Multivalent trap-antibody fusions

Abstract

The present disclosure relates to multivalent antibody fusions, methods of making, and methods of use thereof. Specifically, aspects of the present disclosure are related to trap-based bispecific molecules, and method of making trap-based bi-specific molecules, that may be used to effectively treat a disease with multiple underlying signaling pathways.

Description

KDIAK.191WO PATENT MULTIVALENT TRAP-ANTIBODY FUSIONS INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Ser. No.63 / 487,606, filed February 28, 2023, which is hereby incorporated by reference in its entirety. REFERENCE TO SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled KDIAK191WOSEQLIST.XML, which was created and last modified on February 09, 2024, which is 85,255 bytes in size. The information in the electronic Sequence Listing is hereby incorporated by reference in its entirety. FIELD

[0003] The present disclosure relates to multivalent antibody fusions, methods of making, and methods of use thereof. BACKGROUND

[0004] Multivalent molecules can bind to more than one target or more than one section of a target molecule. SUMMARY

[0005] Some embodiments provided herein are described by way of the following provided embodiments and also provided as possible combinations or overlapping embodiments:

[0006] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the trap and antibody are connected in tandem by a linker; the trap-antibody fusion comprises both an interleukin (IL) binding site and an antigen binding site; and wherein the IL and antigen binding sites are located at separate 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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.

[0007] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and antibody are connected 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 and antigen binding sites are located at separate 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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.

[0008] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and alight chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and 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. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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-Fab fusion, comprising: an IL trap and fragment antigen-binding (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL accessory protein; the IL trap and 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 and antigen binding sites are located at separate 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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-Fab fusion, comprising: an IL trap and fragment antigen-binding (Fab fragment), wherein the IL trap and antibody are connected intandem by a linker. In some embodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising aVL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and antibody 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 and antigen binding sites are located at separate 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and 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; 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused toan IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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.

[0014] A multivalent interleukin (IL) trap-Fab fusion, comprising: an IL trap and fragment antigen-binding (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL accessory protein; the IL trap and 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 and antigen binding sites are located at separate 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 are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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-Fab fusion, comprising: an IL trap and fragment antigen-binding (Fab fragment), wherein the IL trap and Fab are connected in tandem by a linker; and wherein the multivalent IL trap-Fab fusion is conjugated to a polymer.

[0016] A method of inhibiting cytokine, for example, but not limited to, 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 someembodiments disclosed herein, the trap-antibody and / or trap-Fab fusion is bispecific. In some embodiments, these bispecific molecules are comprised of 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 anti-IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. In some embodiments, the bispecific molecules comprise a TNFĮ trap fused to an IL-6 antibody. In some embodiments, the bispecific molecules comprise a TNFĮ 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 THE DRAWINGS

[0017] FIG.1 is a representative illustration of some embodiments of a multivalent interleukin (IL) trap-antibody fusion.

[0018] FIG.2 is a representative illustration of some embodiments of a multivalent interleukin (IL) trap-antibody fusion bound to IL and an antigen.

[0019] FIG.3 is a flow chart and representative illustration of some embodiments of a method of inhibiting interleukin signaling.

[0020] FIG.4 is a schematic illustrating some embodiments of IL-1 trap and IgG fusion configurations. The dark crescent shapes represent either IL1R1 or IL1R2. The light crescent shapes represent IL1RAcP.

[0021] FIG.5 is an overlay of SPR sensorgrams demonstrating that IL-1 trap anti- HTRA1 (TA97) can simultaneously bind to both IL-1ȕ and HTRA1. SPR from injecting HTRA1 then IL-1ȕ (top sensorgram) or IL-1ȕ then HTRA1 (bottom sensorgram).

[0022] FIG. 6 graphs the actual / expected SPR response upon injecting HTRA1 then IL-1ȕ (left) or IL-1ȕ then HTRA1 (right) to a surface captured with two configurations of the IL-1 trap anti-HTRA1 (TA97 and TA98) and anti-HTRA1 antibody (aHTRA1.36).

[0023] FIG. 7 shows that IL-1 trap anti-HTRA1 (TA97) efficiently inhibits HTRA1 activity even when bound to IL-1ȕ. HTRA1 activity measured in H2-Opt assay is plotted against the log scale of trap-antibody concentration (M). The open square indicates inhibited HTRA1 activity even with excess IL-1ȕ.

[0024] FIG.8 demonstrates that the mass of IL-1 trap anti-HTRA1 (TA105) shifts accordingly when bound to HTRA1 and / or IL-1ȕ as measured on mass photometry.

[0025] FIG. 9 displays the pH-dependent (upper panel) and NaCl concentration- dependent (lower panel) thermal stability of the IL-1 trap x anti-HTRA1 (TA97) stability. Each point represents the average Tm from triplicates measured in DSF.

[0026] FIG. 10 shows the SDS-PAGE of IL-1 trap anti-HTRA1 (TA105) before and after biopolymer conjugation.

[0027] FIG. 11 demonstrates that the biopolymer-conjugated IL-1 trap anti- HTRA1 (TA105) binds to IL-1ȕ in an IL-1ȕ Lumit assay.

[0028] FIG. 12 demonstrates that the biopolymer-conjugated IL-1 trap anti- HTRA1 (TA105) inhibits the proteolytic activity of HTRA1 as measured in H2-opt assay.

[0029] FIG.13 shows the SDS-PAGE of IL-1 trap anti-IL-6 Fab (TF2) before and after biopolymer conjugation.

[0030] FIG. 14 demonstrates that the biopolymer-conjugated IL-1 trap anti-IL-6 Fab (TF2) competitively bind to IL-1ȕ in an IL-1ȕ sandwich ELISA.

[0031] FIG. 15 demonstrates that the biopolymer-conjugated IL-1 trap anti-IL-6 Fab (TF2) inhibits IL-6 binding to IL-6RĮ in an IL-6 / IL-6RĮ DuoSet ELISA.

[0032] FIG.16 is an illustrative representation of some multivalent interleukin (IL) trap-antibody fusions conjugated to a polymer.

[0033] FIG. 17 shows representative embodiments of full-length and regions of IL-1, IL-6, IL-33, and VEGF receptor sequences.

[0034] FIG. 18 shows some representative embodiments of IgG constant and variable region sequences.

[0035] FIG.19 shows some representative embodiments of linkers suitable for use in connecting an IL receptor protein with an antibody variable domain.

[0036] FIG. 20 shows some representative embodiments of signal peptide sequences suitable for use in the trap-antibody fusions disclosed herein.

[0037] FIG.21 shows some representative embodiments of full-length heavy chain sequences suitable for use in the trap-antibody fusions disclosed herein.

[0038] FIG.22 shows some representative embodiments of full-length light chain sequences suitable for use in the trap-antibody fusions disclosed herein.

[0039] FIG.23 shows some representative embodiments of full-length heavy chain sequences suitable for use in the trap-Fab fusions disclosed herein.

[0040] FIG.24 shows some representative embodiments of full-length light chain sequences suitable for use in the trap-Fab fusions disclosed herein.

[0041] FIG. 25 is a table listing embodiments of medical indications for which administration of a trap-antibody or trap-Fab fusion may be suitable.

[0042] FIG.26 shows OG1786.

[0043] FIG.27 shows OG1801.

[0044] FIG.28 shows OG1802.

[0045] FIG. 29 demonstrates that the IL-1 trap anti-IL-6 knob-in-hole antibodies competitively bind to IL-1ȕ in an IL-1ȕ sandwich ELISA.

[0046] FIG.30 is a graph showing some embodiments of a demonstration that the IL-1 trap anti-IL-6 knob-in-hole antibodies inhibit IL-6 binding to IL-6RĮ in an IL-6 / IL-6RĮ DuoSet ELISA, even when an excess of IL-1ȕ is present.

[0047] FIG. 31A is a graph showing some embodiments of the experimental / expected SPR response upon injecting IL-6 then IL-1ȕ to a surface captured with the IL-1 trap anti-IL-6 knob-in-hole antibodies.

[0048] FIG. 31B is a graph showing some embodiments of the experimental / expected SPR response upon injecting IL-1ȕ then IL-6 to a surface captured with the IL-1 trap anti-IL-6 knob-in-hole antibodies.

[0049] FIG. 32A graphs the experimental / expected SPR response upon injecting IL-6 then TNFĮ to a surface captured with the TNFĮ trap anti-IL-6 antibodies.

[0050] FIG. 32B graphs the experimental / expected SPR response upon injecting TNFĮ then IL-6 to a surface captured with the TNFĮ trap anti-IL-6 antibodies.

[0051] FIG.33 is a graph showing some embodiments of a demonstration that the mass of anti-TNFĮ VHH anti-IL-6 antibody (TA189) shifts accordingly when bound to TNFĮ and / or IL-6 as measured on mass photometry.

[0052] FIG. 34A is a graph showing some embodiments of the experimental / expected SPR response upon injecting IL-6 then TNFĮ to a surface captured with the anti-TNFĮ VHH anti-IL-6 antibodies.

[0053] FIG. 34B is a graph showing some embodiments of the experimental / expected SPR response upon injecting TNFĮ then IL-6 to a surface captured with the anti-TNFĮ VHH anti-IL-6 antibodies. DETAILED DESCRIPTION

[0054] Provided herein are multivalent antibody fusions, methods of making, and methods of use thereof. Some aspects of the present disclosure are related to trap-based bispecific molecules, and method of making trap-based bi-specific molecules. In some embodiments, one or more of the multivalent antibody fusions and / or trap-based bi-specific molecules may be used to effectively treat a disease with multiple underlying signaling pathways. In some embodiments, the disease comprises inflammation of the eye, or ocular inflammation.

[0055] Growth factors (GF) and cytokines mediate critical intercellular communications in intracrine, autocrine and paracrine manners. They regulate cellular activities including proliferation, differentiation, and migration which ultimately result in 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 GF and cytokines involves the homo- or heteromultimerization of the cognate receptor(s) on the surface of the responsive cells upon 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 to ligands while the intracellular part exhibits intrinsic kinase activity or contains “adapter” domains that interact with kinases; Grötzinger 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.

[0056] Cytokine dysregulation is associated with a myriad of health issues 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–. Cytokine-targeting therapies have shown clinical benefits. Molecular design of various drugs is based on Fc-fusion format, in which native ECD domains are fused to the immunoglobulin G (IgG) fragment crystallizable (Fc) region; 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 moiety forms a dimer via interdomain interactions, which is further stabilized by interchain disulfide bridges. This in turn places receptors in proximity in a manner that allows ECD domains to dimerize and engage to their targets with high affinity (trap mechanism).

[0057] Bispecific antibodies have shown to be a promising strategy to overcome some of the fundamental limitations of monospecific antibody therapies, which cannot address the multiple cross-talking signaling pathways underlying the targeted diseases. Although efforts have been taken to address the immunogenicity, chain mispairing issues and manufacturing scalability associated with multivalent molecules, there remains a need for the development of a bispecific format that effectively addresses these issues; Brinkmann U, Kontermann RE. 2017. "The making of bispecific antibodies." mAbs 9: 182–212; Godar et Godar M, de Haard 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 related multivalent antibody fusions, methods of making, and methods of use thereof.

[0058] Some aspects of the present disclosure are related to trap-based bispecific molecules exploring the native dimeric interface of variable heavy (VH) and variable light (VL) regions found in antibodies. In this format, receptor domains are connected in tandem with VH and VL regions. This configuration places ECDs in an orientation favorable for ligand binding. The heterodimeric nature of the VH:VL pairing allows for the design of homo- or heterodimeric based traps without further engineering (e.g. Fc knobs-into-holes) and the complementarity determining regions (CDR)s allow binding of a second target of interest.

[0059] Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. It is a complex disease with various 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 suggest GFs and cytokines participate in the onset and progression of AMD. Inhibition of VEGF-A has proven to effectively treat neovascularization and slow down the 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 linked to the anti-VEGF treatment resistance. Currently there is no effective treatment for the dominant form of AMD (dry AMD) also termed geographic atrophy, which accounts for approximately 90% of cases. Genetic risk factors and dysregulated inflammatory response form a complex interplay of signaling pathways that likely prevent the development of an efficacious monospecific therapy.

[0060] Overall, cytokines have been shown to play a critical role in the development of retinal diseases. Patients with AMD have been reported to have increased serum levels of pro-inflammatory cytokine interleukin 6 (IL-6). IL-6 has been observed to stimulate defective angiogenesis, which might be due to an indirect result of IL-6 mediated upregulation of VEGF expression. Additionally, more direct functions of IL-6 such as endothelial cell proliferation and migration have been reported in the presence of VEGF inhibitors, indicating its angiogenic signaling occurs independently of VEGF. Other studies have shown that retinal pigment epithelial (RPE) cells release IL-1D when dying or under stress conditions, which could contribute to the recruitment of immune cells. Hence, the IL-1ȕ production by activated microglia and macrophage cells could promote further macrophagerecruitment to the tissue affected area 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.

[0061] Genome-wide association studies (GWAS) identified a locus at human chromosome 10q26 linked to risk of AMD where two genes ARMS2 and HTRA1 lie in proximity to each other. These studies suggest a correlation between disease progression and single-nucleotide polymorphisms (SNPs) at the promoter region of HTRA1, which resulted in its 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 A1 (HTRA1) is a serine protease known to cleave a plethora of extracellular matrix (ECM) proteins and TGF-beta family members; 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 extracellular debris accumulation that 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-Maigné 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–.” HTRA1 has also been shown to induce expression of inflammatory cytokines and VEGF, and overexpression of HTRA1 in the retina of mouse models recapitulates key physiological markers of AMD. These data corroborate theobservation that HTRA1 risk alleles show strong and nearly equal association with wet and dry forms of AMD.

[0062] In some embodiments, the present disclosure is directed to reducing the concurrent inflammation and defective angiogenesis that drive AMD pathogenesis.

[0063] In some embodiments, the present disclosure is directed to reducing inflammation of the eye, or ocular inflammation.

[0064] Some aspects of the present disclosure are directed to bispecific molecules. Some aspects of the present disclosure are directed to bispecific molecules that simultaneously block combinations of cytokines, GF, and HTRA1 for reducing the concurrent inflammation and defective angiogenesis that drive AMD pathogenesis.

[0065] In some embodiments, these bispecific molecules are comprised of 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 anti-IL-6 antibody. Bispecifics were built in the design of heterodimeric trap fusion to the VH and VL regions. Additionally, Fab versions of an anti-IL- 6 in tandem with IL-1 trap (heterodimer) and VEGF trap (homodimer) were generated. Each of these dual inhibitor molecules has the option to be equipped with an unpaired cysteine at its C-terminus region that can be conjugated with a half-life extending phosphorylcholine-based biopolymer. In some embodiments, the bispecific molecules comprise a TNFĮ inhibitor. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ trap. In some embodiments, the TNFĮ inhibitor comprises a TNFĮ VHH. Definitions

[0066] As used herein, the term “interleukin” (IL) refers to one or more of a group of related proteins made by leukocytes (white blood cells) and other cells in the body. Interleukins regulate immune responses. An interleukin is a type of cytokine.

[0067] As used herein, the term “cytokine” refers to small proteins, polypeptides, or peptides that are involved in inflammatory signaling or proteins released by one cell population that act on another cell as intercellular mediators or have an autocrine effect on the cells producing the proteins. 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, INFĮ, INFȕ, INFȖ, IL-1, IL-1Į, IL-1ȕ, 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-36Į, IL-36ȕ, IL-36Ȗ, IL-37, IL-38, GM-CSF, TNFĮ, TNFȕ, TNFȖ, TGF-I-3 TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15, TNFSF18, or TNFSF19, leukemia inhibitor factor (LIF), ciliary neurotrophic factor (CNTF), CNTF-like cytokine (CLC), cardiotrophin (CT), Kit ligand (KL), or any combination thereof.

