Potent asgpr-binding heterobifuctional compounds for the degradation of targeted extracellular proteins

Abstract

This invention provides extracellular protein degraders and compositions that have an asialoglycoprotein receptor (ASGPR) Binding Ligand bound to an Extracellular Protein Targeting Ligand for the selective degradation of the Target Extracellular Protein for example an immunoglobulin or other extracellular protein in vivo to treat disorders mediated by that protein.

Description

[0001] POTENT ASGPR-BINDING HETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF TARGETED EXTRACELLULAR PROTEINS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 645,075, filed May 9, 2024; U.S. Provisional Application No.63 / 645,078, filed May 9, 2024; U.S. Provisional Application No. 63 / 677,954, filed July 31, 2024; U.S. Provisional Application No. 63 / 760,990, filed February 20, 2025; and U.S. Provisional Application No.63 / 774,677, filed March 19, 2025. The entirety of each of these applications is hereby incorporated by reference for all purposes. FIELD OF THE INVENTION This invention provides extracellular protein degraders and compositions that have an asialoglycoprotein receptor (ASGPR) Binding Ligand bound to an Extracellular Protein Targeting Ligand for the selective degradation of the Target Extracellular Protein for example an immunoglobulin or other extracellular protein in vivo to treat disorders mediated by that protein. INCORPORATION BY REFERENCE The contents of the xml file named “19121-039WO1_st26” which was created on April 21, 2025, and is 1,384,448 bytes in size, are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION Historically, therapeutic strategies for the inhibition of proteins employed small molecule inhibitors which bound in an enzymatic pocket or at an allosteric position. Those proteins which are not enzymes are difficult to control, and some are considered “not druggable.” However, many non-enzymatic proteins remain valuable targets for drug discovery because of their role in signaling pathways. Immunoglobulins represent an important non-enzymatic drug target because of their role in signaling immune responses throughout the body. The asialoglycoprotein receptor (ASGPR) is a Ca2+-dependent lectin that is primarily expressed in parenchymal hepatocyte cells. The main role of ASGPR is to help regulate serum glycoprotein levels by mediating endocytosis of desialylated glycoproteins. The receptor binds ligands with a terminal galactose or N-acetylgalactosamine. Asialoglycoproteins bind to ASGPRs and are then cleared by receptor-mediated endocytosis. The receptor and the protein are dissociated in the acidic endosomal compartment and the protein is eventually degraded by lysosomes. Publications describing various utilizations of the ASGPR mechanism include: U.S. Patent Nos. 9,340,553; 9,617,293; 10,039,778; 10,376,531, and 10,813,942 assigned to Pfizer Inc.; Sanhueza et al. (JACS, 2017, 139, 3528); Petrov et al. (Bioorganic and Medicinal Chemistry Letters, 2018, 28, 382); WO 2018 / 223073 and WO2018 / 223081 assigned to Pfizer Inc. and Wave Life Sciences Ltd.; WO 2018 / 223056 assigned to Wave Sciences Ltd.; Schmidt et al. (Nucleic Acids Research, 2017, 45, 2294); Huang et al. (Bioconjugate Chem. 2017, 28, 283); WO 2019 / 199621, WO 2019 / 199634; Banik et al. (Nature, 2020, 584, 291); WO 2020 / 132100 assigned to The Board of Trustees of the Leland Stanford Junior University; WO 2021 / 072246, WO 2021 / 072269, WO 2021 / 142377 assigned to Lycia Therapeutics; WO 2022 / 192478, WO 2022 / 178425 assigned to Yale University; WO 2022 / 084331 assigned to Sanofi; WO2022 / 192478 assigned to Biohaven Therapeutics; and an article from the Bertozzi group titled “LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation,” (Ahn, et al. Nat. Chem. Biol. (2021)) published in the journal Nature Chemical Biology. Additional heterobifunctional compounds which utilize ASGPR-mediated endocytosis to degrade extracellular proteins are described in WO2021 / 155317, WO2022 / 235699, and WO2024 / 098039 filed by Avilar Therapeutics Inc. Avilar has disclosed heterobifunctional compounds which utilize mannose 6-phosphate receptor-mediated endocytosis to degrade extracellular proteins in WO2023 / 028338 and WO2024 / 182772. Avilar has also disclosed compounds in WO2022 / 035997 which assemble in vivo to form targeted protein degraders and compounds in WO2025 / 064721 which deliver oligonucleotides to the liver. While some progress has been made in the area of targeted degradation of extracellular proteins, there remains a need for additional therapeutic compounds and methods for their use and manufacture for the degradation of extracellular proteins to treat disorders mediated by those proteins. SUMMARY OF THE INVENTION Novel extracellular protein degraders and pharmaceutically acceptable salts and compositions thereof that degrade a Target Extracellular Protein, for example IgG, IgA, IL-17, ACPA, an anti-β1AR autoantibody, or other proteins as described below as well as starting materials and intermediates for such extracellular protein degraders and their methods of use and manufacture are provided. The extracellular protein degraders of the present invention contain an ASGPR Binding Ligand covalently attached by a Linker to an Extracellular Protein Targeting Ligand. The ASGPR Binding Ligands used in the degraders described herein include derivatives of six-carbon pyranose moieties, specifically galactose and talose. These two sugars, shown below, differ only in the stereochemistry of the C2substituent. The “down” C2configuration corresponds to the stereochemistry of galactose, while the C2substituent in the “up” configuration corresponds to the stereochemistry of talose. It has been discovered that certain substituents at the C2position of these two sugars improves the binding of the ligand to ASGPR. While traditional medicinal chemistry approaches to treat diseases associated with extracellular proteins have failed due to their extracellular circulation, size, and / or lack of active site, the extracellular protein degraders of the present invention can degrade a Target Extracellular Protein by trafficking the protein to the hepatocytes. In some embodiments, these compounds feature select ASGPR ligands that feature high binding affinity for ASGPR. As a result of this high ASGPR binding affinity, the extracellular protein degraders of the present invention may be administered in lower doses, have fewer side effects, decreased side effects, increased efficacy, faster therapeutic effect, longer metabolic stability, and / or longer therapeutic benefit than previously disclosed extracellular protein degraders. In certain aspects a compound of Formula I, Formula II, Formula III, or Formula IV is provided:

