light induces oscillating dipoles within the molecule. These oscillating dipoles re-radiate light, which can be measured using a MALS detector such as the Wyatt miniDawn TREOS. The intensity of the radiated light depends on the size of the induced dipoles within the macromolecule, which is proportional to the polarizability of the macromolecule; the larger the induced dipole, the greater the intensity of the scattered light. Therefore, to analyze the scattering of such macromolecular solutions, their polarizability relative to the surrounding medium (e.g., the solvent) should be known. This can be achieved by measuring dn / dc using a Wyatt Optilab T-rEX differential refractometer. The value of the refractive index n of the solution is measured as a function of molecular concentration. Changes The two molar mass parameters used in MALS determination are number-average molecular weight (Mn) and weight-average molecular weight (Mw), where the polydispersity index (PDI) is equal to Mw divided by Mn. SEC also allows for another average molecular weight determination of the peak molecular weight Mp, which is defined as the molecular weight of the highest peak in the SEC.

[0357] PDI is used as a measure of the width of the molecular weight distribution of polymers and bioconjugates derived from the conjugation of discrete proteins with polydisperse biopolymers (e.g., OG1802). For protein samples, the polydispersity is close to 1.0 because it is a product of translation, where each protein molecule in solution is expected to have nearly identical length and molar mass. Conversely, due to the polydispersity of biopolymers, where polymer chains of varying lengths are synthesized during polymerization, determining the PDI of a sample as one of its quality properties of narrow molecular weight distribution is crucial. As used herein, the term "biopolymer" indicates that a polymer has been attached to a target protein. The term can also be described as a "conjugated" form of a protein. This can be done for all proteins described herein. Therefore, trap-antibody fusion biopolymers and trap-Fab fusion biopolymers are intended for use with all such trap-antibody and trap-Fab fusions presented herein.

[0358] Size exclusion chromatography (SEC) is a chromatographic technique in which molecules in solution are separated according to their size. Typically, an aqueous solution is used to deliver the sample through a column packed with resin of various pore sizes. It is expected that the resin is inert to the analytes as they pass through the column, and that the analytes are separated from each other based on their unique size and the pore size characteristics of the selected column.

[0359] Coupled SEC with MALS or SEC / MALS provides a precise distribution of molar mass and size (root mean square radius) compared to relying on a set of SEC calibration standards. This arrangement offers several advantages over traditional column calibration methods. Because light scattering and concentration are measured for each elution fraction, molar mass and size can be determined independently of the elution site. This is particularly relevant for substances with non-spherical macromolecules, such as biopolymers (OG1802) or bioconjugates; these substances typically do not elute in the manner described by a set of column calibration standards.

[0360] In some implementations, SEC / MALS analysis includes a Waters HPLC system with an Alliance 2695 solvent delivery module and a Waters 2996 Photodiole array detector equipped with a Shodex SEC-HPLC column (7.8 x 300 mm). This is connected online to a Wyatt miniDawn TREOS and a Wyatt Optilab T-rEX differential refractometer. Waters' Empower software is used to control the Waters HPLC system, and Wyatt's ASTRA V 6.1.7.16 software is used to obtain MALS data from the Wyatt miniDawn TREOS, dn / dc data from the T-rEX detector, and mass recovery data using the A280 absorbance signal from the Waters 2996 Photodiole array detector. SEC can be performed at 1 mL / min in 1xPBS pH 7.4. After sample injection, the MALS and RI (or UV) signals can be analyzed using ASTRA software to determine the absolute molar mass (Mp, Mw, Mn) and polydispersity index (PDI). In addition, the calculations also include input dn / dc values ​​for the polymer and protein, which are 0.142 and 0.183, respectively. In some embodiments, for the dn / dc value of the bioconjugate, the dn / dc is calculated based on the weighted MW of the polymer and protein, which is approximately 0.148, using the following formula:

[0361] The conjugate dn / dc = 0.142 x [MW] 聚合物 / (MW 聚合物 +MW 蛋白质 )]+ 0.183 x [MW 蛋白质 / (MW 聚合物 +MW 蛋白质 )]

[0362] Among them, MW of OG1802 聚合物 It's 800 kDa, TA105's MW. 蛋白质 It is 352 kDa.

[0363] In some embodiments, the trap-antibody fusion is conjugated to a phosphorylcholine-containing polymer. In some embodiments, the antibody is conjugated to a poly(acryloyloxyethyl phosphorylcholine) polymer, such as an acrylic polymer containing at least one acryloyloxyethyl phosphorylcholine monomer (e.g., 2-methacryloyloxyethyl phosphorylcholine (i.e., 2-methacryloyl-2'-trimethylammonium ethyl phosphate)).

[0364] In some embodiments, the polymer is a water-soluble polymer, meaning a polymer that is soluble in water. A solution of the water-soluble polymer can transmit at least about 75%, more preferably at least about 95%, of light transmitted by the same filtered solution. Based on weight, the water-soluble polymer or a segment thereof can be at least about 35%, at least about 50%, about 70%, about 85%, about 95%, or 100% (by weight of dry polymer) soluble in water.

[0365] In some embodiments, the polymer has at least two, three, or more arms. Some polymers have 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 arms. In some embodiments, the polymer has 3, 6, or 9 arms. In some embodiments, the polymer has 9 arms. In some embodiments, the polymer has a peak molecular weight of 300,000 to 1,750,000 Da. In some embodiments, the polymer has a peak molecular weight of 500,000 to 1,000,000 Da. In some embodiments, the polymer has a peak molecular weight of 600,000 to 800,000 Da.

[0366] In some embodiments, the peak molecular weight of the polymer is measured by size exclusion chromatography-multi-angle light scattering (hereinafter “SEC-MALS”) from 300,000 to 1,750,000 Daltons. In some embodiments, the peak molecular weight of the polymer is measured by SEC-MALS from 500,000 to 1,000,000 Daltons. In some embodiments, the peak molecular weight of the polymer is measured by SEC-MALS from 600,000 to 800,000 Daltons.