[0068] As used herein, the terms “valence,” “valency,” or “valent,” refers to the relative capability of a substance (e.g. antibody) to act upon, react, or bind with a biological substrate (e.g. antigen); the number of antigen binding sites that an antibody has, or the number of antigenic determinants an antigen has. In some embodiments, valency refers to the number of binding sites on a molecule. In some embodiments, valency refers to a property of atom or radical that indicates 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, quinquevalent, quinquivalent, hexavalent, sexivalent, heptavalent, septivalent, octavalent, nonavalent, decavalent, dodecavalent, polyvalent, or multivalent.

[0069] The term “antibody” includes intact antibodies and binding fragments thereof. A binding fragment refers to a molecule other than an intact antibody that comprises 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, antibody fragments comprise single chain polypeptides having the characteristics of a VH domain or region, namely being able to assemble together with a VL domain or region, or of a VL domain or region, namely being able to assemble together with a VH domain or region to a functional antigen binding site and thereby providing the antigenbinding property of full-length antibodies. The terms “domain” and “region” are used interchangeably.

[0070] As used herein, the term “fragment antigen-binding (Fab fragment) refers to an antibody fragment that binds antigens. Fab fragments comprises one constant and one variable domain of each of the heavy and light chain.

[0071] The term “VHH domains”, also known as VHHs, VHH domains, VHH antibody fragments, and VHH antibodies, have originally been described as the antigen binding immunoglobulin (Ig) (variable) domain of “heavy chain antibodies” (i.e., of “antibodies devoid of light chains”; Hamers-Casterman et al (1993) Nature 363: 446-448). The term “VHH domain” has been chosen to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VL domains”). For a further description of VHHs and Nanobody , reference is made to the review article by Muyldermans (Reviews in Molecular Biotechnology 74: 277-302, 2001)

[0072] Specific binding of an antibody to its target antigen(s) means an affinity of at least 106, 107, 108, 109, or 1010M-1. Specific binding is detectably higher in magnitude and distinguishable from non-specific binding occurring to at least one unrelated target. Specific binding can be the result of formation of bonds between particular functional groups or particular spatial fit (e.g., lock and key type) whereas nonspecific binding is usually the result of van der Waals forces. Specific binding does not however necessarily imply that an antibody or fusion protein binds one and only one target.

[0073] A 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 or domain of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms “domain” and “region” are used interchangeably. This variable region is initially expressed linked to a cleavable signal peptide. The variable region without the signal peptide is sometimes referred to as a mature variable region. Thus, for example, a light chain mature variable region means a light chain variable region without the light chain signal peptide. However, reference to a variable region does not mean that a signal sequenceis necessarily present; and in fact signal sequences are cleaved once the antibodies or fusion proteins have been expressed and secreted. A pair of heavy and light chain variable regions defines a binding region of an antibody. The carboxy-terminal portion of the light and heavy chains respectively defines light and heavy chain constant regions. The heavy chain constant region is primarily responsible for effector function. In IgG antibodies, the heavy chain constant region is divided into CH1, hinge, CH2, and CH3 regions. The CH1 region binds to the light chain constant region by disulfide and noncovalent bonding. The hinge region provides flexibility between the binding and effector regions of an antibody and also provides sites for intermolecular disulfide bonding between the two heavy chain constant regions in a tetramer subunit. The CH2 and CH3 regions are the primary site of effector functions and FcR binding, i.e., FcRn and FcRȖ.

[0074] Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or 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, with the heavy chain also including a "D" segment of about 10 or more amino acids. (See generally, Fundamental Immunology (Paul, W., ed., 2nd ed. Raven Press, N.Y., 1989), Ch. 7) (incorporated by reference in its entirety for all purposes).

[0075] The mature variable regions of each light / heavy chain pair form the antibody binding site. Thus, an intact antibody has two binding sites, i.e., is divalent. In natural antibodies, the binding sites are the same. However, bispecific antibodies can be made 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 exhibit 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-terminal to C-terminal, both light and heavy chains comprise the domains FRl, CDRl, FR2, CDR2, FR3, CDR3 and FR4. For convenience, the variable heavy CDRs can be referred to as CDRH1, CDRH2 and CDRH3; the variable light chain CDRs can be referredto as CDRL1, CDRL2 and CDRL3. The assignment of amino acids to each domain is in accordance with the definitions of 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 widely used numbering convention (Kabat numbering) 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, EU numbering is more commonly used, as is the case in this application. Although specific sequences are provided for exemplary antibodies disclosed herein, it will be appreciated that after expression of protein chains one to several amino acids at the amino or carboxy terminus of the light and / or heavy chain, particularly a heavy chain C-terminal lysine residue, may be missing or derivatized in a proportion or all of the molecules.

[0076] The term "epitope" refers to a site on an antigen to which an antibody or extracellular trap segment binds. An epitope on a protein can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed from contiguous amino acids (also known as linear epitopes) are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding (also known as conformational epitopes) are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g., Epitope Mapping Protocols, in Methods in Molecular Biology, Vol.66, Glenn E. Morris, Ed. (1996).

[0077] Antibodies that recognize the same or overlapping epitopes can be identified in a simple immunoassay showing the ability of one antibody to compete with the binding of another antibody to a target antigen. The epitope of an antibody can also be defined by X-ray crystallography of the antibody (or Fab fragment) bound to its antigen to identify contact residues.

[0078] 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. 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.

[0079] Competition between antibodies is determined by an assay in which an antibody under test 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 a test antibody (e.g., at least 2x, 5x, 10x, 20x or l00x) inhibits binding of the reference antibody by at least 50%. In some embodiments the test antibody inhibits binding of the reference antibody by 75%, 90%, or 99% as measured in a competitive binding assay. Antibodies identified by competition assay (competing antibodies) include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur.

[0080] As used herein, the term “Trap” or similar term refers to a molecule comprising the binding domains or a fragment thereof that allows for the molecule to work as a trap, preventing a protein or other molecule from binding to cellularly expressed receptors or other binding partners. Various embodiments of Trap proteins are known in the art and can be found, for example in U.S. Pub. No. 20150376271, the entirety of which, with respect to various Trap embodiments and fusions thereof, is incorporated herein by reference. In some embodiments, the term “Trap” or similar term refers to a molecule comprising the full-length extracellular region or any portion thereof, or combination of portions from different molecules that can antagonize signaling between at least one molecule and another.

[0081] “HTRA1” as used herein refers to a HtrA serine protease. HTRA1 can refer to, without limitation, 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”).

[0082] “aHTRA1” and “anti-HTRA1 antibody” are used interchangeably herein to refer to an antibody that binds to HTRA1, as provided herein.

[0083] As used herein, “potency” with reference to an anti-HTRA1 antibody denotes the ability to inhibit or the extent of inhibition of a HTRA1 activity (e.g., HTRA1 proteolytic activity) when the antibody is bound thereto.

[0084] As used herein, “IL-6 antibody-HTRA1Trap fusion”, “IL-6 antibody- HTRA1Trap”, “Ab IL-6-HTRA1Trap”, “Anti-IL-6-HTRA1Trap”, “HTRA-AntiIL6”, “HTRA-AntiIL-6”, “HTRA1Trap-anti-IL6 Antibody Fusion (TAF)”, “HTRA1Trap-IL6”, “HTRA1IL-6”, “IL6- HTRA” or similar term or inverse terms (e.g. “HTRA1Trap-IL-6 Ab,” “HTRA1Trap-IL-6 antibody fusion,” etc.) denote the fusion between the IL-6 antibody and the HTRA1Trap. When used generically, the order of the two terms can be swapped. When used specifically, the order of the two terms denotes the relative position of the components in the construct. the term “IL-6 Ab- HTRA1Trap” “Ab IL-6 HTRA1Trap” or “anti-IL-6 HTRA1Trap”, “Trap-Ab”, AntiIL-6- HTRA, AntiIL6- HTRA1 or other similar term or inverse terms (e.g. “HTRA1Trap-IL-6 Ab,” “HTRA1Trap-IL-6 antibody fusion,” etc.) denotes the arrangement of the Ab fused to the relevant domains of a HTRA1binding protein so as to provide a HTRA1trap.

[0085] As noted above, this section of the HTRA1 binding protein is one that prevents HTRA1from binding to substrates. As described herein, the arrangement (ordering) of the Trap and antibody sections can be varied. Thus, unless denoted otherwise explicitly or by context, the phrases used herein regarding Ab-Trap (or HTRA1 / IL-1 trap, IL-6 / IL-1 trap, etc.) fusions, denote all disclosed embodiments for the positioning of the antibody and the Trap. If the orientation is specifically denoted, it can be denoted, for example, by stating that the “arrangement” can be one of: Trap-Ab, Trap IL-1 Ab, Trap IL-6 Ab, VEGF Trap Ab IL-6. Similarly, it will be appreciated that the context of some of the present Examples specific orientations or arrangements of the molecules, which are denoted by the context of the Example. Both arrangements (in the alternative and combined) are explicitly contemplated for all discussions of fusion proteins provided herein. In addition, due to the ordering, it is appreciated that the phrase IL-6 Ab, when used in the context of the fusion protein, includes both the option where the antibody is contiguous, left-hand side, and where the TRAP is positioned “within” the Ab. Again, the term “Ab” or “antibody”, when used in the fusion protein context (or other similar term), encompasses all three options unless otherwise noted. In some embodiments, the IL-1 Trap is fused to IL-6 or HTRA1 in one of the followingmanners: to an N-terminal end of a heavy chain comprising IL-6 or HTRA1 VH; or between a hinge region and after a CH1 domain of a heavy chain comprising IL-6 or IL-1 VH. There is no difference between the designations of Ab, antibody, “anti’” or other similar term when used in a name to designate and antibody or fragment thereof. There is no difference between the designations of “Il-6” or “IL6” or “IL-6.” There is no difference between the designations of “Il-1” or “IL1” or “IL-1.”

[0086] 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 cysteine-knot superfamily of signaling molecules having eight conserved cysteine residues that form a cysteine knot structure. The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, PlGF (placental growth factor), VEGF-E (Orf-VEGF), and Trimeresurus flavoviridis svVEGF. With the exception of the latter 2 members, 5 genes of the VEGF family exist in mammalian genomes, including humans.

[0087] “aVEGF” and “anti-VEGF antibody” are used interchangeably herein to refer to an antibody that binds to VEGF, as provided herein.

[0088] As used herein, “VEGF Trap” or similar term denotes the VEGF binding domains (VEGFR1 domain 2, VEGFR2 domain 3). This fragment allows for the protein to work as a VEGF trap, preventing VEGF from binding to cellularly expressed VEGF receptors. In some embodiments, the VEGF Trap only includes 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 entirety of which, with respect to various VEGF Trap embodiments (which are VEGFR proteins or fragments thereof) and fusions thereof, is incorporated herein by reference. In some embodiments, the term “VEGF Trap” or similar term refers to a full-length extracellular region or any portion thereof, or combination of portions from different VEGF receptors that can antagonize signaling between at least one VEGF and VEGFR.

[0089] As used here, the term “IL trap” or similar terms denotes interleukin binding domains of the interleukin receptor protein and accessory protein. In some embodiments this denotes only the extracellular domain, or a portion thereof, of the interleukin receptor protein and accessory protein. These fragments allow for the protein to work as an IL trap, preventing IL from binding to cellularly expressed IL receptors. For example, but not limited to, the term“IL-1 trap” denotes the three IG like domains (D1-D3) of the extracellular domain of 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 the function of the IL-1 trap. These fragments allow for the protein to work as an IL-1 trap, preventing I-1L from binding to cellularly expressed IL-1 receptors.

[0090] As used herein, the term “TNFĮ trap” or similar terms denotes interleukin binding domains of TNFR1 and / or TNFR2. In some embodiments this denotes the extracellular domain of TNFR1 and / or TNFR2. These fragments allow for the protein to work as a TNFĮ trap, preventing TNFĮ from binding to cellularly expressed TNFĮ receptors.

[0091] As used herein, “IL-6 antibody-VEGF Trap fusion”, “IL-6 antibody-VEGF Trap”, “Ab IL-6-VEGF Trap”, “AntiIL-6-VEGF Trap”, “VEGFR-AntiIL6”, “VEGFR-AntiIL- 6”, “VEGF Trap-anti-IL6 Antibody Fusion (TAF)”, “VEGF Trap-IL6”, “VEGFR IL-6”, “IL6- VEGFR” or similar term or inverse terms (e.g. “VEGF Trap-IL-6 Ab,” “VEGF Trap-IL-6 antibody fusion,” etc.) denote the fusion between the IL-6 antibody and the VEGF Trap. When used generically, the order of the two terms can be swapped. When used specifically, the order of the two terms denotes 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 “antiIL-6 VEGF Trap”, AntiIL-6-VEGFR, AntiIL6-VEGFR or other similar term or inverse terms (e.g. “VEGF Trap- IL-6 Ab,” “VEGF Trap-IL-6 antibody fusion,” etc.) denotes the arrangement of the Ab fused to the relevant domains of a VEGF binding protein so as to provide a VEGF trap. As noted above, this section of the VEGF binding protein is one that prevents VEGF from binding to VEGF receptors. As described herein, the arrangement (ordering) of the Trap and antibody sections can be varied. Thus, unless denoted otherwise explicitly or by context, the phrases used herein regarding Ab-Trap (or Il-6 / VEGF Trap, etc.) fusions, denote all disclosed embodiments for the positioning of the antibody and the Trap. If the orientation is specifically denoted, it can be denoted, for example, by stating that the “arrangement” can be one of: Trap IL-6 Ab, VEGF Trap Ab IL-6, VEGF Trap Ab IL6.

[0092] The term "patient" includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.

[0093] For purposes of classifying amino acid substitutions as conservative or nonconservative, amino acids are grouped as follows: Group I (amino acids with negativelycharged side chains): Asp, Glu; Group II (amino acids with positively charged side chains): Arg, His, Lys; Group III (amino acids with polar uncharged side chains): Ser, Thr, Cys, Pro, Asn, Gln; Group IV (amino acids with nonpolar alipathic side chains): Gly, Ala, Val, Leu, Met, Ile; and Group V ( amino acids with nonpolar aromatic side chains): Phe, Tyr, Trp.

[0094] Percentage sequence identities are determined with antibody sequences maximally aligned by the Kabat numbering convention for a variable region or EU numbering for a constant region. After alignment, if a subject antibody region (e.g., the entire mature variable region of a heavy or light chain) is being compared with the same region of a reference antibody, the percentage sequence identity between the subject and reference antibody regions is the number of positions occupied by the same amino acid in both the subject and reference antibody region divided by the total number of aligned positions of the two regions, with gaps not counted, multiplied by 100 to convert to percentage. Sequence identities of other sequences can be determined by aligning sequences using algorithms, such as BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, WI, using default gap parameters, or by inspection, and the best alignment (i.e., resulting in the highest percentage of sequence similarity over a comparison window). Percentage of sequence identity is calculated by comparing two optimally aligned sequences over a window of comparison, determining the number of positions at which the identical residues 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 window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0095] Compositions or methods "comprising" one or more recited elements may include other elements not specifically recited. For example, a composition that comprises antibody may contain the antibody alone or in combination with other ingredients.

[0096] The term "antibody-dependent cellular cytotoxicity", or ADCC, is a mechanism for inducing cell death that depends upon the interaction of antibody-coated target cells (i.e., cells with bound antibody) with immune cells possessing lytic activity (also referred to as effector cells). Such effector cells include natural killer cells, monocytes / macrophages and neutrophils. ADCC is triggered by interactions between the Fc region of an antibody bound to a cell and Fcy receptors, particularly FcȖRI and FcȖRIII, on immune effector cells such asneutrophils, macrophages and natural killer cells. The target cell is eliminated by phagocytosis or lysis, depending on the type of mediating effector cell. Death of the antibody-coated target cell occurs as a result of effector cell activity.

[0097] The term opsonization also known as "antibody-dependent cellular phagocytosis", or ADCP, refers to the process by which antibody-coated cells are internalized, either in whole or in part, by phagocytic immune cells (e.g., macrophages, neutrophils and dendritic cells) that bind to an immunoglobulin Fc region.

[0098] The term "complement-dependent cytotoxicity" or CDC refers to a mechanism for inducing cell death in which an Fc effector domain(s) of a target-bound antibody activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane. Typically, antigen-antibody complexes such as those 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 may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes.