[0002] or a pharmaceutically acceptable salt thereof. In additional embodiments, the invention includes a compound of the structure of Formula IV: salt thereof; that can be used as a process intermediate. In these Formulas, the ASGPR Binding Ligand is selected from: R1, R1b, and R5are independently selected from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, and C0-C6alkylN3, each of which except hydrogen, F, Cl, and Br is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R99; wherein for Formula I, Formula II, and Formula III one of R1, R1b, and R5is replaced with a bond to LinkerA; and wherein for Formula IV one of R1, R1b, and R5is replaced with a bond to LinkerE; in certain embodiments R3, R3a, R3b, and R3care independently selected at each occurrence from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and - NR8R9; R6and R7are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl- NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is selected from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R42is selected from bond, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 alkynyl; R66is independently selected at each instance from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, and C0-C6alkylN3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R100; R67is C(O)R3or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R100; R75is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkylN3, heteroaryl, and aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; R77is selected from hydrogen, C2-C6alkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkylN3, heteroaryl, and aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; R78is selected from hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkylN3, heteroaryl, and aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; n and m are independently 0, 1, 2, 3, or 4, as allowed by valence; ii) 6-membered heterocycle substituted with one R1substituent and optionally substituted with n substituents independently selected from R75; -membered heteroaryl substituted with 1 R1substituent and optionally substituted with 1 or 2 substituents independently selected at each occurrence from R103; R99, R100, R102, and R103are independently selected at each instance from alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, -NR8R9, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR3, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, -C(O)OR3, -C(O)R3, and -SF5; LinkerAis a bond or a moiety that covalently links LinkerB, LinkerC, or LinkerDto the ASGPR Binding Ligand; LinkerBis a bond or a moiety that covalently links LinkerAto an Extracellular Protein Targeting Ligand; LinkerCis a chemical group that links each LinkerAto the Extracellular Protein Targeting Ligand; LinkerDis a chemical group that links each LinkerAto the Extracellular Protein Targeting Ligand; LinkerEis selected from R11, R12, R13, R14, R15, R16, R17, R18, and R19are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, a divalent residue of a natural or unnatural amino acid, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O- (CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, -[C(O)-CH2-O]n-, a divalent residue of a fatty acid, a divalent residue of an unsaturated or saturated mono- or di-carboxylic acid; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; and Extracellular Protein Targeting Ligand is a Ligand that binds to an extracellular protein. Each optional substituent is selected to avoid redundant groups as understood in the art. For example, alkyl substituted by alkyl is redundant whereas alkoxy substituted by alkoxy is not redundant. Thus, when R1is alkyl optionally substituted by R99, the optional R99substituent cannot be alkyl. In certain embodiments the Extracellular Protein Targeting Ligand is a ligand selected from Extracellular Protein Targeting LigandA. In certain embodiments the Extracellular Protein Targeting Ligand is a ligand selected from Extracellular Protein Targeting LigandB. In certain embodiments, L is selected from .In certain embodiments, L is selected from . In certain aspects the ASGPR Binding Ligand has galactose stereochemistry at the C2 position. For example, in certain embodiments the ASGPR Binding Ligand is selected from