[0367] According to another aspect of the invention, a method is provided for synthesizing zwitterionic polymer-trap-antibody fusion conjugates having one or more functional agents and one or more polymer arms, wherein each polymer arm has one or more monomer units, wherein at least one unit is zwitterionic. For example, this method may include the following steps: providing an initiator having one or more monomer polymerization sites and a first connector having an amino group, wherein the initiator is a trifluoroacetate; providing one or more monomers suitable for polymerization, wherein at least one monomer is zwitterionic; reacting the monomers with the initiator to form one or more polymer arms, each polymer arm corresponding to a monomer polymerization site, to provide an initiator-polymer conjugate having a first connector with an amino group; providing a second connector having at least second and third reactive groups; coupling one of the second and third reactive groups of the second connector to an amino group of the first connector of the initiator-polymer conjugate to provide a connector-initiator-polymer conjugate having one or more reactive groups not used in the coupling step; and coupling one or more functional agents to one or more unreacted reactive groups of the connector-initiator-polymer portion to provide a polymer-functional agent conjugate.

[0368] In some embodiments, the conjugating group (e.g., maleimide) is added after polymer synthesis. This is sometimes referred to as a “snap-on strategy” or a “universal polymer strategy.” See, for example, U.S. Patent Application Publication No. 14 / 916,180 (published as U.S. Patent Application Publication No. 20160199501), which is incorporated herein by reference in its entirety. In some embodiments, a single initiator moiety can be used for large-scale polymer synthesis. Thus, optimal polymer synthesis conditions can be developed for scale-up. Such polymers can therefore be adapted to a wide variety of functional agents by “snap-on” various types of linkers. For example, if it is necessary to conjugate a larger functional agent to the polymer of the present invention, such as even an antibody containing a Fab fragment, a longer linker sequence can be snap-on onto the polymer. In contrast, smaller functional agents may require relatively shorter linker sequences.

[0369] In some embodiments of these methods, the initiator has about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 polymer initiation sites. In some embodiments, the initiator has about 3, about 6, or about 9 polymer initiation sites.

[0370] According to another aspect of the invention, the second connector has second, third, fourth, fifth, and sixth reactive groups. More preferably, the second connector has only the second and third reactive groups.

[0371] According to one aspect of this disclosure, each polymer arm has about 20 to about 2000 monomer units. Preferably, each arm has about 100 to 500 monomer units, or about 500 to 1000 monomer units, or about 1000 to 1500 monomer units, or about 1500 to 2000 monomer units.

[0372] According to one aspect of this disclosure, the peak molecular weight of the polymer-functional agent conjugate is about 100,000 to 1,500,000 Da. Preferably, the peak molecular weight of the polymer-functional agent conjugate is about 200,000 to about 300,000 Da, about 400,000 to about 600,000 Da, or about 650,000 to about 850,000 Da.

[0373] According to another aspect of this disclosure, the first connector is preferably alkyl, substituted alkyl, alkylene, alkoxy, carboxylalkyl, haloalkyl, cycloalkyl, cycloalkyl ether, alkenyl, alkenyl, ynyl, ynylene, cycloalkylene, heterocyclic alkyl, heterocyclic alkylene, aryl, arylene, aryl-oxy, heteroaryl, amino, amide, or any combination thereof. More preferably, the first connector has the following formula:

[0374]

[0375] Where m is 1 to 10. In some embodiments, the first connector has the above formula (formula (1)) and m is 4.

[0376] In some embodiments, the initiator preferably comprises a structure selected from the group consisting of...

[0377]

[0378] ,and

[0379]

[0380] X is selected from the group consisting of NCS, F, Cl, Br and I. More preferably, X in equations (2), (3) and / or (4) is Br.

[0381] In some implementations, the monomer is selected from the group consisting of the following:

[0382]

[0383]

[0384]

[0385] ,and

[0386]

[0387] R7 is H or C1-6 alkyl, and t is 1 to 6.

[0388] More preferably, the monomer is selected from the group consisting of 2-(methacryloyloxyethyl)-2'-(trimethylammonium ethyl) phosphate (HEMA-PC) and 2-(acryloyloxyethyl)-2'-(trimethylammonium ethyl) phosphate.

[0389] Most preferably, the monomer is 2-(methacryloyloxyethyl)-2'-(trimethylammonium ethyl) phosphate.

[0390] The second connector portion preferably contains an activated ester having the following structure.

[0391]

[0392] R8 is selected from the following groups.

[0393] and

[0394] And R9 is

[0395]

[0396] Where p ranges from 1 to 12.

[0397] In a more preferred embodiment of the invention, the polymer has 9 arms, m is 2-4, and R9 is...

[0398]

[0399] Where p is 4 to 15. More preferably, m is 4 and p is 12.

[0400] In some implementations, the monomer that can be polymerized by free radicals is

[0401]

[0402] Wherein R1 is H or C1-6 alkyl, R2, R3, and R4 are the same or different and are H or C1-4 alkyl, and X and Y are the same or different and are integers from 1 to 6. In some embodiments, R1, R2, R3, and R4 in formula (12) are each methyl, and X and Y are each 2.

[0403] In some implementations, the monomer that can be polymerized by free radicals is

[0404]

[0405] Wherein R1 is H or C1-6 alkyl, R2 and R3 are the same or different and are H or C1-4 alkyl, R4 is PO4-, SO3- or CO2-, and X and Y are the same or different and are integers from 1 to 6. In some embodiments, R1, R2 and R3 in formula (13) are methyl, R4 is PO4-, and X and Y are each 2.

[0406] In some implementation schemes, the monomer is

[0407]

[0408] Wherein R1 is H or C1-6 alkyl, R2, R3 and R4 are the same or different and are H or C1-4 alkyl, R5 is PO4-, SO3- or CO2-, and X and Y are the same or different and are integers from 1 to 6. In some embodiments, R1, R2, R3 and R4 in formula (14) are methyl, R5 is PO4-, and X and Y are 2.