[0099] A humanized antibody is a genetically engineered antibody in which the CDRs from a non-human "donor" antibody are grafted into human "acceptor" antibody sequences (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 sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a Germline region sequence. Thus, a humanized antibody is an antibody having some or all CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences. Similarly a humanized heavy chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, 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 entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constantregion sequences. Other than nanobodies and dAbs, a humanized antibody comprises a humanized heavy chain and a humanized light chain. A CDR in a humanized antibody is substantially from a corresponding CDR in a non-human antibody when at least 85%, 90%, 95% or 100% of corresponding residues (as defined by Kabat) are identical between the respective CDRs. The variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 85, 90, 95 or 100% of corresponding residues defined by Kabat are identical.

[0100] Although humanized antibodies often incorporate all six CDRs (which can be as defined by Kabat) from a mouse antibody, they can also be made with less than all CDRs (e.g., at least 3, 4, or 5 CDRs from a 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).

[0101] A chimeric antibody is an antibody in which the mature variable regions of light and heavy chains of a non-human antibody (e.g., a mouse) are combined with human light and heavy chain constant regions. Such antibodies substantially or entirely retain the binding specificity of the mouse antibody, and are about two-thirds human sequence.

[0102] As used herein, the term "Knobs-Into-Holes" (KIH) may refer to a strategy pairing the heavy chain part of the constant region in antibodies and fragments thereof. The "knobs" part is engineered by replacing a small amino acid with a larger one. For example, in some embodiments, the Knob comprises a knob that is in SEQ ID No.65. It fits into the "hole", which is engineered by replacing a large amino acid with a smaller one. For example, in someembodiments, the Hole comprises a Hole that is in SEQ ID No.66. What connects the "knobs" to the "holes" are the disulfide bonds between each chain.

[0103] 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 replaces other variable region framework residues that may contribute to B- or T-cell epitopes, for example exposed residues (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) with residues from the corresponding positions of a human antibody sequence. The result is an antibody in which the CDRs are entirely or substantially from a non-human antibody and the variable region frameworks of the non- human antibody are made more human-like by the substitutions. A human antibody can be isolated from a human, or otherwise result from expression of human immunoglobulin genes (e.g., in a transgenic mouse, in vitro or by phage display). Methods for producing human antibodies include the trioma method of Östberg L, Pursch E.1983. Human x (mouse x human) hybridomas stably producing human antibodies. Hybridoma 2:361-367; Östberg, U.S. Patent No. 4,634,664; and Engleman et al., US Patent 4,634,666, use of transgenic mice including human immunoglobulin genes (see, e.g., Lonberg et al., W093 / 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.

[0104] “Pharmaceutically acceptable excipient” refers to an excipient that can be included in compositions and that causes no significant adverse toxicological effect on the patient and is approved or approvable by the FDA for therapeutic use, particularly in humans. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose and the like.

[0105] “Therapeutic proteins” are administered in an effective regime meaning a dosage, route of administration and frequency of administration that delays the onset, reduces the severity, inhibits further deterioration, and / or ameliorates at least one sign or symptom of a disorder. If a patient is already suffering from a disorder, the regime can be referred to as atherapeutically effective regime. In some embodiments, the disorder comprises diabetic retinopathy, early, intermediate, advanced age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, inflammation of the eye, an HTRA1-related disorder, and / or an IL-1 related disorder, scleritis, diabetic macular edema, diabetic retinopathy, wet age-related macular degeneration, uveitis, non-infectious uveitis, uveitic macular edema, cytokine release syndrome following CAR-T or similar immune-oncology therapeutics, and / or abrogating the induction of IL-6 expression observed following treatment with anti-PD-1 / PD-L1 molecules, cancer, cerebral edema in glioblastoma, an IL-6 related disorder, and / or a VEGF related disorder. In some embodiments, the disorder is inflammation of the eye. In some embodiments, the disorder is ocular inflammation. If the patient is at elevated risk of the disorder relative to the general population but is not yet experiencing symptoms, the regime can be referred to as a prophylactically effective regime. In some instances, therapeutic or prophylactic efficacy can be observed in an individual patient relative to historical controls or past experience in the same patient. In other instances, therapeutic or prophylactic efficacy can be demonstrated in a preclinical or clinical trial in a population of treated patients relative to a control population of untreated patients.

[0106] The “biological half-life” of a substance is a pharmacokinetic parameter which specifies the time required for one half of the substance to be removed from a tissue or an organism following introduction of the substance.

[0107] “BCVA” denotes Best Corrected Visual Acuity.

[0108] “OCT-A” denotes OCT-Angiography.

[0109] “SD-OCT” denotes Spectral Domain Optical Coherence Tomography.

[0110] A “neovascular disorder” is a disorder or disease state characterized by altered, dysregulated or unregulated angiogenesis. Examples of neovascular disorders include neoplastic transformation (e.g. cancer) and ocular neovascular disorders including diabetic retinopathy and age-related macular degeneration.

[0111] An “ocular neovascular” disorder is a disorder characterized by altered, dysregulated or unregulated angiogenesis in the eye of a patient. Such disorders include optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidal neovascularization, corneal neovascularization, vitreal neovascularization, glaucoma, pannus,pterygium, macular edema, diabetic retinopathy, diabetic macular edema, vascular retinopathy, retinal degeneration, uveitis, non-infectious uveitis, inflammatory diseases of the retina, and proliferative vitreoretinopathy. Multivalent interleukin (IL) trap-antibody fusion

[0112] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and antibody are connected 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 and antigen binding sites are located at separate positions on the trap-antibody or trap-Fab fusion.

[0113] 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 accessory protein; an antibody or Fab fragment; wherein the antibody or Fab fragment comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and 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.

[0114] FIG.1 is 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 accessory protein are linked to the heavy chain and light chain of the same antibody arm. In some embodiments, the IL receptor protein and accessory protein.

[0115] 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 antibody 102 or Fab fragment are connected in tandem by a linker 103. In some embodiments, the length of the linker is chosen for its ability to promote a desired function or characteristic 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 and antigen binding sites are located at separate positions on the trap-antibody or trap-Fab fusion. For example, in some embodiments, the IL binding site is located on an IL trap linked to the antibody or Fab fragment whereas the antigen binding site is located on an antibody arm. In some embodiments, the IL binding site is linked to the same antibody arm comprising the antigen binding site. In some embodiments, the IL binding site is linked to an antibody arm opposite from the antigen binding site. 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 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.

[0116] FIG.2 is a representative illustration of some embodiments of a multivalent interleukin (IL) trap-antibody fusion or trap-Fab bound to 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 accessory protein are linked to the heavy chain and light chain of the same antibody arm. In some embodiments, the IL receptor protein and accessory protein are linked to in tandem to a heavy chain, light chain, or both of one or both antibody arms.

[0117] 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 3 complementarity determining regions (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3. In some embodiments the antibody fragment comprises a Fab fragments. In some embodiments, the IL trap 201 comprises an IL receptor, and an IL accessory protein. In some embodiments, the IL trap 201 and antibody 202 are connected in tandem by a linker 203. In some embodiments, the length of the linker is chosen for its ability to promote a desired function or characteristic 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 and antigen binding sites are located at separate positions on the trap-antibody or trap-Fab fusion. For example, in some embodiments, the IL binding site is located on an IL trap linked to the antibody whereas the antigen binding site is located on an antibody arm. In some embodiments, the IL binding site is linked to the same antibody arm comprising the antigen binding site. In some embodiments, the IL binding site is linked to an antibody arm opposite from 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 tandem 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.

[0118] FIG. 16 is an illustrative representation of some embodiments of multivalent interleukin (IL) trap-antibody fusions conjugated to a polymer.

[0119] 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.

[0120] Some aspects of the present disclosure relate to a method of inhibiting interleukin signaling in a subject. In some embodiments, the method comprises administering an interleukin trap-antibody-heterodimer fusion. In some embodiments, the heterodimer 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 IL inhibits IL signaling; and binding of the IL trap-antibody-heterodimer fusion to an antigen inhibits antigen activity.

[0121] Some aspects of the present disclosure relate to a method of inhibiting interleukin signaling in a subject. In some embodiments, the method comprises administering an interleukin trap-antibody-heterodimer or trap-Fab fusion. In some embodiments, the heterodimer 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 IL inhibits IL signaling; and binding of the IL trap-antibody-heterodimer or trap-Fab fusion to an antigen inhibits antigen activity.

[0122] FIG.3 is a flow chart and representative illustration of some embodiments of a method of inhibiting interleukin signaling.

[0123] In some embodiments, a method of inhibiting interleukin signaling in a subject 300 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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.

[0124] In some embodiments, the interleukin trap-antibody-heterodimer or trap- Fab fusion is multivalent. In some embodiments, the interleukin trap-antibody-heterodimer fusion is or trap-Fab monovalent, divalent, trivalent, tetravalent, pentavalent, hexavalent, heptavalent, or octavalent.

[0125] In some embodiments, the interleukin trap-antibody-heterodimer 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.

[0126] In some embodiments, the interleukin trap-antibody-heterodimer or trap- Fab fusion is conjugated to a polymer. In some embodiments, the antibody conjugate has the structure of Formula (I):letter H, and each light chain of the anti-HTRA1 antibody is denoted by the letter L; the polymer is bonded to the anti-HTRA1 antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains; PC is, where the curvy line indicates the point of attachment to the rest of the polymer; wherein X is a) –OR where R is – H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and either 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, where R is a sugar, an aminoalkyl, mono- substituted, poly-substituted or unsubstituted variants of the following residues: saturated C1 -C24 alkyl, unsaturated C2 -C24 alkenyl or C2 -C24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy,aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl including polyhalogenated alkyl, --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 separately selected from the group consisting of a hydrogen atom, halogen atom, mono-substituted, poly-substituted or unsubstituted variants of the following residues: saturated C1- C24 alkyl, unsaturated C2 -C24 alkenyl or C2- C24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl including polyhalogenated alkyl, a 5-membered ring, and a 6- membered ring.

[0128] In some embodiments, the antibody conjugate has the structure of Formula (II):

[0130] “n.” is an integer from 1 to 50 and “n.i” is an integer from 1 to 50;

[0131] each heavy chain of the anti-HTRA1 antibody is denoted by the letter H, and each light chain of the anti-HTRA1 antibody is denoted by the letter L; the polymer is bonded to the anti-HTRA1 antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains; PC is, where the curvy line indicates the point of attachment to the rest of the polymer; wherein X is a) –OR where R is –H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and either 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%.

[0132] In some embodiments, the half-life of the anti-HTRA1 antibodies is extended by attachment of a “half-life (“half life”) extending moieties” or “half-life (“half life”) extending groups”. Half-life extending moieties include peptides and proteins which canbe expressed in frame with the biological drug of issue (or conjugated chemically depending on the situation) and various polymers which can be attached or conjugated to one or more amino acid side chain or end functionalities such as -SH, -OH, -COOH, -CONH2, -NH2, or one or more N- and / or O-glycan structures. Half-life extending moieties generally act to increase the in vivo circulatory half-life of biologic drugs.

[0133] Suitable peptide / protein half-life extending moieties include, without limitation, Fc fusion, human serum albumin (HAS) fusion, carboxy terminal peptide (CTP) fusion, genetic fusion of non-exact repeat peptide sequence (XTEN) fusion, 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 fusion, proline-alanine-serine (PASylation), homo-amino acid polymer (HAPylation) and gelatin like protein (GLK) fusion.

[0134] Examples of polymer half-life extending moieties include polyethylene glycol (PEG), branched PEG, PolyPEG® (Warwick Effect Polymers; Coventry, UK), polysialic acid (PSA), starch, hydroxylethyl starch (HES), hydroxyalkyl starch (HAS), carbohydrate, polysaccharides, pullulane, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, polyacryloylmorpholine, polyvinyl alcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anyhydride, polystyrene-co-maleic acid anhydride, poly(1- hydroxymethyethylene hydroxymethylformal) (PHF), a zwitterionic polymer, a phosphorylcholine containing polymer and a polymer comprising MPC, Poly (Glyx-Sery), Hyaluronic acid (HA), Heparosan polymers (HEP), Fleximers, Dextran, and Poly-sialic acids (PSA).

[0135] In one embodiment a half-life extending moiety can be conjugated to an antibody via free amino groups of the protein using N-hydroxysuccinimide (NHS) esters. Reagents targeting conjugation to amine groups can randomly react to ^-amine group of lysines, Į-amine group of N-terminal amino acids, and į-amine group of histidines.

[0136] In some embodiments, a half-life extending moiety is coupled to one or more free SH groups using any appropriate thiol-reactive chemistry including, without limitation, maleimide chemistry, or the coupling of polymer hydrazides or polymer amines tocarbohydrate moieties of the antibody after prior oxidation. In some embodiments maleimide coupling is used. In some embodiments, coupling occurs at cysteines naturally present or introduced via genetic engineering.

[0137] In some embodiments, a polymer is covalently attached to a cysteine residue introduced into anti-HTRA1 antibodies by site directed mutagenesis, or to a non-native cysteine. In some embodiments, the cysteine residue is employed 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, the sites to introduce cysteine residues into an Fc region are provided in WO 2013 / 093809, US 7,521,541, WO 2008 / 020827, US 8,008,453, US 8,455,622 and US2012 / 0213705, incorporated herein by reference for all purposes. In some embodiments, the cysteine mutations are Q347C (EU numbering) and L443C referring to the human IgG heavy chain by EU numbering.

[0138] In some embodiments, conjugates of antibody and high MW polymers serving as half-life extenders are provided. In some embodiments, a conjugate comprises an antibody that is coupled to a zwitterionic polymer wherein the polymer is formed from one or more monomer units and wherein at least one monomer unit has a zwitterionic group is provided. In some embodiments, the zwitterionic group is phosphorylcholine.

[0139] In some embodiments, one of the monomer units is HEMA-PC. In some embodiments, a polymer is synthesized from a single monomer which is HEMA-PC.

[0140] 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 conjugate has 9 arms.

[0141] In some embodiments, polymer-antibody conjugates have a polymer portion with a molecular weight of between 100,000 and 1,500,000 Da. In some embodiments, the conjugate has a polymer portion with a molecular weight between 500,000 and 1,000,000 Da. In some embodiments, the conjugate has a polymer portion with a molecular weight between 600,000 to 800,000 Da. In some embodiments, the conjugate has a polymer portion with a molecular weight between 600,000 and 850,000 Da and has 9 arms. When a molecular weight is given for an antibody conjugated to a polymer, the molecular weight will be theaddition of the molecular weight of the protein, including any carbohydrate moieties associated therewith, and the molecular weight of the polymer.

[0142] In some embodiments, an anti-HTRA1 antibody has a HEMA-PC polymer which has a molecular weight measured by Mw of between about 100 kDa and 1650 kDa is provided. In some embodiments, the molecular weight of the polymer as measured by Mw is between about 500 kDa and 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 polymer molecular weight as measured by Mw is 750 kDa plus or minus 15%.

[0143] 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 a signal peptide in any one of SEQ ID NO.: 16-23. In some embodiments the signal peptide comprises a 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a signal peptide in any one of SEQ ID NO.: 16-23.

[0144] In some embodiments, the interleukin trap-antibody-heterodimer fusion simultaneously bind an IL and an antigen. In some embodiments, the interleukin trap-antibody- heterodimer fusion sequentially bind an IL and an antigen.