[0003] or a pharmaceutically acceptable salt thereof. Non-limiting examples of ASGPR Binding Ligands with galactose stereochemistry include: , , , , , , , and ; Other examples of ASGPR Binding Ligands include: ,, , ,, and . Additional non-limiting examples of ASGPR Binding Ligands of the present invention include: , In certain aspects the ASGPR Binding Ligand has talose stereochemistry at the C2 position. For example, in certain embodiments the ASGPR Binding Ligand is selected from Additional non-limiting examples of ASGPR Binding Ligands of the present invention include: , In certain embodiments the ASGPR Binding Ligand is selected from: . In certain embodiments, the ASGPR Binding Ligand is a compound selected from , , ,

[0004] In certain embodiments, the ASGPR Binding Ligand is a compound selected from In some aspects of the invention, the Extracellular Protein Targeting Ligand targets an immunoglobulin, for example IgG, IgA, IgM, or IgE. The immunoglobulin degrading compounds described herein degrade a target immunoglobulin, for example IgG, IgA, IgM, or IgE, by linking a ligand for the selected immunoglobulin to a potent ASGPR binder through specific linking groups. In certain embodiments of the present invention, the selected immunoglobulin degrader degrades IgG. In certain aspects an immunoglobulin degrading compound of Formula I-A, Formula II-A, or Formula III-A is provided: or a pharmaceutically acceptable salt thereof; wherein: Immunoglobulin Targeting Ligand is a Ligand that binds to an immunoglobulin, for example IgG, IgA, IgM, or IgE. In certain aspects an IgG degrading compound of Formula I-B, Formula II-B, or Formula III-B is provided:

[0005] or a pharmaceutically acceptable salt thereof; wherein: IgG Targeting Ligand is a Ligand that binds to immunoglobulin G. In certain embodiments, the IgG Targeting Ligand binds an antibody to either a foreign antigen or an autologous antigen (i.e. an autoantibody). In certain embodiments, the IgG Targeting Ligand binds an autoantibody. The IgG Targeting Ligand can bind a certain subclass of IgG, including IgG1, IgG2, IgG3, and IgG4, or a combination thereof. For example a pan-IgG degrading compound could bind all subclasses of IgG. In certain embodiments, the IgG Targeting Ligand binds IgG1 and IgG2. In certain embodiments, the IgG Targeting Ligand binds IgG1, IgG2, and IgG4. In some aspects of the present invention an IgG degrader of the present invention uses a 2:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In other aspects of the present invention an IgG degrader of the present invention uses a 1:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In certain embodiments the IgG Targeting Ligand is a peptide. In certain embodiments, the peptide IgG Targeting Ligand is a cyclic or linear peptide. In certain embodiments, the peptide IgG Targeting Ligand comprises one or more, or is entirely D-amino acids. In certain embodiments, the peptide-based IgG targeting ligand is the peptide Fc- BP2. For example, an IgG Targeting Ligand of structure: .