[0409] When a polymer is conjugated via a cysteine ​​residue (or other specific residue), the polymer can be directly or indirectly attached to the residue (e.g., through the intervention of an initiator and / or a spacer group, etc.).

[0410] In some embodiments, the phosphorylcholine-containing polymer comprises the monomer 2-(methacryloyloxyethyl)-2'-(trimethylammonium)ethyl phosphate (MPC) as described below:

[0411] ,

[0412] The polymer contains the following repeating units:

[0413] ;

[0414] Where n is an integer from 1 to 3000, and the wavy line represents the connection point between monomer units in the polymer.

[0415] In some embodiments, the polymer has three or more arms, or is synthesized using an initiator containing three or more polymeric initiation sites. In some embodiments, the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 arms, or is synthesized using an initiator containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 polymeric initiation sites. More preferably, the polymer has 3, 6, or 9 arms, or is synthesized using an initiator containing 3, 6, or 9 polymeric initiation sites. In some embodiments, the polymer has 9 arms, or is synthesized using an initiator containing 9 polymeric initiation sites.

[0416] In some embodiments, the added polymer has a molecular weight of about 300,000 to about 1,750,000 Da (SEC-MALs). In some embodiments, the polymer has a molecular weight of about 500,000 to about 1,000,000 Da. In some embodiments, the polymer has a molecular weight of about 600,000 to about 900,000 Da. In some embodiments, the polymer has a molecular weight of about 750,000 to about 850,000 Da. In some embodiments, the polymer has a molecular weight of about 800,000 to about 850,000 Da. In some embodiments, the polymer has a molecular weight of about 750,000 to about 800,000 Da.

[0417] In some embodiments, any of the trap-antibody fusions described herein may be further conjugated with a polymer to form a bioconjugate. The molecular weight of the bioconjugate (generally, SEC-MALs) can be from about 350,000 to 2,000,000 Daltons, for example, from about 450,000 to 1,900,000 Daltons, from about 550,000 to 1,800,000 Daltons, from about 650,000 to 1,700,000 Daltons, from about 750,000 to 1,600,000 Daltons, or from about 850,000 to 1,500,000 Daltons. The molecular weights are approximately 900,000 to 1,400,000 Daltons, approximately 950,000 to 1,300,000 Daltons, approximately 900,000 to 1,000,000 Daltons, approximately 1,000,000 to 1,300,000 Daltons, approximately 850,000 to 1,300,000 Daltons, approximately 850,000 to 1,000,000 Daltons, and approximately 1,000,000 to 1,200,000 Daltons. In some embodiments, the molecular weight of the bioconjugate is approximately 350,000 to 1,900,000 Daltons.

[0418] In some implementations, the trap-antibody conjugate has the following structure:

[0419]

[0420] Wherein: each heavy chain of the trap-antibody is represented by the letter H, and each light chain of the trap-antibody is represented by the letter L; the polymer binds to the trap-antibody via the thiol group of C443 (EU number), which is depicted on one of the heavy chains; PC is:

[0421]

[0422] The curves represent the connection points with the remainder of the polymer; where X is a) –OR, where R is –H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and i) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different and are integers from 0 to 3000; or ii) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different, such that the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is 2500 ± 15%. In some embodiments, the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is from about 1500 to about 3500 plus or minus about 10% to about 20%. In some embodiments, X is -OR, where R is a sugar, an aminoalkyl group, or a monosubstituted, polysubstituted, or unsubstituted variant of the following residues: saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl or C2-C24 alkynyl, acyl, acyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxycarbonyl, alkoxycarbonylacyl, amino, aminocarbonyl, aminocarbonyloxy, nitro, azide, phenyl, hydroxyl, alkylthio, arylthio, oxysulfonyl, carboxyl, cyano, and haloalkyl (including polyhaloalkyl), -CO-O-R7, carbonyl-CCO-R7, -CO-NR8R9, -(CH2)n-COOR7, -CO-(CH)n-CO OR7, -(CH2)n-NR8R9, ester, alkoxycarbonyl, aryloxycarbonyl, where n is an integer from 1 to 6, wherein each R7, R8 and R9 is selected from the group consisting of: hydrogen atom, halogen atom, monosubstituted, polysubstituted or unsubstituted variants of the following residues: saturated C1-C24 alkyl, unsaturated C2-C24 alkenyl or C2-C24 alkynyl, acyl, acyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxycarbonyl, alkoxycarbonylacyl, amino, aminocarbonyl, aminocarbonyloxy, nitro, azide, phenyl, hydroxyl, alkylthio, arylthio, oxysulfonyl, carboxyl, cyano and haloalkyl (including polyhaloalkyl), 5-membered ring and 6-membered ring. In some implementations, Formula 17 may be part of a fusion protein that also includes some or all of the sequences in Tables 6 and 7, or any combination thereof, to produce an IL-1 trap anti-HTRA1 fusion protein.

[0423] In some implementations, the conjugate has the following structure:

[0424]

[0425] Wherein: each heavy chain of the trap-antibody fusion is represented by the letter H, and each light chain of the trap-antibody fusion is represented by the letter L; the polymer binds to the antibody via the thiol group of C443 (EU number), which is depicted on one of the heavy chains;

[0426] PC is The curve represents the connection point with the rest of the polymer, where X is a) –OR, where R is –H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and i) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different and are integers from 0 to 3000; or ii) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different, such that the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is 2500 ± 15%. In some embodiments, the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is from about 1500 to about 3500 plus or minus about 10% to about 20%.

[0427] In some embodiments, the conjugate has the structure of formula (II):

[0428]

[0429] in:

[0430] "n." is an integer from 1 to 50, and "ni" is an integer from 1 to 50;

[0431] Each heavy chain of the trap-antibody fusion is represented by the letter H, and each light chain of the anti-HTRA1 antibody is represented by the letter L; the polymer binds to the anti-HTRA1 antibody via the thiol group at C443 (EU number), which is depicted on one of the heavy chains; PC is , where the curve represents the connection point with the rest of the polymer; where X is a) –OR, where R is –H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and i) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different and are integers from 0 to 3000; or ii) n1, n2, n3, n4, n5, n6, n7, n8, and n9 are the same or different, such that the sum of n1, n2, n3, n4, n5, n6, n7, n8, and n9 is 2500 ± 15%.