[0145] In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap with 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 100pM, or a binding affinity that is in a range defined by any two of the preceding values. For example, in some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap with an IL binding affinity of between or no greater than about 0.01 and 100, 0.01 and 75, 0.01 and 50, 0.01 and 25, 0.01 and 10, 0.01 and 5, 0.01 and 1, 0.01 and 0.05, 0.05 and 100, 0.05 and75, 0.05 and 50, 0.05 and 25, 0.05 and 10, 0.05 and 5, 0.05 and 0.1, 0.1 and 100, 0.1 and 75, 0.1 and 50, 0.1 and 25, 0.1 and 10, 0.1 and 5, 0.1 and 1, 0.1 and 0.5, 0.5 and 100, 0.5 and 75, 0.5 and 50, 0.5 and 25, 0.5 and 10, 0.5 and 5, 0.5 and 1, 1 and 100, 1 and 75, 1 and 50, 1 and 25, 1 and 10, 1 and 5, 5 and 100, 5 and 75, 5 and 50, 5 and 25, 5 and 10, 10 and 100, 10 and 75, 10 and 50, 10 and 25, 25 and 100, 25 and 75, 25 and 50, 50 and 100, 50 and 75, or 75 and 100 pM.

[0146] In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an antibody with an antigen binding affinity of between about 50 and 500 pM. In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an antibody with 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 in a range that is defined by any two of the preceding values or no greater than any designated value. For example, in some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an antibody with an antigen binding affinity of between or no greater than about 50 and 500, 50 and 450, 50 and 300, 50 and 250, 50 and 200, 50 and 150, 50 and 100, 100 and 500, 100 and 450, 100 and 400, 100 and 350, 100 and 300, 100 and 250, 100 and 200, 200 and 500, 200 and 400, 200 and 300, 250 and 500, 250 and 400, 300 and 500, 300 and 400, and 400 and 500 pM.

[0147] In some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap with 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 in a range that is defined by any two of the preceding values, and an antibody with an antigen binding affinity of between about 50 and 500 pM. For example, in some embodiments, the interleukin trap-antibody-heterodimer fusion comprises an IL trap with an IL binding affinity of about or no greater 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 with 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 that is in a range defined by any two of the preceding values. For example, in some embodiments, the antibody has an antigen binding affinity of between or no greater 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 antibody has an antigen binding affinity of at least about 0.001 pM..

[0148] In some embodiments, the IL trap has an IL IC50 of 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 x10-9 M, or has an IC50 in a range that is defined by any two of the preceding values. For example, in some embodiments, the IL trap has an IL IC50 of 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 x10-10M. In some embodiments, the IL trap has an IL IC50 of less than or equal to 2 nM.

[0149] In some embodiments, the IL trap is an IL-1, IL-1Į, IL-1ȕ, 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-36Į, IL-36ȕ, IL-36Ȗ, IL-37, or IL-38, trap.

[0150] In some embodiments, the IL trap comprises a trap for a member of the IL- 1 family, for example, IL-1Į, IL-1ȕ, IL-1Ra, IL-18, IL-33, IL-36Į, IL-36ȕ, IL-36Ȗ, IL-36Ra, IL-37, or IL-38. In some embodiments, the IL trap comprises the same receptor accessory protein for binding to IL-1Į, IL-1ȕ, IL-1Ra, IL-33, IL-36Į, IL-36ȕ, IL-36Ȗ.

[0151] In some embodiments, the IL trap comprises an IL receptor protein. In some embodiment, the IL trap receptor protein comprises an IL-1R1, IL-2Rȕ, IL-2RȖ, IL-3RĮ, CSF2RB, IL-4R, IL-2RȖ / IL-13RĮ1, IL-5RĮ, IL-6RĮ, gp130, IL-7RĮ, IL-9R, , IL-11RĮ, IL- 12Rȕ1, IL-12Rȕ2, IL-13RĮ1, IL-13RĮ2, IL-4R, IL-15RĮ, CD4, CD9, IL-21R, IL-12Rȕ1, IL- 23R, IL-27RĮ, IL-31RĮ, OSMR, CSF-1R, or ST2, receptor protein.

[0152] In some embodiments, the IL trap comprises a trap for a member of the IL- family, for example, IL-6, LIF, CNTF, CLCF1, OSM, IL-11, IL-27, IL-35, IL-39.

[0153] In some embodiments, IL-trap is a trap for an IL comprising the common cytokine receptor Ȗ chain, Ȗc, e.g., IL-2, IL-4, IL-7, IL-9, IL-15, IL-21. In some embodiments, IL-trap is a trap for an IL comprising the common cytokine ȕ receptor chain, ȕc, e.g., IL-3, IL- 5, GM-CSF.

[0154] In some embodiments, the IL accessory protein is IL1RacP. In some embodiments, the IL accessory protein is GP130(IL6Rb).

[0155] In some embodiments, the antibody or fragment thereof is an anti-HTRA1 antibody or fragment thereof.

[0156] In some embodiments, the trap-antibody fusion or trap-Fab comprises an IL trap that is an IL-1 trap and an antibody or fragment thereof that is an anti-HTRA1 antibody or fragment thereof.

[0157] In some embodiments, the trap-antibody fusion comprises an IL trap that 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 between about 0.01 to 100 pM and an antibody that 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 that is in a range defined by any two of the preceding values. For example, in some embodiments, the IL-1 trap has an IL-1 binding affinity of between or no greater 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 an HTRA1 binding affinity of about or no greater than 50-500 pM. For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of about or no greater 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 an HTRA1 binding affinity that is in a range defined by any two of the preceding values. For example, in some embodiments, the anti- HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of between or no greater 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 an HTRA1 binding affinity of at least about 0.01 pM.

[0158] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that 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 trap-antibody fusion comprises an antibody or fragment thereof that is an anti-HTRA1 antibody or fragment thereof. In some embodiments, the anti-HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of less than about 1 nM.

[0159] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-33 trap and an antibody or fragment thereof that is an anti-HTRA1 antibody or fragment thereof.

[0160] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RacP; and an antibody or fragment thereof that is an anti-HTRA1 antibody.

[0161] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that 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; an antibody or fragment thereof that 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.

[0162] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that 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 between about 0.01 and 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 that is in a ranged defined by any twoof the preceding values. For example, in some embodiments, the IL-33 trap has an IL-33 binding affinity of between or no greater than 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-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 that is an anti-HTRA1 antibody or fragment thereof. In some embodiments, the anti-HTRA1 antibody has an HTRA1 binding affinity of between or no greater than about 5 and 500 pM. For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of about or no greater 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 that is in a range defined by any two of the preceding values. For example, in some embodiments, the anti-HTRA1 antibody has an HTRA1 binding affinity of between or no greater 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 an HTRA1 binding affinity of at least about 0.01 pM.

[0163] In some embodiments, the trap-antibody or trap-Fab fusion comprise an IL trap that is an IL-6 trap and an antibody that is an anti-HTRA1 antibody or fragment thereof.

[0164] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap. In some embodiments, the IL-6 trap comprises gp130(IL6RE) and IL- 6RD. In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody that is an anti-HTRA1 antibody or fragment thereof.

[0165] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap. In some embodiments, the IL-6 trap comprises gp130 (IL6RE) and IL- 6RD. 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 that 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.

[0166] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap. In some embodiments, the IL-6 trap comprises gp130(IL6RE) and IL- 6RD. In some embodiments, the IL-6 trap has an IL-6 binding affinity of between about 0.01 and 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 that is in a ranged defined by any two of the preceding values. For example, in some embodiments, the IL-33 trap has an IL-33 binding affinity of between 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 that is an anti-HTRA1 antibody or fragment thereof. In some embodiments, the anti-HTRA1 antibody or fragment thereof has an HTRA1 binding affinity of between about 5 and 500 pM. For example, in some embodiments, the anti-HTRA1 antibody or fragment thereof has an 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 that is in a range defined by any two of the preceding values. For example, in some embodiments, the anti-HTRA1 antibody has an HTRA1 binding affinity of between 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.

[0167] FIG. 17 shows representative embodiments of full-length and regions of IL-1, IL-6, IL-33, and VEGF receptor sequences.

[0168] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap comprising a receptor sequence that is a receptor sequence in FIG.17.

[0169] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap comprising a receptor sequence that is a receptor sequence in any one of SEQ ID NO.: 1- 15, or 67-71. In some embodiments, the trap-antibody fusion comprises a receptor sequence having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a receptor sequence in any one of SEQ ID NO.: 1-15 or 67-71. In some embodiments, the trap-antibody fusion comprises a receptor sequence having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a receptor sequence in any one of SEQ ID NO.: 1-15 or 67-71.

[0170] Table 1 lists some embodiments of full-length and regions of IL-1, IL-6, IL-33, VEGF, and TNFĮ receptor sequences.

[0171] Table 1: SEQ Name SEQID No.Amino Acid SequenceSERCDDWGLDTMRQIQVFEDEPARIKCPLFEHFLKFNYSTAHSAGLTL IWYWTRQDRDLEEPINFRLPENRISKEKDVLWFRPTLLNDTGNYTCML D C E E Y V V K T A Y L L D C E E Y I A D L P Y S Y S P D LSKQSWGLENEALIVRCPRQGKPSYTVDWYYSQTNKSIPTQERNRVFAS GQLLKFLPAAVADSGIYTCIVRSPTFNRTGYANVTIYKKQSDCNVPDYELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTN HFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGI TIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWAT en

[0173] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IL trap, which comprises a receptor sequence that is a receptor sequence in Table 1.

[0174] FIG. 18 shows some representative embodiments of IgG constant and variable region sequences.

[0175] In some embodiments, the trap-antibody or trap-Fab fusion comprises an IgG constant and variable region sequence that is an IgG constant and variable region sequence in FIG.18.

[0176] In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a variable domain sequence that is a variable domain sequence in 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a variable domain sequence in 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a variable domain sequence in any one of SEQ ID NO.: 30-44.

[0177] In some embodiments, the trap-antibody or trap-Fab fusion comprises an antibody having a constant domain sequence that is a constant domain sequence in 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a constant domain sequence in 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a constant domain sequence in any one of SEQ ID NO.: 28-29, 45-47, or 64-66.

[0178] Table 2 lists some embodiments of IgG constant and variable region sequences.

[0179] Table 2: SEQ Name SEQ Amino Acid SequenceS K CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFaHTRA- DIQLTQSPSSLSASVGDRVTITCRSSQSLLDEAGETYLAWFQQKPGKA LC21 VL44PKLLIYEVSLLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQA TYFPYTFGQGTKVEIK anantibody having a variable domain sequence that is a variable domain sequence in Table 2.

[0181] FIG.19 shows some representative embodiments of linkers suitable for use in connecting an IL receptor protein with an antibody variable domain.

[0182] In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker in FIG.19.

[0183] 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, theone or more repeats comprises repeats of GGGGS (SEQ ID NO.: 24). In some embodiments, the trap-antibody fusion comprises a linker comprises 1, 2, 3, 4, 5, 6, 7, or 8, repeats. In some embodiments, the trap-antibody fusion comprises a linker comprises 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 in any one of SEQ ID NO.: 24-27. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is a linker in 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 in any one of SEQ ID NO.: 25 (GGGGSGGGGS). In some embodiments, the trap-antibody fusion comprises a linker that is a linker in 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 in any one of SEQ ID NO.: 27 (GGGGSGGGGSGGGGS). In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a linker in any one of SEQ ID NO.: 24-27. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a linker in any one of SEQ ID NO.: 24-27.

[0184] Table 3 depicts some embodiments of linkers suitable for use in connecting an IL receptor protein with an antibody variable domain.

[0185] Table 3. SEQ Name SEQ ID No. Amino Acid Sequence (GS1) 24GGGGS

[0186] In some embodiments, 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a linker in Table 3. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a linker in Table 3.

[0187] In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker up to 20 amino acids. In some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20amino acids, or a number of amino acids that is in a range defined by any two of the preceding values. For example, in some embodiments, the trap-antibody or trap-Fab fusion comprises a linker that is 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 long.

[0188] FIG. 20 shows some representative embodiments of signal peptide sequences suitable for use in the trap-antibody or trap-Fab fusions disclosed herein.

[0189] In some embodiments, the trap-antibody fusion or trap-Fab comprises a signal peptide that is a signal peptide in FIG.20.

[0190] Table 4. depicts some embodiments of signal peptide sequences suitable for use in the trap-antibody or trap-Fab fusions disclosed herein.

[0191] Table 4: SEQ Name SEQ ID No. Amino Acid Sequence IL-2 signal 16MYRMQLLSCIALSLALVTNSs a signalpeptide that is a signal peptide in Table 4. In some embodiments, the trap-antibody or trap- Fab fusion comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a signal peptide in Table 4. In some embodiments, the trap-antibody or trap-Fab fusion comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a signal peptide in Table 4.

[0193] In some embodiments, the trap antibody or trap-Fab fusion is 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, each receptor is fused N- terminal to either the VH or VL regions. The HC / LC heterodimer places the IL-1 receptors in proximity in a manner that allows it to mimic the native binding mechanism for IL-1. In some embodiments, IL1RAcP is linked (with either ILR1 or ILR2 in tandem then fused to the anti-IL-6 antibody heavy chain and / or light chain. The fusion proteins are then combined with different signal peptides to drive mammalian cell extracellular secretion.

[0194] FIG.4 is a schematic illustrating various embodiments of IL-1 trap and IgG fusion configurations. The dark crescent shapes represent either IL1R1 or IL1R2. The light crescent shapes represent IL1RAcP. In some embodiments, IL1RAcP and IL1R1 or IL1R2 are connected in tandem to the heavy chain or light chain of an antibody at both arms. In some embodiments, IL1RAcP and IL1R1 or IL1R2 are connected in tandem to both heavy chain and light chain of an antibody at both arms. In some embodiments, each of IL1R1 or IL1R2 and IL1RAcP are respectively connected to the heavy chain and light chain of both antibody arms. In some embodiments, each of IL1RAcP and IL1R1 or IL1R2 and are respectively connected to the heavy chain and light chain of both antibody arms.

[0195] Table 5 lists some embodiments of the sequence composition of the IL-1 trap anti-IL-6 antibody, IL-6 trap, IL-33 trap, IL-1 trap anti-IL-6 Fab and dual VEGF trap anti- IL-6 Fab. As listed in Table 5, the sequence composition represents the SEQ IDs that may be covalently linked to each other, starting from left to right for heavy chain and light chain formation.

[0196] Table 5: SEQ ID No. Sample H Ch in Li ht Ch in L 9999 9 9 9 9999 9 9 9 9TA15 16 1 30 28 16 3 39 29TA16 16 2 30 28 16 1 39 2999999999999999999999999 999 9 9 9 9999999999TA74 30 28 18 2 24 39 29TA75 30 28 18 2 26 39 2999 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 999 9 9 9 9 9 9 9 9 99TA115 16 9 25 31 28 16 40 29 TA11616 31 28 16 9 25 40 299 9 9 9 9 9 9 999 9 9 9 9 9 9 999 9 9 9 9 9 9 9 9 999 9999 9 9 9

[0197] 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a trap-antibody fusion in Table 5.

[0198] 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a trap-antibody or trap- Fab fusion comprising a combination of SEQ IDs disclosed in Table 5.

[0199] In some embodiments, any one of the constructs in Table 5. may be used to treat one or more disorders. In some embodiments, the disorder comprises diabetic retinopathy, early, intermediate, advanced age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, inflammation of the eye, an HTRA1-related disorder, and / or an IL-1 related disorder, scleritis, diabetic macular edema, diabetic retinopathy, wet age-related macular degeneration, uveitis, non-infectious uveitis, uveitic macular edema, cytokine release syndrome following CAR-T or similar immune-oncology therapeutics, and / or abrogating the induction of IL-6 expression observed following treatment with anti-PD-1 / PD- L1 molecules, cancer, cerebral edema in glioblastoma, an IL-6 related disorder, and / or a VEGF related disorder. In some embodiments, the disorder is inflammation of the eye. In some embodiments, the disorder is ocular inflammation. In some embodiments, any one of the constructs in Table 5. may be used to treat one or more disorders in FIG.25.

[0200] FIG.21 shows some representative embodiments of full-length heavy chain sequences suitable for use in the trap-antibody fusions disclosed herein. In some embodiments, the trap-antibody fusion comprises a heavy chain in FIG.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 FIG. 21. In some embodiments, the trap-antibody fusioncomprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a heavy chain in FIG.21.

[0201] FIG.22 shows some representative embodiments of full-length light chain sequences suitable for use in the trap-antibody or trap-Fab fusions disclosed herein. In some embodiments, the trap-antibody fusion comprises a light chain in FIG. 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 FIG. 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 FIG.22.