[0006] In certain embodiments, the peptide-based IgG Targeting Ligand is the peptide Fc-III-4C. For example, an IgG targeting ligand of structure: . In certain embodiments, the peptide-based IgG Targeting Ligand is the peptide Fc-III. For example, an IgG targeting ligand of structure: , ,

[0007] In certain embodiments, these IgG degrading compounds have a small molecule or nonpeptidic IgG Targeting Ligand. Non-limiting examples of small molecule IgG Targeting Ligand include: . The selective targeting of IgG can be particularly beneficial when the present invention is used in the treatment of a disease known to be caused primarily by IgG, such as thyroid eye disease, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, warm autoimmune hemolytic anemia, and type-1 autoimmune pancreatitis. In certain embodiments a compound of the present invention which degrades IgG is used to treat a disorder selected from Graves’ eye disease, Graves’ ophthalmopathy, Graves’ orbitopathy, thyroid eye disease, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). In certain embodiments, a compound of the present invention which degrades IgG is used to treat a disorder selected from dilated cardiomyopathy, glaucoma, Postural orthostatic tachycardia syndrome (POTS), post-Covid syndrome, Duchenne’s muscular dystrophy (DMD), bronchial dysplasia, and Chagas’ heart disease. In certain aspects the treatment of a disorder mediated by IgG is provided comprising administering an effective amount of an IgG degrader or a pharmaceutically acceptable salt thereof to the patient. In certain embodiments the IgG disorder is selected from antiphospholipid Ab syndrome, Behcet syndrome, Hashimoto thyroiditis, MGUS, necrobiotic xanthogranuloma, rheumatoid arthritis, cancer, for example multiple myeloma or peripheral multiple myeloma, paraproteinemia, chronic urticaria, scleroderma, scleromyxedema, thrombocytopenia for example heparin-induced thrombocytopenia, cryoglobulinema, granulomatosis with polyanglititis, for example ANCA associated vasculitis, idiopathic thrombocytopenic purpura, thrombocytopenia, IgG4-RD, paroxysmal nocturnal hemoglobinuria (PNH), warm autoimmune hemolytic anemia, rhabdomyolysis, lupus nephritis, acute disseminated encephalomyelitis, Guillaine-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, Miller Fisher syndrome, neuromyelitis optica spectrum disorder, opsoclonus-myoclonus syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), peripheral neuropathy, transverse myelitis, fibrosis, IPF / fibrosis, and transplantation rejection. In some aspects of the present invention an IgA degrader uses a 2:1 ratio of ASGPR Binding Ligands to IgA Binding Ligand. In some aspects of the present invention an IgA degrader uses a 1:1 ratio of ASGPR Binding Ligands to IgA Binding Ligand. In certain embodiments the IgA degrader uses a peptide-based IgA targeting ligand, such as but not limited to OPT-1, OPT-2, or OPT-3. In certain embodiments, the peptide-based IgA targeting ligand is a cyclic peptide. In certain embodiments, the peptide-based IgA ligand is a stapled peptide. In certain embodiments, the peptide-based IgA ligand comprises one or more or is entirely D-amino acids.