[0432] In some embodiments, the polymers disclosed herein may comprise one or more of the following: zwitterions, phosphorylcholine, or PEG connectors that bridge the center of the polymer branch point to a maleimide functional group. In some embodiments, any of the polymers provided herein can be added to proteins using the methods provided herein.

[0433] Figure 25 It is a table listing the possible medical indications for which the administration of trap-antibody or trap-Fab fusion may be applicable.

[0434] In some implementations, trap-antibodies or trap-Fab fusions can be used to treat, or in combination with, conditions related to IL, IL-1, IL-6, IL-33, HTRA1, and / or VEGF. For example, in some implementations, the IL-1trap anti-HTRA1 fusion can be used to treat, or in combination with, conditions related to diabetic retinopathy, early, intermediate, and late age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoid choroidal angiopathy, ocular inflammation, HTRA1-related conditions, and / or IL-1-related conditions. In some implementations, the VEGF trap anti-IL6 fusion may be used to treat, or in combination with, scleritis, diabetic macular edema, diabetic retinopathy, wet age-related macular degeneration, uveitis, non-infectious uveitis, uveitis-related macular edema, cytokine release syndrome following CAR-T or similar immuno-oncology therapy, and the induction of IL-6 expression observed after blocking anti-PD-1 / PD-L1 molecular therapy. It can be used in combination with checkpoint inhibitors such as PD-1 / PDL-1 modulators to synergistically treat cancer, cerebral edema in glioblastoma (where anti-IL-6 therapy may show additional benefit from anti-VEGF therapy), IL-6-related conditions, and / or VEGF-related conditions. In some implementations, the trap-antibody or Fab fragment fusion may be used to treat trap-related conditions, antibody-related conditions, or both. In some implementations, the trap-antibody or Fab fragment fusion may be used to treat ocular inflammation. In some implementations, the trap-antibody or Fab fragment fusion may be used to treat TNFα-related conditions.

[0435] Numbering arrangement:

[0436] Some of the embodiments provided herein are described by the following numbering arrangement, and are also provided as possible combinations or overlapping embodiments:

[0437] 1. A multivalent trap-antibody and / or trap-Fab fusion compound, comprising:

[0438] traps and antibodies or fragments thereof, in which

[0439] The antibody or fragment thereof comprises:

[0440] The heavy chain variable region (VH) comprises three complementarity-determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and

[0441] The light chain variable region (VL) includes VL CDR1, VL CDR2 and VL CDR3;

[0442] in

[0443] The trap and the antibody or its fragment are connected in series via a connector;

[0444] The trap-antibody and / or trap-Fab fusion comprises both a cytokine binding site and an antigen binding site; and wherein...

[0445] The cytokine binding sites and antigen binding sites are located at different positions on the trap-antibody and / or trap-Fab fusion.

[0446] 2. A multivalent interleukin (IL) trap-antibody and / or trap-Fab fusion compound, comprising:

[0447] IL traps and antibodies or fragments thereof, in which

[0448] The antibody or fragment thereof comprises:

[0449] The heavy chain variable region (VH) comprises three complementarity-determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and

[0450] The light chain variable region (VL) includes VL CDR1, VL CDR2 and VL CDR3;

[0451] The IL trap contains an IL receptor and an IL accessory protein;

[0452] in

[0453] The IL trap and the antibody or its fragment are connected in series via a adapter;

[0454] The IL trap-antibody and / or trap-Fab fusion composite contains both an IL binding site and an antigen binding site; and wherein...

[0455] The IL binding site and antigen binding site are located at different positions on the trap-antibody and / or trap-Fab fusion.

[0456] 3. A multivalent interleukin (IL) trap-antibody fusion compound comprising:

[0457] IL trap; wherein; wherein the IL trap includes

[0458] IL receptors, and

[0459] IL accessory proteins;

[0460] Antibodies; among which

[0461] The antibody comprises: a heavy chain variable region (VH), wherein the heavy chain variable region (VH) includes three complementarity-determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and

[0462] The light chain variable region (VL) includes VL CDR1, VL CDR2, and VL CDR3; wherein...

[0463] The interleukin trap and the antibody are connected in series via a connector;

[0464] The interleukin trap-antibody fusion contains both an IL-binding site and an antigen-binding site; wherein

[0465] The IL trap-antibody fusion polymer binds to IL, inhibiting IL signaling; and wherein

[0466] The IL trap-antibody fusion polymer binds to the antigen, inhibiting antigen activity.

[0467] 4. A multivalent interleukin (IL) trap-Fab fusion compoun...

Claims

1. A multivalent trap-antibody and / or trap-Fab fusion comprising: a trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the trap and the antibody or fragment thereof are connected in tandem by a linker; the trap-antibody and / or trap-Fab fusion comprises both a cytokine binding site and an antigen binding site; and wherein the cytokine binding site and the antigen binding site are located at different locations on the trap-antibody and / or trap-Fab fusion.

2. A multivalent interleukin (IL) trap-antibody and / or trap-Fab fusion comprising: an IL trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and the antibody or fragment thereof are connected in tandem by a linker; the IL trap-antibody and / or trap-Fab fusion comprises both an IL binding site and an antigen binding site; and wherein the IL binding site and the antigen binding site are located at different locations on the trap-antibody and / or trap-Fab fusion.

3. A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap; wherein; wherein the IL trap comprises an IL receptor, and an IL accessory protein; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and the antibody are connected in tandem by a linker; the interleukin trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and wherein binding of the IL trap-antibody fusion to an antigen inhibits antigen activity.

4. A multivalent interleukin (IL) trap-Fab fusion comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL accessory protein; and The IL trap comprises an IL receptor, and an IL accessory protein; Fab; wherein The Fab comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein The IL trap and Fab are connected in tandem by a linker; The IL trap-Fab fusion comprises both an IL binding site and an antigen binding site; wherein The IL binding site and antigen binding site are located at different positions on the trap-Fab fusion.