[0202] 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.

[0203] Table 6 shows some embodiments of trap-antibody full length heavy chain sequences.

[0204] Table 6. Sample ^ SEQ ID No. Heavy^chain P N A P Y V I S P I Y K Q P V R P G VMTLLWCVVSLYFYGILQSDASERCDDWGLDTMRQIQVFEDEP ARIKCPLFEHFLKFNYSTAHSAGLTLIWYWTRQDRDLEEPIN FRLPENRISKEKDVLWFRPTLLNDTGNYTCMLRNTTYCSKVA P Y V I S G I Y K Q P V R P G V P N A P Y V I S G I Y K Q P V R P G V P N A P Y V IDVTINESISHSRTEDETRTQILSIKKVTSEDLKRSYVCHARS AKGEVAKAAKVKQKVPAPRYTVEGGGGSGGGGSQVQLVESGG GVV PGGSLRLSCAASGFSLTFYHVHWVR APGKGLEWVASI Y K Q P V R P G V P I E I L Q E R W D A P K R N A W F S R P K D V E R W D A P K R NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW ESNG PENNYKTTPPVLDSDGSFFLYSKLTVDKSRW GNVF ker

[0206] In some embodiments, trap-antibody fusion comprises a heavy chain in Table 6. 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 Table 6. 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 Table 6.

[0207] Table 7 shows some embodiments of trap-antibody fusion full length light chain sequences.

[0208] Table 7: Sample SEQ ID No. Light chain R V A L T G T G D T S S H R V A L T G T G E T SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQS GNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH GLSSPVTKSFNRGEC^ R V A L T G T G E T S S H R V A L T G T G E T S S H P N A P Y V I S P L C A T C^ S RSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSP LSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYS ES KFSC LAVPEGDSSFYIVSMCVASSVGSKFSKT TFQG R A T L M S Y ^ kerq .

[0210] In some embodiments, trap-antibody fusion comprises a light chain in Table 7. In some embodiments, the trap-antibody fusion comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a light chain in Table 7. In some embodiments, the trap-antibody fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a heavy chain in Table 7.

[0211] FIG.23 shows some representative embodiments of full-length heavy chain sequences suitable for use in the trap-Fab fusions disclosed herein.

[0212] In some embodiments, the trap-Fab fusion comprises a heavy chain in FIG. 23. In some embodiments, the trap-Fab fusion comprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a heavy chain in FIG.23. In some embodiments, the trap-Fab fusion comprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a heavy chain in FIG.23.

[0213] FIG.24 shows some representative embodiments of full-length light chain sequences suitable for use in the trap-Fab fusions disclosed herein.

[0214] In some embodiments, the trap-Fab fusion comprises a light chain in FIG. 24. In some embodiments, the trap-Fab fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a light chain in FIG.24. In some embodiments, the trap-Fab fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a light chain in FIG.24.

[0215] Table 8 shows some embodiments of trap-Fab fusion full length heavy chain sequences.

[0216] Table 8: Sample SEQ ID IDNo.Heavy chainR P V T G I E P F S V S N R N I K V F D V N N kersequence is underlined.

[0218] 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a heavy chain in Table 8. In some embodiments, the trap-Fab fusion comprises a heavy chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a heavy chain in Table 8.

[0219] Table 9 shows some embodiments of trap-antibody fusion full length light chain sequences.

[0220] Table 9: Sample SEQ ID IDNo.Light chainC V L G E G H S L F R Y R N I K V V T F S T kersequence is underlined.

[0222] 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 having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to a light chain in Table 9. In some embodiments, the trap-Fab fusion comprises a light chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to a heavy light in Table 9.

[0223] In some embodiments, the conjugate shown in FIGS.10, 11, or 12 can be used with the sequences as shown in FIG. 21 or 22. In some embodiments, the conjugate shown in FIGS.13, 14, or 15 can be used with the sequences as shown in FIG.23 or 24.

[0224] In some embodiments, the trap-antibody fusion is an IL-1 trap anti-HTRA1 antibody biopolymer conjugate. As used herein, the term “biopolymer” denotes that a polymer has been linked to the protein of interest. The term can also be described as the “conjugated”form of the 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 that is SEQ ID No.: 51. In some embodiments, the trap-antibody fusion comprises a heavy sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 51. In some embodiments, the trap-antibody fusion comprises a heavy sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 51. In some embodiments, the IL-1 trap anti-HTRA1 antibody biopolymer conjugate comprises a light chain sequence that is SEQ ID No.: 57. In some embodiments, the trap- antibody fusion comprises a light sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 57. In some embodiments, the trap-antibody fusion comprises a light sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 57. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 38, a CH that is SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 1, 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.: 38, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28.In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 38, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 44, a CL that is 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.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 2, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ IDNo.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 44, 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 to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 2, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 44, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29. In some embodiments the IL-1 trap anti- HTRA1 fusion may be used to treat, or used in conjunction with a treatment for, diabetic retinopathy, early, intermediate, advanced age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, inflammation of the eye, an HTRA1-related disorder, and / or an IL-1 related disorder.

[0225] 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 that is SEQ ID No.: 60. In some embodiments, the trap-Fab fusion comprises a heavy sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 60. In some embodiments, the trap-Fab fusion comprises a heavy sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 60. In some embodiments, the trap-Fab fusion comprises a light chain sequence that is SEQ ID No.: 62. In some embodiments, the trap-Fab fusion comprises a light sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 62. In some embodiments, the trap-Fab fusion comprises a light sequence chain having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 62. In some embodiments, the trap-Fab fusion heavy chain comprises a signal peptide that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 46. In some embodiments, the trap-Fab fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 1, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 46. In some embodiments, the trap-Fab fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 46. In some embodiments, the trap-Fab fusion light chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29. In some embodiments, the trap-Fab fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 2, 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, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 29. In some embodiments, the trap-Fab fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 2, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0226] In some embodiments, the trap-antibody fusion comprises an IL-1 trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 1, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chaincomprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 2, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 2, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0227] In some embodiments, the trap-antibody fusion comprises an IL-1 trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25,a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 2, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 2, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 1, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ IDNo.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0228] In some embodiments, the trap-antibody fusion comprises an IL-1 trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 1, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 2, 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, 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 to SEQ ID No.: 18, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 2, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%,80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0229] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0230] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0231] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%,75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0232] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker thatis SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0233] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65.In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0234] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chaincomprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 67, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 17, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 1, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0235] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0236] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%,75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0237] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises asignal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0238] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about70%, 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 68, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0239] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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%, or100%, homology to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0240] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%,homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0241] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0242] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29. In some embodiments, thetrap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0243] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identityto SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0244] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0245] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.:69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0246] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 69, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0247] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 toSEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0248] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ IDNo.: 29. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0249] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0250] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0251] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%,75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0252] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker thatis SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0253] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0254] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.:66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0255] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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 VH having about 70%, 75%,80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 70, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0256] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chaincomprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0257] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.:71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0258] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CHhaving about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16 a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0259] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or100%, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0260] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0261] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 64. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 64. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0262] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%,75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 73, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0263] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.:71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0264] In some embodiments, the trap-antibody fusion comprises a TNFĮ trap and IL-6 antibody. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 16, a VH having about70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 65. In some embodiments, the trap- antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 65. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 66. In some embodiments, the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 72, a trap having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 71, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, aVL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0265] In some embodiments, an anti-TFFĮ VHH anti-IL-6 antibody fusion is disclosed. In some embodiments, the fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VHH that is SEQ ID NO.: 74, a linker that is SEQ ID NO.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VHH that is SEQ ID No.: 74, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0266] In some embodiments, an anti-TFFĮ VHH anti-IL-6 antibody fusion is disclosed. In some embodiments, the fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VHH that is SEQ ID NO.: 74, a linker that is SEQ ID NO.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap fusion heavy 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 VH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavy chain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 74, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is 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 VL having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 39, 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 to SEQ ID No.: 16, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0267] In some embodiments, an anti-TFFĮ VHH anti-IL-6 antibody fusion is disclosed. In some embodiments, the fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28. In some embodiments, the trap fusion heavy 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, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, homology to SEQ ID No.: 28. In some embodiments, the trap-antibody fusion heavychain comprises a signal peptide having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 16, a VH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 30, a CH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 28. In some embodiments, the fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VHH that is SEQ ID No.: 58, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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, 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 to SEQ ID No.: 16, a VHH having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 58, a linker having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 25, a VL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 39, a CL having about 70%, 75%, 80%, 90%, 95%, or 100%, identity to SEQ ID No.: 29.

[0268] Some embodiments herein are directed to a nucleic acid encoding any of the trap-antibody or trap-Fab fusions disclosed herein. For example in some embodiments, the nucleic acid encodes any of the trap-antibody or trap-Fab fusions in Table 5. Some embodiments herein are directed to a vector comprising a nucleic acid encoding any of the trap-antibody or trap-Fab fusions disclosed herein. For example in some embodiments, the vector comprises a nucleic acid encoding any of the trap-antibody or trap-Fab fusions in Table 5. Some embodiments herein are directed to a cell comprising a vector encoding any of the trap-antibody or trap-Fab fusions disclosed herein. For example in some embodiments, the cell comprises a vector encoding any of the trap-antibody or trap-Fab fusions in Table 5.

[0269] In some embodiments, the receptor protein and antibody are configured as depicted in FIG.4.

[0270] In some embodiments, binding of the IL trap to an IL reduces the activity of the IL. In some embodiments, binding of the antibody to an antigen inhibits the activity ofthe antigen. In some embodiments, simultaneous binding of the IL trap to an IL and binding of the antibody to an antigen inhibits the activity of the IL and the antigen.

[0271] In some embodiments, binding of the IL trap to an IL reduces the activity of the IL by about 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 that is defined by any two of the preceding values. For example, in some embodiments, binding of the IL trap to an IL reduces the activity of the IL by between about 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%.

[0272] In some embodiments, binding of the antibody to an antigen reduces the activity of the antigen by about 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 that is defined by any two of the preceding values. For example, in some embodiments, binding of the antibody to an antigen reduces the activity of the antigen by between about 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%.

[0273] In some embodiments, the IL trap-antibody or trap-Fab fusion has an IL association rate constant (ka) of about 1x104, 2x104, 3x104, 4x104, 5x104, 6x104, 7x104, 8x104, 9x104, 1x105, 2x105, 3x105, 4x105, 5x105, 6x105, 7x105, 8x105, 9x105, 1x106, 2x106, 3x106, 4x106, 5x106, 6x106, 7x106, 8x106, 9x106, 1x107, 2x107, 3x107, 4x107, 5x107, 6x107, 7x107, 8x107, 9x107, 1x108, 2x108, 3x108, 4x108, 5x108, 6x108, 7x108, 8x108, 9x108, 1x109, 2x109, 3x109, 4x109, 5x109, 6x109, 7x109, 8x109, or 9x109(1 / Ms), or has an IL association rate constant that is in a range defined by any two of the preceding values. For example, in some embodiments, the IL trap-antibody or trap-Fab fusion has an IL association rate constant of between about 1x104and 9x109, 1x104and 5x109, 1x104and 1x109, 1x104and 9x108, 1x104and 5x109, 1x104and 1x108, 1x104and 9x107, 1x104and 5x107, 1x104and 1x107, 1x104and 9x106, 1x104and 5x106, 1x104and 1x106, 1x104and 9x105, 1x104and 5x105, 1x104and 5x105, 1x104and 1x105, 1x105and 9x109, 1x105and 5x109, 1x105and 1x109, 1x105and 9x108, 1x105and 5x109, 1x105and 1x108, 1x105and 9x107, 1x105and 5x107, 1x105and 1x107, 1x105and 9x106, 1x105and 5x106, 1x105and 1x106, 1x106and 9x109, 1x106and 5x109, 1x106and 1x109, 1x106and 9x108, 1x106and 5x108, 1x106and 1x108, 1x106and 9x107, 1x106and 5x107, 1x106and 1x107, 1x107and 9x109, 1x107and 5x109, 1x107and 1x109, 1x107and 9x108, 1x107and 5x109, 1x107and 1x108, 1x108and 9x109, 1x108and 5x109, 1x108and 1x109, 1x108and 9x108, or 1x108and 5x108(1 / Ms).

[0274] In some embodiments, the IL trap-antibody or trap-Fab fusion has an IL dissociation rate constant (kd) of about 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(1 / s), or has an IL dissociation rate constant that is in a range defined by any two of the preceding values. For example, in some embodiments, the IL trap-antibody or trap-Fab fusion has an IL dissociation rate constant of between about 1x10-1and 9x10-7, 1x10-1and 5x10-7, 1x10-1and 1x10-7, 1x10-1and 9x10-6, 1x10-1and 5x10-6, 1x10-1and 1x10-6, 1x10-1and 9x10-5, 1x10-1and 5x10-5, 1x10-1and 1x10-5, 1x10-1and 9x10-4, 1x10-1and 5x10-4, 1x10-1and 1x10-4, 1x10-1and 9x10-3, 1x10-1and 5x10-3, 1x10-1and 1x10-3, 1x10-1and 9x10-2, 1x10-1and 5x10-2, 1x10-1and 1x10-2, 1x10-2and 9x10-7, 1x10-2and 5x10-7, 1x10-1and 1x10-7, 1x10-2and 9x10-6, 1x10-2and 5x10-6, 1x10-2and 1x10-6, 1x10-2and 9x10-5, 1x10-2and 5x10-5, 1x10-2and 1x10-5, 1x10-2and 9x10-4, 1x10-2and 5x10-4, 1x10-2and 1x10-4, 1x10-2and 9x10-3, 1x10-2and 5x10-3, 1x10-2and 1x10-3, 1x10-3and 9x10-7, 1x10-3and 5x10-7, 1x10-3and 1x10-7, 1x10-3and 9x10-6, 1x10-3and 5x10-6, 1x10-3and 1x10-6, 1x10-3and 9x10-5, 1x10-3and 5x10-5, 1x10-3and 1x10-5, 1x10-3and 9x10-5, 1x10-3and 5x10-4, 1x10-3and 1x10-4, 1x10-4and 9x10-7, 1x10-4and 5x10-7, 1x10-4and 1x10-7, 1x10-4and 9x10-6, 1x10-4and 5x10-6, 1x10-4and 1x10-6, 1x10-4and 9x10-5, 1x10-4and 5x10-5, 1x10-4and 1x10-5, 1x10-5and 9x10-7, 1x10-5and 5x10-7, 1x10-5and 1x10-7, 1x10-5and 9x10-6, 1x10-5and 5x10-6,1x10-5and 1x10-6, 1x10-6and 9x10-7, 1x10-6and 5x10-7, 1x10-6and 1x10-7, 1x10-7and 9x10-7, or 1x10-7and 5x10-7(1 / s).

[0275] In some embodiments, the IL trap-antibody or trap-Fab fusion has an IL equilibrium dissociation constant (KD) of about 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, 7x10-108x10-10, 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 9x10-13M, or has an IL equilibrium dissociation constant that is in a range defined by any two of the preceding values. For example, in some embodiments, the IL trap- antibody or trap-Fab fusion has an IL equilibrium dissociation constant of between about 1x10-8and 9x10-13, 1x10-8and 5x10-13, 1x10-8and 1x10-13, 1x10-8and 9x10-12, 1x10-8and 5x10-12, 1x10-8and 1x10-12, 1x10-8and 9x10-11, 1x10-8and 5x10-11, 1x10-8and 1x10-11, 1x10-8and 9x10-10, 1x10-8and 5x10-10, 1x10-8and 1x10-10, 1x10-8and 9x10-9, 1x10-8and 5x10-9, 1x10-8and 1x10-9, 1x10-8and 9x10-8, 1x10-8and 5x10-8, 1x10-9and 9x10-12, 1x10-9and 5x10-12, 1x10-9and 1x10-12, 1x10-9and 9x10-11, 1x10-9and 5x10-11, 1x10-9and 1x10-11, 1x10-9and 9x10-10, 1x10-9and 5x10-10, 1x10-9and 1x10-10, 1x10-9and 9x10-9, 1x10-9and 5x10-9, 1x10-10and 9x10-12, 1x10-10and 5x10-12, 1x10-10and 1x10-12, 1x10-10and 9x10-11, 1x10-10and 5x10-11, 1x10-10and 1x10-11, 1x10-10and 9x10-10, 1x10-10and 5x10-10, 1x10-11and 9x10-12, 1x10-11and 5x10-12, 1x10-11and 1x10-12, 1x10-11and 9x10-11, 1x10-11and 5x10-11, 1x10-12and 9x10-12, or 1x10-12and 5x10-12M. Polymer:

[0276] A “polymer” is a molecule composed of many repeating subunits. The subunits, also sometimes referred to as “monomers” can be the same or different. There are both natural and synthetic polymers. DNA, protein and complex carbohydrates are examples of natural polymers. Poly-styrene and poly-acrylamide 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 or sometimes a heteropolymer. A copolymer in which certain monomer types are clustered together are sometimes called block copolymers. Polymers can be linear or branched. When the polymer is branched, polymer chains having a common origin are sometimes referred to as a polymer arm(s).