[0008] In certain embodiments, the peptide-based IgA targeting ligand is OPT-1. For example, an IgA targeting ligand of structure: . In certain embodiments, the peptide-based IgA targeting ligand is OPT-2. For example, an IgA targeting ligand of structure: . In certain embodiments, the peptide-based IgA targeting ligand is OPT-3. For example, an IgA targeting ligand of structure: . In certain embodiments, the peptide-based IgA targeting ligand is . The selective targeting of IgA can be particularly beneficial when the present invention is used in the treatment of a disease known to be caused primarily by IgA, such as Henoch-Schönlein purpura, also known as IgA vasculitis. Additional disorders mediated by IgA include cryoglobulinemia, granulomatosis with polyangiitis, thrombocytopenia, peripheral neuropathy, MGUS, IgA nephropathy, and Henoch Schönlein purpura. An extracellular protein degrading compound described herein can be used to treat a disorder mediated by an immunoglobulin, for example IgG or IgA, including for example an autoimmune disorder, other immune dysfunction, abnormal cellular proliferation such as tumors and cancer, hematology-related disorder, renal disorder, allergic condition, or liver disorder. In certain embodiments, the autoimmune disorder is mediated by an autoantibody that can be degraded by the immunoglobulin degrader described herein. In certain aspects of the invention, a method for treating a disorder mediated by an immunoglobulin is provided that includes administering to a host in need thereof an effective amount of an immunoglobulin degrader described herein, or its pharmaceutically acceptable salt, prodrug, N-oxide, and / or a pharmaceutically acceptable composition thereof optionally in a pharmaceutically acceptable carrier. In certain embodiments the extracellular protein degrader of the present invention is provided as an isotopically enriched extracellular protein degrader, for example an immunoglobulin degrader, with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope. For example, deuterium can replace one or more hydrogens in the extracellular protein degrader and13C can replace one or more carbon atoms. In certain embodiments, the isotopic substitution is in one or more positions of the ASGPR Ligand. In another embodiment, the isotopic substitution is in one or more positions of the Linker portion of the molecule. In another embodiment, the isotopic substitution is in one or more positions of the Extracellular Protein Targeting Ligand portion of the molecule. In some embodiments, other extracellular proteins can be degraded as described further below. For example, in non-limiting illustrative embodiments, a selected Extracellular Protein described generally herein can be targeted, for example, where relevant, using a selected Targeting Ligand of Figures 1-7 or 9-10 or as otherwise known. The present invention thus includes at least the following features: (i) An extracellular protein degrader described herein or a pharmaceutically acceptable salt thereof, prodrug, N-oxide, and / or a pharmaceutical composition thereof as described herein; (ii) An extracellular protein degrader described herein for use in treating a medical disorder which is associated with the extracellular protein; (iii) An isotopically enriched derivative of an extracellular protein degrader described herein or pharmaceutically acceptable salt, prodrug, N-oxide, and / or a pharmaceutical composition thereof; (iv) A process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder mediated by an extracellular protein, characterized in that an extracellular protein degrader described herein is used in the manufacture; (v) An extracellular protein degrader described herein or a salt thereof as described herein in purified or substantially pure form (e.g., at least 90, 95, 96, 97, 98, 99, 99.5, or 99.9%); (vi) A method for the manufacture of an extracellular protein degrader described herein; (vii) An immunoglobulin degrader described herein or a pharmaceutically acceptable salt thereof, prodrug, N-oxide, and / or a pharmaceutical composition thereof as described herein; (viii) An immunoglobulin degrader described herein for use in treating a medical disorder which is associated with an immunoglobulin, such as an autoimmune disorder, other immune dysfunction, hematology-related disorder, renal disorder, allergic condition, or liver disorder; (ix) An isotopically enriched derivative of an immunoglobulin degrader described herein or pharmaceutically acceptable salt, prodrug, N-oxide, and / or a pharmaceutical composition thereof; (x) A process for manufacturing a medicament intended for the therapeutic use for treating or preventing a disorder mediated by an immunoglobulin, characterized in that an immunoglobulin degrader described herein is used in the manufacture; (xi) An immunoglobulin degrader described above or a salt thereof as described herein in purified or substantially pure form (e.g., at least 90, 95, 96, 97, 98, 99, 99.5, or 99.9%); and (xii) An ASGPR Binding Ligand described herein. BRIEF DESCRIPTION OF THE FIGURES The Extracellular Protein Targeting Ligand (“EPTL”) is covalently bound to Linker in the ASGPR-binding extracellular protein degrader compound through the Anchor Bond (which is the chemical bond between the EPTL and either Linker B, Linker C or Linker D). This bond can be placed at any location on the ligand that does not unacceptably disrupt the ability of the EPTL to bind to the Target Extracellular Protein. The Anchor Bond is depicted on the nonlimiting examples of Extracellular Protein Targeting Ligands in the figures as: FIG.1A provides a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-1 (IL-1). FIG.1B-1F provide a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-2 (IL-2). FIG.1G-1J provide a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-6 (IL-6). FIG.1K and 1L provide a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-5 (IL-5). FIG.1M provides a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-8 (IL-8). FIG.1N and 1O provide a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-10 (IL-10). FIG.1P and 1Q provide a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-21 (IL-21). FIG.1R and 1S provide a non-limiting list of Extracellular Protein Targeting Ligands that target Interleukin-22 (IL-22). FIG. 1T-1X provide a non-limiting list of Extracellular Protein Targeting Ligands that target Kallikrein 1. FIG.1Y provides a non-limiting list of Extracellular Protein Targeting Ligands that target Immunoglobulin A (IgA). FIG.1Z provides a non-limiting list of Extracellular Protein Targeting Ligands that target Immunoglobulin G (IgG). FIG.1AA-1EE provide a non-limiting list of Extracellular Protein Targeting Ligands that target Immunoglobulin E (IgE). FIG.1FF-1PP provide a non-limiting list of Extracellular Protein Targeting Ligands that target Macrophage migration inhibitory factor (MIF), also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase. FIG.2 provides non-limiting examples of formulas of the present invention. DETAILED DESCRIPTION OF THE INVENTION Novel extracellular protein degraders and their pharmaceutically acceptable salts and compositions thereof that degrade a Target Extracellular Protein, for example IgG, as well as starting materials and intermediates for such extracellular protein degraders and their methods of use and manufacture are provided. These extracellular protein degraders are highly potent binders of both ASGPR and their respective extracellular protein targets. Some of the extracellular protein degraders of the present invention use high binding ASGPR Binding Ligands. This increased binding affinity for ASGPR results extracellular protein degraders with various advantages over previously known extracellular protein degraders. For example, in certain embodiments an extracellular protein degrader of the present invention can be dosed at a lower dose, less frequently, with less side effects, and / or with increased potency when compared to other extracellular protein degraders. In some embodiments, an extracellular protein degrader that incorporates one of the high binding ASGPR ligands as described herein can be sufficiently active in the form of a monodentate compound (i.e., 1:1 extracellular protein ligand to ASGPR ligand in the therapeutic molecule). Other extracellular protein degraders described herein use ASGPR Binding Ligands with improved properties for medical treatment, for example improved selectivity, pharmacokinetics, pharmacodynamics, solubility, fewer side effects and / or improved tolerability. In certain embodiments, the extracellular protein degrading compound degrades an immunoglobulin. The immunoglobulin degraders described herein degrade a selected immunoglobulin by covalently binding a ligand of the selected immunoglobulin to a potent ASGPR binder through selected linking groups. The immunoglobulins that can be targeted according to the present invention include but are not limited to IgA, IgG, IgD, IgE, and IgM, and mutants thereof. In certain aspects of the present invention the selected immunoglobulin degrader degrades IgG. In certain aspects the compound of the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: , , ,