5. A multivalent interleukin (IL) trap-Fab fusion comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein wherein The IL trap and Fab are connected in tandem by a linker.

6. A multivalent VHH-antibody and / or VHH-Fab fusion comprising: a VHH and an antibody or fragment thereof, wherein The antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein The VHH and the antibody or fragment thereof are connected in tandem by a linker; The VHH-antibody and / or VHH-Fab fusion comprises both a cytokine binding site and an antigen binding site; and wherein The cytokine binding site and antigen binding site are located at different positions on the VHH-antibody and / or VHH-Fab fusion.

7. A multivalent VHH-antibody and / or VHH-Fab fusion comprising: a VHH and an antibody or fragment thereof, wherein The antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein The VHH and the antibody or fragment thereof are connected in tandem by a linker; The VHH-antibody and / or VHH-Fab fusion comprises both a cytokine binding site and an antigen binding site; and wherein The cytokine binding site and antigen binding site are located at different positions on the VHH-antibody and / or VHH-Fab fusion.

8. A method of inhibiting interleukin signaling in a subject, comprising administering an interleukin trap-antibody fusion, the fusion comprising: an IL trap; an antibody; wherein The antibody comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3; wherein; The IL trap-antibody fusion comprises an IL binding site and an antigen binding site; wherein Binding of the IL trap-antibody fusion to IL inhibits IL signaling; and Binding of the IL trap-antibody fusion to an antigen inhibits antigen activity.

9. A method of inhibiting cytokine signaling in a subject comprising administering a cytokine trap-antibody fusion, the fusion comprising: a cytokine trap; an antibody; wherein The antibody comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3; wherein; The cytokine trap-antibody fusion comprises a cytokine binding site and an antigen binding site; wherein Binding of the cytokine trap-antibody fusion to a cytokine inhibits cytokine signaling; and Binding of the cytokine trap-antibody fusion to an antigen inhibits antigen activity.

10. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion is bivalent.

11. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion is tetravalent.

12. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion comprises two traps and two antibody arms.

13. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion is conjugated to a polymer.

14. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion further comprises a signal peptide.

15. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion is capable of simultaneously binding a cytokine and an antigen.

16. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises a cytokine trap having a cytokine binding affinity of about 0.01 pM to 10 nM.

17. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises a cytokine trap having a cytokine binding affinity of about 0.01 pM to 5 nM.

18. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises a cytokine trap having a cytokine binding affinity of about 0.01 pM to 1 nM.

19. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises a cytokine trap having a cytokine binding affinity of about 0.01 to 100 pM.

20. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an antibody having an antigen binding affinity of about 0.01 to 500 pM.

21. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises a cytokine trap having a cytokine binding affinity of about 0.01 to 100 pM.

22. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises a cytokine trap having a cytokine binding affinity of about 0.01 to 100 pM, and an antibody or Fab having an antigen affinity of about 0.01 to 500 pM.

23. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the cytokine trap and antibody or Fab bind to a cytokine and an antigen simultaneously.

24. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap is an IL-1 trap.

25. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap is an IL-6 trap.

26. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap is an IL-33 trap.

27. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap is a TNFα trap.

28. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap is a VEGF trap.

29. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the IL receptor protein is encoded by IL1R1.

30. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the IL receptor protein is ST2.

31. The IL trap-antibody or trap-Fab fusion body according to any of the preceding claims, wherein the IL accessory protein is IL1RAcP.

32. The IL trap-antibody or trap-Fab fusion body according to any of the preceding claims, wherein the IL accessory protein is gpl30 (IL6Rβ).

33. The IL trap-antibody or trap-Fab fusion body according to any of the preceding claims, wherein the antibody or Fab is an anti-HTRA1 antibody or Fab.

34. The IL trap-antibody fusion body according to any of the preceding claims, wherein the antibody or Fab is an IL-6 antibody or Fab.

35. The IL trap-antibody or trap-Fab fusion body according to any of the preceding claims, wherein the trap-antibody or trap-Fab fusion body comprises an IL trap which is an IL-1 trap, and an antibody which is an anti-HTRA1 antibody.

36. The IL trap-antibody fusion body according to any of the preceding claims, wherein the trap-antibody fusion body comprises an IL trap which is an IL-1 trap, wherein the IL-1 trap comprises IL1R1 and IL1RAcP; and and an antibody which is an anti-HTRA1 antibody.

37. The IL trap-antibody fusion body according to any of the preceding claims, wherein the trap-antibody fusion body comprises an IL trap which is an IL-1 trap, wherein the IL-1 trap comprises IL1R1 and IL1RAcP; wherein the IL-1 trap has an IL-1 binding affinity of about 0.01-100 pM; the antibody or Fab which is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of about 0.01-500 pM.

38. The IL trap-antibody fusion body according to any of the preceding claims, wherein the trap-antibody fusion body comprises an IL trap which is an IL-1 trap, wherein the IL-1 trap comprises IL1R1 and IL1RAcP; wherein the IL-1 trap has an IL-1 binding affinity of less than about 1 nM; the antibody which is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of less than about 1 nM.

39. The IL trap-antibody fusion body according to any of the preceding claims, wherein the trap-antibody fusion body comprises an IL trap which is an IL-1 trap, wherein the IL-1 trap comprises IL1R1 and IL1RAcP; wherein the IL-1 trap has an IL-1 binding affinity of about 0.01 to 100 pM; the antibody which is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of about 0.01 to 500 pM.

40. The IL trap-antibody of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap, which is an IL-33 trap, and an antibody, which is an anti-HTRA1 antibody.

41. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap, which is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RAcP; and an antibody or Fab, which is an anti-HTRA1 antibody.

42. The IL trap-antibody of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap, which is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RAcP; wherein the IL-33 trap has an IL-33 binding affinity of less than about 1 nM; and an antibody, which is an anti-HTRA1 antibody, or Fab; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of less than about 1 nM.

43. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RAcP; wherein the IL-33 trap has an IL-33 binding affinity of about 0.01 to 100 pM; and an antibody, which is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of about 0.01-500 pM.

44. The IL trap-antibody of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap, which is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RAcP; wherein the IL-33 trap has an IL-33 binding affinity of about 0.01 to 100 pM; and an antibody, which is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of about 0.01 to 500 pM.

45. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an IL trap, which is an IL-6 trap, and an antibody, which is an anti-HTRA1 antibody.

46. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion or trap-Fab comprises an IL trap, which is an IL-6 trap, wherein the IL-6 trap comprises gpl30 (IL6R beta) and IL-6R alpha; and an antibody, which is an anti-HTRA1 antibody. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 47. The IL trap-antibody fusion or trap-Fab of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap, wherein the IL-6 trap comprises gpl30 (IL6Rb) and IL-6Ra; wherein the IL-6 trap has an IL-6 binding affinity of less than about 1 nM; the antibody is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of less than about 1 nM.

48. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap, wherein the IL-6 trap comprises gpl30 (IL6Rb) and IL-6Ra; wherein the IL-6 trap has an IL-6 binding affinity of about 0.01 to 500 pM; the antibody is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of about 5 to 500 pM.

49. The IL trap-antibody or fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap, wherein the IL-6 trap comprises gpl30 (IL-6Rb) and IL-6Ra; wherein the IL-6 trap has an IL-6 binding affinity of about 0.01 to 100 pM; the antibody is an anti-HTRA1 antibody, or Fab; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of about 0.01 to 500 pM.

50. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion heavy chain comprises an IL receptor protein linked to an antibody VH; and the trap-antibody or trap-Fab fusion light chain comprises an IL accessory protein linked to an antibody VL.

51. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion heavy chain comprises an IL receptor protein linked to an antibody VL; and the trap-antibody or trap-Fab fusion light chain comprises an IL accessory protein linked to an antibody VH.

52. The IL trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab heavy chain and / or light chain comprises a receptor protein that is a receptor protein selected from the group comprising SEQ ID NO. 1-15 and 67-71.

53. The IL trap-antibody or trap-Fab fusion body according to any one of the preceding claims, wherein the trap-antibody or trap-Fab heavy and / or light chain comprises a linker which is the linker in SEQ ID NO. 24-27.

54. The IL trap-antibody or trap Fab fusion body according to any one of the preceding claims, wherein the trap-antibody or trap-Fab heavy and / or light chain comprises an antibody which is an antibody selected from the group comprising SEQ ID NO. 28-47 and 64-66.

55. The IL trap-antibody or trap-Fab fusion body according to any one of the preceding claims, wherein the trap-antibody or trap-Fab light chain comprises a signal peptide which is selected from the group comprising SEQ ID NO. 16-23 and 72-73.

56. The IL trap-antibody or trap-Fab fusion body according to any one of the preceding claims, wherein binding of the IL trap to IL reduces the activity of IL.

57. The IL trap-antibody or trap-Fab fusion body according to any one of the preceding claims, wherein binding of the antibody or Fab to antigen inhibits the activity of the antigen.

58. The IL trap-antibody or trap-Fab fusion body according to any one of the preceding claims, wherein simultaneous binding of the IL trap to IL and the antibody or Fab to antigen inhibits the activity of IL and antigen.

59. The IL trap-antibody or trap-Fab fusion body according to any one of the preceding claims, wherein sequential binding of the IL trap to IL and the antibody or Fab to antigen inhibits the activity of IL and antigen.

60. The IL trap-antibody fusion body according to any one of the preceding claims, wherein the trap-antibody fusion body heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 38, a CH of SEQ ID No.:

28.

61. The IL trap-antibody fusion body according to any one of the preceding claims, wherein the trap-antibody fusion body heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 38, a CH of SEQ ID No.:

28.

62. The IL trap-antibody or trap Fab fusion of any of the preceding claims, wherein the trap-antibody or trap Fab fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 44, a CL of SEQ ID No.:

29.

63. The IL trap-antibody or trap Fab fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 44, a CL of SEQ ID No.:

29.

64. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 38, a CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 44, a CL of SEQ ID No.:

29.

65. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 38, a CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 44, a CL of SEQ ID No.:

29.

66. The IL trap-Fab fusion of any of the preceding claims, wherein the trap-Fab fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

46.

67. The IL trap-Fab fusion of any of the preceding claims, wherein the trap-Fab fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

46.

68. The IL trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

69. The IL trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

70. The IL trap-Fab fusion of any of the preceding claims, wherein the trap-Fab fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 46; and the trap-Fab fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

71. The IL trap-Fab fusion of any of the preceding claims, wherein the trap-Fab fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 46; and the trap-Fab fusion light chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

72. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 17, the trap of SEQ ID No.: 1, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

65.

73. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 1, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

65.

74. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 18, the trap of SEQ ID No.: 2, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

66.

75. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 2, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

66.

76. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

77. The trap-antibody or fusion of any of the preceding claims, wherein the trap-antibody or fusion light chain comprises the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

78. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 17, the trap of SEQ ID No.: 1, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 18, the trap of SEQ ID No.: 2, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29. The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

79. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and The trap-antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

80. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; and The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

81. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; and The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

82. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

83. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

84. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

85. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

86. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

87. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

88. The trap-antibody fusion of any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; and The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

89. The trap-antibody fusion of any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; and The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

90. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion heavy chain comprises a signal peptide of SEQ ID No.: 17, a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

91. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion heavy chain comprises a trap of SEQ ID No.: 1, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

92. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises a signal peptide of SEQ ID No.: 18, a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

93. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises a trap of SEQ ID No.: 2, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

94. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 17, the trap of SEQ ID No.: 1, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 18, the trap of SEQ ID No.: 2, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

95. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 1, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 2, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

96. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

64.

97. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

64.

98. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

99. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

100. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

101. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

102. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

103. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 67, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

104. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody heavy chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

64.

105. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

106. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

107. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

108. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

109. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

110. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

111. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

112. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

113. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

114. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

115. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

116. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

117. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

118. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

119. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

120. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

121. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 67, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

122. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

123. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

124. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

125. The trap-antibody of any of the preceding claims, wherein the trap-antibody light chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

126. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

127. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

128. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

129. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

130. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

131. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

132. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 68, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

65.

133. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

134. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

135. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

136. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

137. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

138. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

139. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 68, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

140. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

141. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

142. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

143. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

144. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

145. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

146. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

147. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

148. The trap-antibody of any of the preceding claims, wherein the trap-antibody light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

149. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

150. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

151. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

152. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

153. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

154. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

155. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

156. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

157. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 16, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

158. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 28; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 69, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

159. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

160. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

161. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

162. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

163. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

164. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

165. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

166. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 69, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

167. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

168. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

169. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

170. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

171. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

172. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

173. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 70, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.:

64.

174. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

175. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

176. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

177. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

178. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

179. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29. The trap-Fab fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

180. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-Fab fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

181. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

182. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

183. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

184. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

185. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

186. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

187. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and The trap-antibody fusion light chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

188. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

189. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

190. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

191. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

192. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

193. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

194. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

192. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

193. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

194. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29. the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

195. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 70, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

196. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

197. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

198. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

199. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

200. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

201. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

202. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

203. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

64.

204. The trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

205. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the signal peptide of SEQ ID No.: 72, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

206. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

207. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the signal peptide of SEQ ID No.: 73, the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-Fab fusion light chain comprises the signal peptide of SEQ ID No.: 16, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29.

208. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VH of SEQ ID No.: 30, the CH of SEQ ID No.: 64; and the trap-antibody fusion light chain comprises the trap of SEQ ID No.: 71, the linker of SEQ ID No.: 25, the VL of SEQ ID No.: 39, the CL of SEQ ID No.:

29. The trap-antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

209. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

210. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

211. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

212. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

213. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 64; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

214. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 73, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

215. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and The trap-antibody fusion light chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

216. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

217. The trap-antibody fusion according to any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

65.

218. The trap-antibody fusion according to any of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

219. The trap-antibody fusion according to any one of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66. The trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

220. The trap-antibody fusion according to any one of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

221. The trap-antibody fusion according to any one of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

66.

222. The trap-antibody fusion according to any one of the preceding claims, wherein The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; The trap-antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and The trap-antibody fusion light chain comprises a signal peptide of SEQ ID No.: 72, a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

223. The trap-antibody fusion according to any one of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap of SEQ ID No.: 71, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

224. The antibody fusion of any of the preceding claims, wherein the antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

28.

225. The antibody fusion of any of the preceding claims, wherein the antibody fusion heavy chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.:

28.

226. The antibody fusion of any of the preceding claims, wherein the antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

227. The antibody fusion of any of the preceding claims, wherein the antibody fusion light chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

228. The antibody fusion of any of the preceding claims, wherein the antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

229. The antibody fusion of any of the preceding claims, wherein the antibody fusion heavy chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the antibody fusion light chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

230. The antibody fusion according to any one of the preceding claims, wherein the antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

231. The antibody fusion according to any one of the preceding claims, wherein the antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

232. The antibody fusion according to any one of the preceding claims, wherein the antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

233. The antibody fusion according to any one of the preceding claims, wherein the antibody fusion heavy chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the antibody fusion light chain comprises a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

234. The antibody fusion according to any one of the preceding claims, wherein the antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the antibody fusion light chain comprises a signal peptide of SEQ ID No.: 16, a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

235. The antibody fusion according to any one of the preceding claims, wherein the antibody fusion heavy chain comprises a VH of SEQ ID No.: 30, a CH of SEQ ID No.: 28; and the antibody fusion light chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29. The antibody fusion light chain comprises a VHH of SEQ ID No.: 74, a linker of SEQ ID No.: 25, a VL of SEQ ID No.: 39, a CL of SEQ ID No.:

29.

236. The antibody fusion of any one of the preceding claims, wherein The antibody fusion heavy chain comprises a signal peptide of SEQ ID No.: 16, a VH of SEQ ID No.: 30, and a CH of SEQ ID No.:

28.

237. A conjugate comprising: any of the multivalent trap-antibody fusions of any of the preceding claims; and a polymer, wherein the polymer is covalently linked to the antibody.

238. A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap and an antibody or fragment thereof, wherein the antibody or fragment thereof comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL co-factor; wherein the IL trap and the antibody are linked in tandem by a linker; the IL trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein the IL binding site and antigen binding site are located at different positions on the trap-antibody fusion; and wherein the multivalent IL trap-antibody fusion is conjugated to a polymer.

239. A multivalent interleukin (IL) trap-antibody fusion comprising: an IL trap; wherein; wherein the IL trap comprises an IL receptor, and an IL co-factor; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and the antibody are linked in tandem by a linker; the interleukin trap-antibody fusion comprises both an IL binding site and an antigen binding site; wherein binding of the IL trap-antibody fusion to IL inhibits IL signaling; and wherein binding of the IL trap-antibody fusion to an antigen inhibits antigen activity; and wherein the multivalent IL trap-antibody fusion is conjugated to a polymer.

240. A multivalent interleukin (IL) trap-Fab fusion comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL co-factor; the IL trap and the Fab fragment are connected in tandem by a linker; the IL trap-Fab fusion comprises both an IL binding site and an antigen binding site; wherein the IL binding site and the antigen binding site are located at different positions on the trap-Fab fusion; wherein the multivalent IL trap-antibody fusion is conjugated to a polymer.

241. A multivalent interleukin (IL) trap-Fab fusion comprising: an IL trap and an antigen binding fragment (Fab fragment), wherein wherein the IL trap and the Fab are connected in tandem by a linker; and wherein the multivalent IL trap-Fab fusion is conjugated to a polymer. The multivalent interleukin (IL) trap-Fab fusion according to any of the preceding claims, wherein the trap-Fab fusion comprises an IL-1 trap and an anti-IL-6 Fab; and wherein the multivalent IL trap-antibody fusion is conjugated to a polymer.