[0277] An “initiator” is a compound capable of serving as a substrate on which one or more polymerizations can take place using monomers or comonomers as described herein. The polymerization can be a conventional free radical polymerization or preferably a controlled / ”living” radical polymerization, such as Atom Transfer Radical Polymerization (ATRP), Reversible Addition-Fragmentation-Termination (RAFT) polymerization or nitroxide mediated polymerization (NMP). The polymerization can be a “pseudo” controlled polymerization, such as degenerative transfer. Initiators suitable for ATRP contain one or more labile bonds which can be homolytically cleaved to form an initiator fragment, I, being a radical capable of initiating a radical polymerization, and a radical scavenger, I’, which reacts with the radical of the growing polymer chain to reversibly terminate the polymerization. The radical scavenger I’ is typically a halogen, but can also be an organic moiety, such as a nitrile. In some embodiments of the present invention, the initiator contains one or more 2-bromoisobutyrate groups as sites for polymerization via ATRP.

[0278] A “chemical linker” refers to a chemical moiety that links two groups together, such as a half-life extending moiety and a protein. The linker can be cleavable or non-cleavable. Cleavable linkers can be hydrolysable, enzymatically cleavable, pH sensitive, photolabile, or disulfide linkers, among others. Other linkers include homobifunctional and heterobifunctional linkers. A “linking group” is a functional group capable of forming a covalent linkage consisting of one or more bonds to a bioactive agent. Non-limiting examples include those illustrated in Table 1 of WO2013059137 (incorporated by reference).

[0279] The term "reactive group" refers to a group that is capable of reacting with another chemical group to form a covalent bond, i.e. is covalently reactive under suitable reaction conditions, and generally represents a point of attachment for another substance. The reactive group is a moiety, such as maleimide or succinimidyl ester, is capable of chemically reacting with a functional group on a different moiety to form a covalent linkage. Reactive groups generally include nucleophiles, electrophiles and photoactivatable groups.

[0280] As used herein, “phosphorylcholine,” also denoted as “PC,” refers to the following: O 3

[0281] where * denotes the point of attachment. The phosphorylcholine is a zwitterionic group and includes salts (such as inner salts), and protonated and deprotonated forms thereof.

[0282] As used herein, “phosphorylcholine-based polymer” is a polymer that contains phosphorylcholine. “Zwitterion containing polymer” refers to a polymer that contains a zwitterion.

[0283] Poly(acryloyloxyethyl phosphorylcholine) containing polymer refers to a polymer containing 2-(acryloyloxy)ethyl-2-(trimethylammonium)ethyl phosphate as monomer.

[0284] Poly(methacryloyloxyethyl phosphorylcholine) containing polymer refers to a polymer containing 2-(methacryloyloxy)ethyl-2-(trimethylammonium)ethyl phosphate as monomer.

[0285] As used herein, “molecular weight” in the context of the polymer can be expressed as either a number average molecular weight, or a weight average molecular weight or a peak molecular weight. Unless otherwise indicated, all references to molecular weight herein refer to the peak molecular weight. These molecular weight determinations, number average (Mn), weight average (Mw) and peak (Mp), can be measured using size exclusion chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values can also be used, such as the use of end-group analysis or the measurement of colligative properties (e.g., freezing-point depression, boiling-point elevation, or osmotic pressure) to determine number average molecular weight, or the use of light scattering techniques, ultracentrifugation or viscometry to determine weight average molecular weight. In a preferred embodiment of the present invention, the molecular weight is measured by SEC-MALS (size exclusion chromatography – multi angle light scattering). The polymeric reagents of the present disclosure are typically polydisperse (i.e., number average molecular weight and weight average molecular weight of the polymers are not equal). The Poly Dispersity Index (PDI) provides a measure for the dispersity of polymers in a mixture. PDI is given by the formula Mw / Mn. In this regard a homogenous protein will have a PDI of 1.0 (Mn is the same as Mw). Typically, the PDI for polymers will be above 1.0. Polymers in accordance with the present invention preferably have relatively low polydispersity (PDI) values of, for example, less than about 1.5, as judged, for example, by SEC-MALS. In other embodiments,the polydispersities (PDI) are more preferably in the range of about 1.4 to about 1.2, still more preferably less than about 1.15, and still more preferably less than about 1.10, yet still more preferably less than about 1.05, and most preferably less than about 1.03.

[0286] As used herein, “protected,” “protected form,” “protecting group” and “protective group” refer to the presence of a group (i.e., the protecting group) that prevents or blocks reaction of a particular chemically reactive functional group in a molecule under certain reaction conditions. Protecting groups vary depending upon the type of chemically reactive group being protected as well as the reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule, if any. Suitable protecting groups include those such as found in the treatise by Greene et al., “Protective Groups In Organic Synthesis,” 3rd Edition, John Wiley and Sons, Inc., New York, 1999.

[0287] As used herein, “alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. For example, C1-C6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Other alkyl groups include, but are not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl 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.

[0288] The term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines a compound or radical which can be branched or unbranched with up to and including 7, preferably up to and including 4 and (as unbranched) one or two carbon atoms.

[0289] As used herein, “alkylene” refers to an alkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene. For instance, a straight chain alkylene can be the bivalent radical of -(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, sec-butylene, pentylene and hexylene.

[0290] Substituents for the alkyl, alkenyl, alkylene, heteroalkyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl radicals can be one or more of a variety of groups selected from, but not limited to: -OR’, =O, =NR’,=N-OR’, -NR’R”, -SR’, -halogen, -SiR’R”R”’, -OC(O)R’, -C(O)R’, -CO2R’, -CONR’R”, -O C(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 a number ranging from 1 to (2m’+1), where m’ is the total number of carbon atoms in such radical. Each of R’, R”, R”’ and R”” independently refers to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., aryl substituted with 1-3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When R’ and R” are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.

[0291] As used herein, “alkoxy” refers to alkyl group attached to an oxygen atom and forms radical –O-R, wherein R is alkyl. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described herein. For example, the alkoxy groups can be substituted with halogens to form a “halo-alkoxy” group.

[0292] As used herein, “carboxyalkyl” means an alkyl group (as defined herein) substituted with a carboxy group. The term “carboxycycloalkyl” means an cycloalkyl group (as defined herein) substituted with a carboxy group. The term alkoxyalkyl means an alkyl group (as defined herein) substituted with an alkoxy group. The term “carboxy” employed herein refers to carboxylic acids and their esters.

[0293] As used herein, “haloalkyl” refers to alkyl as defined above where some or all of the hydrogen atoms are substituted with halogen atoms. Halogen (halo) preferably represents chloro or fluoro, but may also be bromo or iodo. For example, haloalkyl includes trifluoromethyl, fluoromethyl, 1,2,3,4,5-pentafluoro-phenyl, etc. The term “perfluoro” defines a compound or radical which has all available hydrogens that are replaced with 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 can also be referred to as halo-substitute alkyl, such as fluoro-substituted alkyl.

[0294] As used herein, “cytokine” in the context of this invention is a member of a group of protein signaling molecules that may participate in cell-cell communication inimmune and inflammatory responses. Cytokines are typically small, water-soluble glycoproteins that have a mass of about 8-35 kDa.

[0295] As used herein, “cycloalkyl” refers to a saturated mono- or multi- cyclic aliphatic ring system that contains from about 3 to 12, from 3 to 10, from 3 to 7, or from 3 to 6 carbon atoms. When cycloalkyl group is composed of two or more rings, the rings may be joined together with a fused ring or a spiro ring structure. When cycloalkyl group is composed of three or more rings, the rings may also join together forming 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, bicyclco[2.1.1]heptane, norbornane, decahydronaphthalene and adamantane. For example, C3-8 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane.

[0296] As used herein, “endocyclic” refers to an atom or group of atoms which comprise part of a cyclic ring structure.

[0297] As used herein, “exocyclic” refers to an atom or group of atoms which are attached but do not define the cyclic ring structure.

[0298] As used herein, “cyclic alkyl ether” refers to a 4 or 5 member cyclic alkyl group having 3 or 4 endocyclic carbon atoms and 1 endocyclic oxygen or sulfur atom (e.g., oxetane, thietane, tetrahydrofuran, tetrahydrothiophene); or a 6 to 7 member cyclic alkyl group having 1 or 2 endocyclic oxygen or sulfur atoms (e.g., tetrahydropyran, 1,3-dioxane, 1,4-dioxane, tetrahydrothiopyran, 1,3-dithiane, 1,4-dithiane, 1,4-oxathiane).

[0299] As used herein, “alkenyl” refers to either a straight chain or branched hydrocarbon of 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-hexatrienyl. Alkenyl groups can also have from 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 carbons.

[0300] As used herein, “alkenylene” refers to an alkenyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkenylene can be linked to the same atom or different atoms of the alkenylene.Alkenylene groups include, but are not limited to, ethenylene, propenylene, isopropenylene, butenylene, isobutenylene, sec-butenylene, pentenylene and hexenylene.

[0301] As used herein, “alkynyl” refers to either a straight chain or branched hydrocarbon of 2 to 6 carbon atoms, having at least one triple bond. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can also have from 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 carbons.

[0302] As used herein, “alkynylene” refers to an alkynyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the alkynylene can be linked to the same atom or different atoms of the alkynylene. Alkynylene groups include, but are not limited to, ethynylene, propynylene, butynylene, sec-butynylene, pentynylene and hexynylene.

[0303] As used herein, “cycloalkylene” refers to a cycloalkyl group, as defined above, linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties linked to the cycloalkylene can be linked to the same atom or different atoms of the cycloalkylene. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene.

[0304] As used herein, “heterocycloalkyl” refers to a ring system having from 3 ring members to about 20 ring members and from 1 to about 5 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heterocycle includes, but is not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl and 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl.

[0305] As used herein, “heterocycloalkylene” refers to a heterocyclalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heterocycloalkylene can be linked to the same atom or different atoms of the heterocycloalkylene.

[0306] As used herein, “aryl” refers to a monocyclic or multicyclic (e.g., fused bicyclic, tricyclic or greater) aromatic ring assembly containing 6 to 16 carbon atoms. For example, aryl may be phenyl, benzyl or naphthyl, preferably phenyl. Aryl groups can be mono-, di- or tri-substituted by one, two or three radicals selected from alkyl, alkoxy, aryl, hydroxy, halogen, cyano, amino, amino-alkyl, trifluoromethyl, alkylenedioxy and oxy-C2-C3-alkylene; all of which are optionally further substituted, for instance as hereinbefore defined; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Alkylenedioxy is a divalent substitute attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C2-C3-alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. An example for oxy- C2-C3-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.

[0307] Preferred as aryl is naphthyl, phenyl or phenyl mono- or disubstituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, especially phenyl or phenyl-mono- or disubstituted by alkoxy, halogen or trifluoromethyl, and in particular phenyl.

[0308] Examples of substituted phenyl groups as R are, e.g. 4-chlorophen-1-yl, 3,4-dichlorophen-1-yl, 4-methoxyphen-1-yl, 4-methylphen-1-yl, 4-aminomethylphen-1-yl, 4-methoxyethylaminomethylphen-1-yl, 4-hydroxyethylaminomethylphen-1-yl, 4-hydroxyethyl-(methyl)-aminomethylphen-1-yl, 3-aminomethylphen-1-yl, 4-N-acetylaminomethylphen-1-yl, 4-aminophen-1-yl, 3-aminophen-1-yl, 2-aminophen-1-yl, 4-phenyl-phen-1-yl, 4-(imidazol-1-yl)-phenyl, 4-(imidazol-1-ylmethyl)-phen-1-yl, 4-(morpholin-1-yl)-phen-1-yl, 4-(morpholin-1-ylmethyl)-phen-1-yl, 4-(2-methoxyethylaminomethyl)-phen-1-yl and 4-(pyrrolidin-1-ylmethyl)-phen-1-yl, 4-(thiophenyl)-phen-1-yl, 4-(3-thiophenyl)-phen-1-yl, 4-(4-methylpiperazin-1-yl)-phen-1-yl, and 4-(piperidinyl)-phenyl and 4-(pyridinyl)-phenyl optionally substituted in the heterocyclic ring.

[0309] As used herein, “arylene” refers to an aryl group, as defined above, linking at least two other groups. The two moieties linked to the arylene are linked to different atoms of the arylene. Arylene groups include, but are not limited to, phenylene.

[0310] As used herein, “arylene-oxy” refers to an arylene group, as defined above, where one of the moieties linked to the arylene is linked through an oxygen atom. Arylene-oxy groups include, but are not limited to, phenylene-oxy.

[0311] Similarly, substituents for the aryl and heteroaryl groups are varied and are 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, -N R’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, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where 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.

[0312] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR’- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)s-X-(CH2)t-, where s and t are independently integers of 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.

[0313] As used herein, “heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 4 of the ring atoms are a heteroatom each N, O or S. For example, heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, furanyl, pyrrolyl, thiazolyl, benzothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any other radicals substituted, especially mono- or di-substituted, by e.g. alkyl, nitro or halogen. Pyridyl represents 2-, 3- or 4-pyridyl, advantageously 2- or 3-pyridyl. Thienyl represents 2- or 3-thienyl. Quinolinyl represents preferably 2-, 3- or 4-quinolinyl. Isoquinolinyl represents preferably 1-, 3- or 4-isoquinolinyl. Benzopyranyl, benzothiopyranyl represents preferably 3-benzopyranyl or 3-benzothiopyranyl, respectively.Thiazolyl represents preferably 2- or 4-thiazolyl, and most preferred, 4-thiazolyl. Triazolyl is preferably 1-, 2- or 5-(1,2,4-triazolyl). Tetrazolyl is preferably 5-tetrazolyl.

[0314] Preferably, heteroaryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furanyl, benzothiazolyl, benzofuranyl, isoquinolinyl, benzothienyl, oxazolyl, indazolyl, or any of the radicals substituted, especially mono- or di-substituted.

[0315] The term “heteroalkyl” refers to an alkyl group having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms can also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms can also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. For example, heteroalkyl can include ethers, thioethers, alkyl-amines and alkyl-thiols.

[0316] The term “heteroalkylene” refers to a heteroalkyl group, as defined above, linking at least two other groups. The two moieties linked to the heteroalkylene can be linked to the same atom or different atoms of the heteroalkylene.

[0317] As used herein, “electrophile” refers to an ion or atom or collection of atoms, which may be ionic, having an electrophilic center, i.e., a center that is electron seeking, capable of reacting with a nucleophile. An electrophile (or electrophilic reagent) is a reagent that forms a bond to its reaction partner (the nucleophile) by accepting both bonding electrons from that reaction partner.

[0318] As used herein, “nucleophile” refers to an ion or atom or collection of atoms, which may be ionic, having a nucleophilic center, i.e., a center that is seeking an electrophilic center or capable of reacting with an electrophile. A nucleophile (or nucleophilic reagent) is a reagent that forms a bond to its reaction partner (the electrophile) by donating both bonding electrons. A “nucleophilic group” refers to a nucleophile after it has reacted with a reactive group. Non limiting examples include amino, hydroxyl, alkoxy, haloalkoxy and the like.

[0319] As used herein, “maleimido” refers to a pyrrole-2,5-dione-1-yl group having the structure: O

[0320] which upon reaction with a sulfhydryl (e.g., a thio alkyl) forms an -S-maleimido group having the structure indicates the point of attachment for the maleimido group and “ of the sulfur atom the thiol to the remainder of the originalsulfhydryl bearing group.

[0322] As used herein, “linear” in reference to the geometry, architecture or overall structure of a polymer, refers to polymer having a single polymer arm.

[0323] As used herein, “branched,” in reference to the geometry, architecture or overall structure of a polymer, refers to a polymer having 2 or more polymer “arms” extending from a core structure contained within an initiator. The initiator may be employed in an atom transfer radical polymerization (ATRP) reaction. A branched polymer may possess 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 is capable of being a site for the growth of a polymer chain by the addition of monomers. For example and not by way of limitation, using ATRP, the site of polymer initiation on an initiator is typically an organic halide undergoing a reversible redox process catalyzed by a transition metal compound such as cuprous halide. Preferably, the halide is a bromine.

[0324] As used herein, “OG1786” is a 9-arm initiator used for polymer synthesis with the structure shown in FIG. 26, which depicts that salt form of OG1786 with trifluoroacetic acid. OG1786 may be used in accordance with the present invention as other salts or as the free base.

[0325] As used herein, “OG1801” is an approximately (+ / - 15%) 750 kDa polymer (either by Mn or Mp) made using OG1786 as an initiator for ATRP synthesis using the monomer HEMA-PC. The structure of OG1801 is shown in FIG.27.

[0326] As used herein, “OG1802” is OG1801 with a maleimide functionality added, and it has the structure shown in FIG.28, wherein each of n1, n2, n3, n4, n5, n6, n7, n8 and n9 is an integer (positive) (from 0 up to about 3000) such that the total molecular weightof the polymer is (Mw) 750,000 ± 15% Daltons. When the term OG1802 is used to modify a protein term (such as trap-antibody fusion, trap-Fab fusion), it designates that the protein is the conjugate protein.

[0327] Multi-angle light scattering (MALS) is a technique of analyzing macromolecules where the laser light impinges on the molecule, the oscillating electric field of the light induces an oscillating dipole within it. This oscillating dipole will re-radiate light and can be measured using a MALS detector such as Wyatt miniDawn TREOS. The intensity of the radiated light depends on the magnitude of the dipole induced in the macromolecule which in turn is proportional to the polarizability of the macromolecule, the larger the induced dipole, and hence, the greater the intensity of the scattered light. Therefore, in order to analyze the scattering from a solution of such macromolecules, one should know their polarizability relative to the surrounding medium (e.g., the solvent). This may be determined from a measurement of the change, ǻn, of the solution's refractive index n with the molecular concentration change, ǻc, by measuring the dn / dc (=ǻn / ǻc) value using a Wyatt Optilab T- rEX differential refractometer. Two molar weight parameters that MALS determination employ are number average molecular weight (Mn) and weight average molecular weight (Mw) where the polydispersity index (PDI) equals Mw divided by Mn. SEC also allows another average molecular weight determination of the peak molecular weight Mp which is defined as the molecular weight of the highest peak at the SEC.

[0328] The PDI is used as a measure of the broadness of a molecular weight distribution of a polymer and bioconjugate which is derived from conjugation of a discrete protein to a polydisperse biopolymer (e.g., OG1802). For a protein sample, its polydispersity is close to 1.0 due to the fact that it is a product of translation where every protein molecule in a solution is expected to have almost the same length and molar mass. In contrast, due to the polydisperse nature of the biopolymer where the various length of polymer chains are synthesized during the polymerization process, it is very important to determine the PDI of the sample as one of its quality attribute for narrow distribution of molecular weight. As used herein, the term “biopolymer” denotes that a polymer has been linked to the protein of interest. The term can also be described as the “conjugated” form of the protein. This can be done for all of the proteins described herein. Thus, trap-antibody fusion biopolymers and trap-Fabfusion biopolymers are contemplated for all such trap-antibody and trap-Fab fusions provided herein.

[0329] Size exclusion chromatography (SEC) is a chromatography technique in which molecules in solution are separated by their size. Typically an aqueous solution is applied to transport the sample through the column which is packed with resins of various pore sizes. The resin is expected to be inert to the analyte when passing through the column and the analytes separate from each other based on their unique size and the pore size characteristics of the selected column.

[0330] Coupling the SEC with MALS or SEC / MALS provides accurate distribution of molar mass and size (root mean square radius) as opposed to relying on a set of SEC calibration standards. This type of arrangement has many advantages over traditional column calibration methods. Since the light scattering and concentration are measured for each eluting fraction, the molar mass and size can be determined independently of the elution position. This is particularly relevant for species with non-globular shaped macromolecules such as the biopolymers (OG1802) or bioconjugates; such species typically do not elute in a manner that might be described by a set of column calibration standards.

[0331] In some embodiments, a SEC / MALS analysis includes a Waters HPLC system with Alliance 2695 solvent delivery module and Waters 2996 Photodiole Array Detector equipped with a Shodex SEC-HPLC column (7.8x300mm). This is connected online with a Wyatt miniDawn TREOS and Wyatt Optilab T-rEX differential refractometer. The Empower software from Waters can be used to control the Waters HPLC system and the ASTRA V 6.1.7.16 software from Wyatt can be used to acquire the MALS data from the Wyatt miniDawn TREOS, dn / dc data from the T-rEX detector and the mass recovery data using the A280 absorbance signal from the Waters 2996 Photodiole Array detector. SEC can be carried out at 1mL / min in 1xPBS pH 7.4, upon sample injection, the MALS and RI (or UV) signals can be analyzed by the ASTRA software for determination of absolute molar mass (Mp, Mw, Mn) and polydisperse index (PDI). In addition, the calculation also involves the input dn / dc values for polymer and protein as 0.142 and 0.183, respectively. In some embodiments, for bioconjugates dn / dc value, the dn / dc is calculated based on the weighted MW of the polymer and the protein to be about 0.148 using the formula below:

[0332] Conjugate dn / dc = 0.142 x [ MWpolymer / (MWpolymer+MWprotein)]+ 0.183 x [MWprotein / (MWpolymer+MWprotein)]

[0333] where MWpolymer foris 352 kDa.

[0334] In some embodiments, the trap-antibody fusion is conjugated with a phosphorylcholine containing polymer. In some embodiments, the antibody is conjugated with a poly(acryloyloxyethyl phosphorylcholine) containing polymer, such as a polymer of acrylic acid containing at least one acryloyloxyethyl phosphorylcholine monomer such as 2- methacryloyloxyethyl phosphorylcholine (i.e., 2-methacryloyl-2'-trimethylammonium ethyl phosphate).

[0335] In some embodiments, the polymer is a water-soluble polymer, which refers to a polymer that is soluble in water. A solution of a water-soluble polymer may transmit at least about 75%, more preferably at least about 95% of light, transmitted by the same solution after filtering. On a weight basis, a water-soluble polymer or segment thereof may 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.

[0336] In some embodiments, the polymer has at least 2 or 3 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 peak molecular weight is between 300,000 and 1,750,000 Da. In some embodiments, the polymer has a peak molecular weight between 500,000 and 1,000,000 Da. In some embodiments, the polymer has a peak molecular weight between 600,000 to 800,000 Da.

[0337] In some embodiments, the polymer has a peak molecular weight between 300,000 and 1,750,000 Daltons as measured by size exclusion chromatography – multi angle light scattering (hereinafter “SEC-MALS”). In some embodiments, the polymer has a peak molecular weight between 500,000 and 1,000,000 Daltons as measured by SEC-MALS. In some embodiments, the polymer has a peak molecular weight between 600,000 to 800,000 Daltons as measured by SEC-MALS.

[0338] In accordance with another aspect of the present invention, provided are methods for synthesizing zwitterionic polymer-trap-antibody fusion conjugates, the conjugate having one or more functional agents and one or more polymer arms wherein each of thepolymer arms has one or more monomer units wherein at least one of the units has a zwitterion. For example, such a method can have the steps of: providing an initiator having one or more sites for monomer polymerization and a first linker having an amine group wherein the initiator is a trifluoro acetic acid salt; providing one or more monomers suitable for polymerization wherein at least one of the monomers is zwitterionic; reacting the monomers with the initiator to form one or more polymer arms each corresponding to the sites for monomer polymerization to provide an initiator-polymer conjugate having the first linker with the amine group; providing a second linker having at least second and third reactive groups; coupling one of the second and third reactive groups of the second linker to the amine group of the first linker of the initiator-polymer conjugate to provide a linker-initiator-polymer conjugate having one or more reactive groups that were not used in the coupling step; and coupling one or more functional agents to one or more of the unreacted reactive groups of the linker-initiator- polymer moiety to provide the polymer-functional agent conjugate.

[0339] In some embodiments, the conjugation group (e.g. maleimide) is added after polymer synthesis. This is sometimes referred to as a “snap-on strategy” or “universal polymer strategy”. See, e.g., U.S. Patent Application No. 14 / 916,180 (published as U.S. Patent Application Publication No. 20160199501), hereby incorporated by reference in its entirety. In some embodiments, a single initiator moiety can be used for large scale polymer synthesis. Thus, conditions can be developed for scaled up optimal polymer synthesis. Such polymers can then be adapted to various types of functional agents by “snapping-on” various types of linkers. For example, if it is desired to conjugate a larger functional agent to a polymer of the present invention such as an antibody of even a Fab fragment, a longer linker sequence can be snapped on to the polymer. In contrast, smaller functional agents may call for relatively shorter linker sequences.

[0340] In some embodiments of the methods, the initiator has about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 sites for polymer initiation. In some embodiments, the initiator has about 3, about 6, or about 9 sites for polymer initiation.

[0341] In accordance with another aspect of the present invention, a second linker has second, third, fourth, fifth, and sixth reactive groups. More preferably, a second linker has just second and third reactive groups.

[0342] In accordance with an aspect of the present disclosure, each polymer arm has from about 20 to about 2000 monomer units. Preferably, each arm has from about 100 to 500 monomer units or from about 500 to 1000 monomer units or from about 1000 to 1500 monomer units or from about 1500 to 2000 monomer units.

[0343] In accordance with an aspect of the present 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.

[0344] In accordance with another aspect of the present disclosure, the first linker is preferably alkyl, substituted alkyl, alkylene, alkoxy, carboxyalkyl, haloalkyl, cycloalkyl, cyclic alkyl ether, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkylene, heterocycloalkyl, heterocycloalkylene, aryl, arylene, arylene-oxy, heteroaryl, amino, amido or any combination thereof. More preferably, the first linker has the formula:(1)

[0346] wherein m is 1 to 10. In some embodiments, the first linker has the above formula (Formula (1)) and m is 4.

[0347] In some embodiments, the initiator preferably includes a structure selected from group consisting of(2)

[0351] wherein X is selected from the group consisting of NCS, F, Cl, Br and I. More preferably, X in Formula (2), Formula (3) and / or Formula (4) is Br.

[0352] In some embodiments, the monomer is selected from the group consisting ofFormula (5)(6)(7)(8), and

[0357] Formula (9)

[0358] wherein R7 is H or C1-6 alkyl and t is 1 to 6.

[0359] More preferably, the monomer is selected from the group consisting of 2-(methacryloyloxyethyl)-2’-(trimethylammoniumethyl) phosphate (HEMA-PC) and 2- (acryloyloxyethyl)-2’-(trimethylammoniumethyl) phosphate.

[0360] Most preferably, the monomer is 2-(methacryloyloxyethyl)-2’- (trimethylammoniumethyl) phosphate.

[0361] The second linker moiety preferably comprises an activated ester having the structure(10)

[0363] wherein R8 is selected from the group consisting of

[0366] wherein p is 1 to 12.

[0367] In more preferred embodiments of the present invention, the polymer has 9 arms, m is 2-4, R9 is

[0369] wherein p is 4 to 15. Still more preferably, m is 4 and p is 12.

[0370] In some embodiments, the radically polymerizable monomer is

[0371] Formula (12)

[0372] wherein R1 is H or C1-6 alkyl, R2, R3, R4 are the same or different and are H or C1-4alkyl and X and Y are the same or different and are integers from 1-6. In some embodiments, R1, R2, R3 and R4 are each methyl and X and Y are each 2 in Formula (12).

[0373] In some embodiments, the radically polymerizable monomer is(13)

[0375] wherein R1 is H or C1-6alkyl, R2 and R3 are the same or different and are H or C1-4alkyl, R4 is PO4-, SO3- or CO2- and X and Y are the same or different and are integers from 1-6. In some embodiments, R1, R2 and R3 are methyl, R4 is PO4- and X and Y are each 2 in Formula (13).

[0376] In some embodiments, the monomer is(14)

[0378] wherein R1 is H or C1-6alkyl, R2, R3 and R4 are the same or different and are H or C1-4alkyl, R5 is PO4-, SO3- or CO2- and X and Y are the same or different and are integers from 1-6. In some embodiments, R1, R2, R3 and R4 are methyl, R5 is PO4- and X and Y are 2 in Formula (14).

[0379] When a polymer is to be conjugated via a cysteine (or other specified residue), the polymer can be linked directly or indirectly to the residue (e.g., with an intervening initiator, and or spacer or the like).

[0380] In some embodiments, the phosphorylcholine containing polymer comprises 2-(methacryloyloxyethyl)-2'-(trimethylammonium)ethyl phosphate (MPC) monomers as set forth below:,

[0382] such that the polymer comprises the following repeating units:

[0384] where n is an integer from 1 to 3000 and the wavy lines indicate the points of attachment between monomer units in the polymer.

[0385] In some embodiments, the polymer has three or more arms, or is synthesized with an initiator comprising 3 or more polymer initiation sites. In some embodiments, the polymer has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 arms, or is synthesized with an initiator comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 polymer initiation sites. More preferably, the polymer has 3, 6, or 9 arms, or is synthesized with an initiator comprising 3, 6, or 9 polymer initiation sites. In some embodiments, the polymer has 9 arms, or is synthesized with an initiator comprising 9 polymer initiation sites.

[0386] In some embodiments, the polymer that is added has a molecular weight between about 300,000 and about 1,750,000 Da (SEC-MALs). In some embodiments, the polymer has a molecular weight between about 500,000 and about 1,000,000 Da. In some embodiments, the polymer has a molecular weight of between about 600,000 to about 900,000 Da. In some embodiments, the polymer has a molecular weight of between about 750,000 to about 850,000 Da. In some embodiments, the polymer has a molecular weight of between about 800,000 to about 850,000 Da. In some embodiments, the polymer has a molecular weight of between about 750,000 to about 800,000 Da.

[0387] In some embodiments, any of the trap-antibody fusions described herein can be further conjugated to a polymer to form a bioconjugate. The molecular weight of the bioconjugate (in total, SEC-MALs) can be between about 350,000 and 2,000,000 Daltons, forexample, between about 450,000 and 1,900,000 Daltons, between about 550,000 and 1,800,000 Daltons, between about 650,000 and 1,700,000 Daltons, between about 750,000 and 1,600,000 Daltons, between about 850,000 and 1,500,000 Daltons, between about 900,000 and 1,400,000 Daltons, between about 950,000 and 1,300,000 Daltons, between about 900,000 and 1,000,000 Daltons, between about 1,000,000 and 1,300,000 Daltons, between about 850,000 and 1,300,000 Daltons, between about 850,000 and 1,000,000 Daltons, and between about 1,000,000 and 1,200,000 Daltons. In some embodiments, the bioconjugate has a molecular weight between about 350,000 and 1,900,000 Daltons.