242. The multivalent interleukin (IL) trap-antibody or trap-Fab fusion according to any of the preceding claims, wherein the trap-antibody or trap-Fab fusion does not comprise a transmembrane and / or cytoplasmic domain of an IL receptor protein.

243. The multivalent interleukin (IL) trap-antibody or trap-Fab fusion according to any of the preceding claims, wherein the trap-antibody or trap-Fab fusion does not comprise a transmembrane and / or cytoplasmic domain of an IL receptor accessory protein.

244. The trap-antibody or trap-Fab fusion according to any of the preceding claims, wherein the trap-antibody or trap-Fab fusion does not comprise a transmembrane and / or cytoplasmic domain of TNFR1.

245. The trap-antibody or trap-Fab fusion according to any of the preceding claims, wherein the trap-antibody or trap-Fab fusion does not comprise a transmembrane and / or cytoplasmic domain of TNFR2.

246. A method of inhibiting cytokine signaling in a subject, comprising administering a cytokine trap-antibody fusion, the fusion comprising: a cytokine trap; an antibody; wherein the antibody comprises: a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDRs): VH CDR1, VH CDR2, and VH CDR3; and a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3; wherein; the IL trap-antibody fusion comprises an IL binding site and an antigen binding site; wherein the binding of the cytokine trap-antibody fusion to a cytokine inhibits cytokine signaling; and the binding of the cytokine trap-antibody fusion to an antigen inhibits antigen activity; and wherein the multivalent cytokine trap-antibody fusion is conjugated to a polymer.

247. The VHH-antibody fusion of any of the preceding claims, wherein the VHH-antibody fusion is conjugated to a polymer.

248. The conjugate of any of the preceding claims, wherein the polymer comprises a phosphorylcholine-containing polymer.

249. The conjugate of any one of the preceding claims, wherein the polymer comprises a zwitterionic monomer, wherein the zwitterionic monomer is selected from the group consisting of HEMA-phosphorylcholine, PEG, biocompatible fatty acids and derivatives thereof, hydroxyalkyl starch (HAS), hydroxyethyl starch (HES), polyethylene glycol (PEG), poly(Gly x -Ser y ) (HAP), hyaluronic acid (HA), heparin precursor polymer (HEP), Fleximers, dextran, polysialic acid (PSA), Fc domain, transferrin, 25 albumin, elastin-like (ELP) peptides, XTEN polymer, PAS polymer, PA polymer, albumin binding peptides, CTP peptides, and FcRn binding peptides.

250. The conjugate of any of the preceding claims, wherein the polymer has a peak molecular weight of 300,000 to 1,750,000 Daltons as measured by size exclusion chromatography- multi-angle light scattering (hereinafter "SEC-MALS").

251. The conjugate of any of the preceding claims, wherein the polymer has a peak molecular weight of 500,000 to 1,000,000 Daltons as measured by SEC-MALS.

252. The conjugate of claim 22, wherein the polymer has a peak molecular weight of 600,000 to 800,000 Daltons as measured by SEC-MALS.

253. The conjugate of any of the preceding claims, wherein the polymer has 2 or more arms.

254. The conjugate of any of the preceding claims, wherein the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 arms.

255. The conjugate of any of the preceding claims, wherein the polymer has 9 arms.

256. The conjugate of any of the preceding claims, wherein the antibody is an IgG.

257. The conjugate of any of the preceding claims, wherein the polymer is covalently bound to a thiol from a cysteine residue on an IgG heavy chain.

258. The conjugate of any of the preceding claims, wherein the antibody comprises a cysteine residue at position 347 or 443 (EU numbering).

259. The conjugate of claim 32, wherein the polymer is covalently bound to a thiol from a cysteine residue at position 347 or 443 (EU numbering).

260. The conjugate of any of the preceding claims, wherein the antibody is further conjugated to a polymer to form a bioconjugate, and wherein the bioconjugate has a molecular weight of about 350,000 to 1,900,000 Daltons.

261. The conjugate of any of the preceding claims, wherein the polydispersity index (PDI) is equal to or less than 1.

5.

262. The conjugate of any of the preceding claims, wherein the polymer has 9 arms; and the polymer has a molecular weight of about 600,000 to about 900,000 Da.

263. The conjugate of any of the preceding claims, comprising the following structure: wherein: each heavy chain of the antibody is represented by the letter H, each light chain of the antibody is represented by the letter L; the polymer is bound to the trap-antibody through a thiol of C443 (EU numbering), which is depicted on one of the heavy chains; PC is wherein the curve represents the point of attachment to the rest of the polymer, wherein X = a) OR, wherein R = H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halide, including Br; and n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n6, n7, n8 and n9 is 2500 plus or minus 15%.

264. The conjugate according to any one of the preceding claims, comprising the following structure: wherein: each heavy chain of the antibody is represented by the letter H, each light chain of the antibody is represented by the letter L; the polymer is bound to the trap-antibody via the thiol group of C443 (EU numbering), which is depicted on one of the heavy chains; PC is wherein the curve represents the point of attachment to the rest of the polymer, wherein X = a) OR, wherein R = H, methyl, ethyl, propyl, isopropyl, b) H, or c) any halide, including Br; and n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different such that the sum of n1, n2, n3, n4, n5, n6, n6, n7, n8 and n9 is 2500 plus or minus 15%.

265. A nucleic acid encoding the trap-antibody or trap-Fab fusion according to any one of the preceding claims.

266. A vector comprising a nucleic acid encoding the trap-antibody or trap-Fab fusion according to any one of the preceding claims.

267. A cell comprising a vector encoding the trap-antibody or trap-Fab fusion according to any one of the preceding claims.

268. The trap-antibody fusion according to any one of the preceding claims, wherein the antibody heavy chain arms are connected via a knob-in-hole structure.

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