[0388] In some embodiments, the trap-antibody conjugate has the following structure:

[0390] wherein: each heavy chain of the trap-antibody is denoted by the letter H, and each light chain of the trap-antibody is denoted by the letter L ; the polymer is bonded tothe trap-antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains; PC is,line indicates the point of attachment to the rest of the polymer; wherein X is a) –OR where R is –H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and either 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 15%. 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, where R is a sugar, an aminoalkyl, mono-substituted, poly-substituted or unsubstituted variants of the following residues: saturated C1 -C24 alkyl, unsaturated C2 -C24 alkenyl or C2 -C24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl including polyhalogenated alkyl, --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 separately selected from the group consisting of a hydrogen atom, halogen atom, mono-substituted, poly-substituted or unsubstituted variants of the following residues: saturated C1- C24 alkyl, unsaturated C2 -C24 alkenyl or C2- C24 alkynyl, acyl, acyloxy, alkyloxycarbonyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, heteroaryl, arylalkoxy carbonyl, alkoxy carbonylacyl, amino, aminocarbonyl, aminocarboyloxy, nitro, azido, phenyl, hydroxy, alkylthio, arylthio, oxysulfonyl, carboxy, cyano, and halogenated alkyl including polyhalogenated alkyl, a 5- membered ring, and a 6-membered ring. In some embodiments, Formula 17 can be part of a fusion protein, which would further include some or all of the sequence of Tables 6 and 7, or any combination thereof, so as to make an IL-1 trap anti-HTRA1 fusion protein.

[0392] In some embodiments, the conjugate has the following structure:

[0394] wherein: each heavy chain of the trap-antibody fusion is denoted by the letter H, and each light chain of the trap-antibody fusion is denoted by the letter L; the polymer is bonded to the antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains; O CH3

[0395] PC i, where the curvy line indicates the point ofattachment to the rest a) –OR where R is –H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and either 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 15%. 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%.

[0396] In some embodiments, the conjugate has the structure of Formula (II):

[0398] “n.” is an integer from 1 to 50 and “n.i” is an integer from 1 to 50;

[0399] each heavy chain of the trap-antibody fusion is denoted by the letter H, and each light chain of the anti-HTRA1 antibody is denoted by the letter L; the polymer is bonded to the anti-HTRA1 antibody moiety through the sulfhydryl of C443 (EU numbering), which O CH3bond is depicted on one of the heavy chains; PCwhere the curvyline indicates the point of attachment to the rest of the polymer; wherein X is a) –OR where R is –H, Methyl, ethyl, propyl, isopropyl, b) H, or c) any halogen, including –Br, –Cl, or –I; and either i) n1, n2, n3, n4, n5, n6, n7, n8 and n9 are the same or different and are integers from 0to 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 15%.

[0400] In some embodiments, the polymers disclosed herein can comprise one or more of the following: a zwitterion, a phosphorylcholine, or a PEG linker bridging a center of a polymer branching point to the maleimide functional group. In some embodiments, any of the polymers provided herein can be added to a protein via the methods provided herein.

[0401] FIG. 25 is a table listing embodiments of medical indications for which administration of a trap-antibody or trap-Fab fusion may be suitable.

[0402] In some embodiments, the trap-antibody or trap-Fab fusion may be used to treat or in combination with treatment of an IL, IL-1, IL-6, IL-33, HTRA1 and / or VEGF related disorder. For example, in some embodiments the IL-1 trap anti-HTRA1 fusion may be used to treat or used in conjunction with a treatment for diabetic retinopathy, early, intermediate, advanced age-related macular degeneration (AMD), retinopathy of prematurity (ROP), dry AMD, geographic atrophy, exudative (neovascular, wet) AMD, polypoidal choroidal vasculopathy, inflammation of the eye, an HTRA1-related disorder, and / or an IL-1 related disorder. In some embodiments, a VEGF trap anti-IL6 fusion may be used to treat, or used in combination with a treatment for, scleritis, diabetic macular edema, diabetic retinopathy, wet age-related macular degeneration, uveitis, non-infectious uveitis, uveitic macular edema, cytokine release syndrome following CAR-T or similar immune-oncology therapeutics, abrogate the induction of IL-6 expression observed following treatment with anti-PD-1 / PD-L1 molecules. It could 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 benefits to anti-VEGF treatments, an IL-6 related disorder, and or a VEGF related disorder. In some embodiments, the trap-antibody or Fab fragment fusion may be used to treat a trap related disorder, an antibody related disorder, or both. In some embodiments, the trap-antibody or Fab fragment fusion may be used to treat inflammation of the eye. In some embodiments, the trap-antibody or Fab fragment fusion may be used to treat a TNFĮ related disorder.Numbered Arrangements:

[0403] Some embodiments provided herein are described by way of the following provided numbered arrangements and also provided as possible combinations or overlapping embodiments: 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the trap and 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 and antigen binding sites are located at separate positions 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and 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 whereinthe IL and antigen binding sites are located at separate positions 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and 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 fragment antigen-binding (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL accessory protein; a Fab; wherein the Fab comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 and antigen binding sites are located at separate positions on the trap-Fab fusion.5. A multivalent interleukin (IL) trap-Fab fusion, comprising: an IL trap and fragment antigen-binding (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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the VHH and 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 and antigen binding sites are located at separate 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the VHH and 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 whereinthe cytokine and antigen binding sites are located at separate 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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. 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light ch...

Claims

WHAT IS CLAIMED IS:

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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the trap and 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 and antigen binding sites are located at separate positions 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and 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 and antigen binding sites are located at separate positions 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and 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 fragment antigen-binding (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL accessory protein; a Fab; wherein the Fab comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 and antigen binding sites are located at separate positions on the trap-Fab fusion.

5. A multivalent interleukin (IL) trap-Fab fusion, comprising: an IL trap and fragment antigen-binding (Fab fragment), wherein whereinthe 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the VHH and 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 and antigen binding sites are located at separate 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the VHH and 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 and antigen binding sites are located at separate 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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.

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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL 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 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 can simultaneously bind 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 with a cytokine binding affinity of between about 0.01 pM and 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 with a cytokine binding affinity of between about 0.01 pM and 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 with a cytokine binding affinity of between about 0.01 pM and 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 with a cytokine binding affinity of between about 0.01 and 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 with an antigen binding affinity of between about 0.01 and 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 with a cytokine binding affinity of between 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 with a cytokine binding affinity of between about 0.01 and 100 pM and an antibody or Fab with an antigen binding affinity of between about 0.01 and 500pM.

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

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 TNFĮ 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 of any of the preceding claims, wherein the IL accessory protein is IL1RAcP.

32. The IL trap-antibody or trap-Fab fusion of any of the preceding claims, wherein the IL accessory protein is gp130(IL6RE).

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

34. The IL trap-antibody fusion of 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 of any of the preceding claims, wherein the trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-1 trap and an antibody that is an anti-HTRA1 antibody.

36. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap that is an IL-1 trap, wherein the IL-1 trap comprises IL1R1 and IL1RacP; and and an antibody that is an anti-HTRA1 antibody.

37. The IL trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap that 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; an antibody or Fab that 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 of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap that 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; an antibody that 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 of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap that 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 between about 0.01 and 100 pM; an antibody that is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of between about 0.01 and 500 pM.

40. The IL trap-antibody of any of the preceding claims, wherein the trap-antibody fusion comprises an IL trap that is an IL-33 trap and an antibody that 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 that is an IL-33 trap, wherein the IL-33 trap comprises ST2 and IL1RAcP; and and an antibody or Fab that 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 that is an IL-33 trap, whereinthe IL-33 trap comprises ST2 and IL1RAcP; wherein the IL-33 trap has an IL-33 binding affinity of less than about 1 nM; an antibody that 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 that 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 between about 0.01 and 100 pM; an antibody that 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 that 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 between about 0.01 and 100 pM; an antibody that is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of between about 0.01 and 500 pM.

45. The IL trap-antibody fusion of any of the preceding claims, wherein the trap- antibody or trap-Fab fusion comprise an IL trap that is an IL-6 trap and an antibody that 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 that is an IL-6 trap, wherein the IL-6 trap comprises gp130(IL6RE) and IL-6RD; and and an antibody that is an anti-HTRA1 antibody.

47. The IL trap-antibody fusion or trap-Fab of any of the preceding claims, whereinthe trap-antibody or trap-Fab fusion comprises an IL trap that is an IL-6 trap, wherein the IL-6 trap comprises gp130 (IL6Rb) and IL-6RD; wherein the IL-6 trap has an IL-6 binding affinity of less than about 1 nM; an antibody that 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 gp130(IL6RE) and IL-6RD; wherein the IL-6 trap has an IL-6 binding affinity of between about 0.01 and 500 pM; an antibody that is an anti-HTRA1 antibody; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of between about 5 and 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 gp130(IL-6RE) and IL-6RD; wherein the IL-6 trap has an IL-6 binding affinity of between about 0.01 and 100 pM ; an antibody that is an anti-HTRA1 antibody or Fab; wherein the anti-HTRA1 antibody has an HTRA1 binding affinity of between about 0.01 and 500 pM.

50. The IL trap-antibody fusion of any of the preceding claims, wherein a trap-antibody or trap-Fab fusion heavy chain comprises an IL receptor protein linked to an antibody VH; and a 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 a trap-antibody or trap-Fab fusion heavy chain comprises an IL receptor protein linked to an antibody VL; anda 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 of any of the preceding claims, wherein the trap-antibody or trap-Fab heavy chain and / or light chain comprises a linker that is a linker in SEQ ID NO.24-27.

54. 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 an antibody that 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 of any of the preceding claims, wherein the trap-antibody or trap-Fab light chain comprises a signal peptide selected from the group comprising: SEQ ID NO.16-23, and 72-73.

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

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

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

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

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

28.

61. The IL trap-antibody fusion of any of the preceding claims, wherein the trap- antibody fusion heavy chain comprises a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 38, a CH that is 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 that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 44, a CL that is 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 that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 44, a CL that is 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 that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 38, a CH that is SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 44, a CL that is 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 that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 38, a CH that is SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 44, a CL that is 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 that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 17, a trap that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 46; and the trap-Fab fusion light chain comprises a signal peptide that is SEQ ID No.: 18, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 1, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 46; and the trap-Fab fusion light chain comprises, a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

65.

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

65.

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

66.

75. The trap-antibody fusion of any of the preceding claims, wherein the trap- antibody fusion heavy chain comprises a trap that is SEQ ID No.: 2, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66.

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

29.

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

29.

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

29.

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

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

66.

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

29.

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

29.

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

29.

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

29.

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

64.

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

64.

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

29.

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

29.

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

29.

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

29.

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

29.

103. The trap-antibody fusion of any of the preceding claims, wherein the trap- antibody fusion heavy chain comprises a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap- antibody fusion light chain comprises a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29.

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

64.

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

64.

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

29.

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

29.

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

29.

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

29.

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

66.

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

29.

121. The trap-antibody fusion of any one of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 67, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

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

29.

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

29.

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

29.

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

29.

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

65.

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

29.

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

66.

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

66.

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

29.

139. The trap-antibody fusion of any one of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 68, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; andthe trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.:

64.

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

29.

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

29.

150. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29.

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

29.

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

29.

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

29.

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

29.

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

29.

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

29.

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

29.

158. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.:

65.

161. The trap-antibody fusion of any of the preceding claims, whereinthe trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; andthe trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 69, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

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

29.

173. The trap-antibody fusion of any of the preceding claims, wherein the trap- antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-Fab fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

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

29.

182. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29.

183. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 73, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

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

29.

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

29.

187. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 28; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29.

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

65.

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

65.

190. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; and the trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 70, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is 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 that is SEQ ID No.: 73, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 that is SEQ ID No.: 73, atrap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

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

29.

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

29.

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

64.

203. The trap-antibody fusion of any of the preceding claims, wherein the trap- antibody fusion heavy chain comprises a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is 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 a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29.

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

29.

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

29.

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

29.

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

29.

209. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; andthe trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 16, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

211. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a signal peptide that is SEQ ID No.: 16, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 64; and the trap-antibody fusion light chain comprises a signal peptide that is SEQ ID No.: 72, a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

29.

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

29.

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

29.

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

29.

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

65.

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

65.

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

29.

219. The trap-antibody fusion of any of the preceding claims, wherein the trap-antibody fusion heavy chain comprises a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 65; the trap-antibody fusion heavy chain comprises a VH that is SEQ ID No.: 30, a CH that is SEQ ID No.: 66; andthe trap-antibody fusion light chain comprises a trap that is SEQ ID No.: 71, a linker that is SEQ ID No.: 25, a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.:

29.

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

66.

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

66.

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

29.

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

29.

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

28.

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

28.

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

29.

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

29.

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

29.

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

29.

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

29.

231. The antibody fusion of any one of the preceding claims, wherein the antibody fusion light chain comprises a VL that is SEQ ID No.: 39, a CL that is SEQ ID No.: 29.

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

29.

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

29.

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

29.

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

28.

237. A conjugate comprising: any of the multivalent trap-antibody fusions of any one of the preceding claims; and a polymer, wherein the polymer is covalently attached 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; the IL trap comprises an IL receptor, and an IL accessory protein; wherein the IL trap and antibody 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 and antigen binding sites are located at separate 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 accessory protein; an antibody; wherein the antibody comprises a heavy chain variable region (VH) comprising 3 complementarity determining regions (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3; wherein the interleukin trap and 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; and whereinthe multivalent IL trap-antibody fusion is conjugated to a polymer.

240. A multivalent interleukin (IL) trap-Fab fusion, comprising: an IL trap and fragment antigen-binding (Fab fragment), wherein the IL trap comprises an IL receptor, and an IL accessory protein; the IL trap and 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 and antigen binding sites are located at separate 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 fragment antigen-binding (Fab fragment), wherein wherein the IL trap and 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 of any one 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 of any one of the preceding claims, wherein the trap-antibody or trap-Fab fusion does not comprise the transmembrane and / or cellular domain of the of the IL receptor protein.

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

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

245. The trap-antibody or trap-Fab fusion of any one of the preceding claims, wherein the trap-antibody or trap-Fab fusion does not comprise the transmembrane and / or cellular 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 (CDR): VH CDR1, VH CDR2, and VH CDR3; and a light chain variable region (VL) comprising a 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 cytokine trap-antibody fusion to a cytokine inhibits cytokine signaling; and 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 one of the preceding claims, wherein the VHH-antibody fusion is conjugated to a polymer.

248. The conjugate of any one 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, Hydroxy Alkyl Starch (HAS), Hydroxy Ethyl Starch (HES), Poly Ethylene Glycol (PEG), Poly (Glyx-Sery) (HAP), Hyaluronic acid (HA), Heparosan polymers (HEP), Fleximers, Dextran, Poly-sialic acids (PSA), Fc domains, Transferrin, 25 Albumin, Elastin like (ELP) peptides, XTEN polymers, PAS polymers, PA polymers, Albumin binding peptides, CTP peptides, and FcRn binding peptides.

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

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

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

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

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

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

257. The conjugate of any one of the preceding claims, wherein the polymer is covalently bonded to a sulfhydryl group from a cysteine residue on the IgG heavy chain.

258. The conjugate of any one 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 bonded to a sulfhydryl group from a cysteine residue at position 347 or 443 (EU numbering).

260. The conjugate of any one 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 between about 350,000 and 1,900,000 Daltons.

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

5.

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

263. The conjugate of any one of the preceding claims, which comprises the following structure:each heavy chain of the antibody is denoted by the letter H, and each light chain of the antibody is denoted by the letter L; the polymer is bonded to the trap-antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains; PC is ^, where the curvy line indicates the point of attachment to the rest of theX=a) OR where 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 of any one of the preceding claims, which comprises the following structure:each heavy chain of the antibody is denoted by the letter H, and each light chain of the antibody is denoted by the letter L; the polymer is bonded to the trap-antibody through the sulfhydryl of C443 (EU numbering), which bond is depicted on one of the heavy chains; PC is ^, where the curvy line indicates the point of attachment to the rest of theX=a) OR where 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 of any one of the preceding claims.

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

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

268. The trap-antibody fusion of any one of the preceding claims, wherein the antibody heavy chain arms are connected by knob-into-holes.

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