[0009] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: , ,

[0010] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: , , ,

[0011] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: or a pharmaceutically acceptable salt thereof. In other aspects the compound of the present invention is a compound of Formula II: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula II: ,

[0012] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula:

[0013] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula:

[0014] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula: , , ,

[0015] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof.

[0017] In certain embodiments, the compound of the present invention is a compound of Formula:

[0018] or a pharmaceutically acceptable salt thereof, Additional non-limiting examples of ASGPR Binding Ligands include:

[0019] In certain aspects an extracellular protein degrading compound of Formula I-X, Formula II-X, or Formula III-X is provided:

[0020] or a pharmaceutically acceptable salt thereof; wherein the ASGPR Binding LigandBis selected from:

[0021] or ASGPR Binding LigandBis selected from: or ASGPR Binding R1, R1b, and R5are independently selected from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, and C0-C6alkylN3, each of which except hydrogen, F, Cl, and Br is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R99; R1cis selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C(O)R3, -S(O)R3, -C(S)R3, and -S(O)2R3; wherein one of R1, R1b, R1c, and R5is replaced with a bond to LinkerA; Lis selected from L2 is selected from R3, R3a, R3b, R3c, and R3dare independently selected at each occurrence from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R4ais selected from hydrogen, alkyl, haloalkyl, and halogen; R4bis selected from hydrogen, alkyl, haloalkyl, halogen, C0-C6alkyl-OR6, C0-C6alkyl-SR6, and C0-C6alkyl-NR6R7; R6and R7are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl- NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is selected from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R42is selected from bond, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 alkynyl; R23Bis selected from bond, , C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 alkynyl; R65, R66, and R67Bare independently selected at each instance from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, and C0-C6alkylN3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R100; R75B, R76B, R77B, R78B, and R79are independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0- C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0- C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkyl-CN, C0-C6alkyl-N3, heteroaryl, and aryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; n, m, and p are independently 0, 1, 2, 3, or 4, as allowed by valence; or 3; heteroaryl; phenyl; is aryl, heterocycle, cycloalkyl, or heteroaryl; is aryl, heterocycle, cycloalkyl, bicycle, or heteroaryl; aryl or heteroaryl; is a bicycle or spirocycle; non-limiting examples of include , X is CH, CR75B, or N; Y is CH, CR75B, or N; Z is selected from -O-, -NR6-, -S-, -S(O)-, -S(O)2-, and -CR3aR3b-; and R99, R100, and R102are independently selected at each instance from alkyl (including C1- C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, -NR8R9, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR3, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, -C(O)OR3, -C(O)R3, and -SF5 wherein the optional substituent is selected such that a stable compound results. In certain embodiments, the ASGPR Binding LigandBis selected from:

[0022] In certain aspects of the invention the ASGPR Binding Ligand or ASGPR Binding LigandBhas galactose stereochemistry at the C2 position. In other aspects of the invention the ASGPR Binding Ligand or ASGPR Binding LigandBhas talose stereochemistry at the C2 position. Several structures are drawn herein which do not depict stereochemistry at the C2 position for convenience. For each of these structures in addition to the structure without stereochemistry assigned at the C2 position the galactose, talose, and racemic version of the structure is also contemplated herein. In certain embodiments the ASGPR Binding Ligand or ASGPR Binding LigandBhas galactose stereochemistry at the C2 position. In other embodiments the ASGPR Binding Ligand or ASGPR Binding LigandBhas talose stereochemistry at the C2 position. In certain embodiments ASGPR Binding LigandBis selected from: .In certain embodiments ASGPR Binding LigandBis selected from:

[0023] In certain embodiments ASGPR Binding LigandBis selected from: . In certain embodiments ASGPR Binding LigandBis selected from: . In certain embodiments, the ASGPR Binding LigandBis selected from: . In certain embodiments, the ASGPR Binding LigandBis selected from: , In certain embodiments, the ASGPR Binding LigandBis selected from:

[0024] In certain embodiments, the ASGPR Binding LigandBis selected from:

[0025] In certain embodiments, the ASGPR Binding LigandBis selected from: In certain embodiments, the ASGPR Binding LigandBis selected from: In certain embodiments ASGPR Binding LigandBis a compound selected from: . In certain embodiments, the ASGPR Binding LigandBis a compound selected from:

[0026] . Non-limiting examples of ASGPR Binding LigandBinclude:

[0027] In certain embodiments, the ASGPR Binding LigandBis selected from: . In certain embodiments, the ASGPR Binding LigandBis selected from:

[0028] ,

[0029] In certain embodiments, ASGPR Binding LigandBis selected from

[0030] In certain embodiments, ASGPR Binding LigandBis selected from

[0031] . In certain embodiments, ASGPR Binding LigandBis selected from In certain embodiments, ASGPR Binding LigandBis selected from In certain embodiments, ASGPR Binding LigandBis selected from

[0032] Other examples of ASGPR Binding LigandBinclude Non-limiting examples of ASGPR Binding LigandBinclude:

[0033] . Additional non-limiting examples of ASGPR Binding LigandBinclude:

[0034] . In certain embodiments, the ASGPR Binding LigandBis selected from: In certain embodiments, the ASGPR Binding In certain embodiments, the ASGPR Binding LigandBis selected from:

[0035] In certain embodiments, the ASGPR Binding LigandBis selected from Non-limiting examples of ASGPR Binding LigandBinclude:

[0036] In certain embodiments, the ASGPR Binding LigandBis selected from:

[0037] . In certain embodiments, the ASGPR Binding LigandBis selected from:

[0038] In certain embodiments, ASGPR Binding LigandBis selected from: In certain embodiments, ASGPR Binding LigandBis selected from: , , . In certain embodiments, ASGPR Binding LigandBis selected from: , , . In certain embodiments, ASGPR Binding LigandBis selected from:

[0039] . In certain embodiments, ASGPR Binding LigandBis selected from: , , . In certain embodiments, ASGPR Binding LigandBis selected from: . In other aspects ASGPR Binding LigandBis selected from: , In certain embodiments ASGPR Binding LigandBis a compound selected from:

[0040] . In certain embodiments ASGPR Binding LigandBis a compound selected from: In certain embodiments ASGPR Binding LigandBis a compound selected from: . In certain embodiments ASGPR Binding LigandBis a compound selected from: . In certain embodiments ASGPR Binding LigandBis a compound selected from: . In certain embodiments ASGPR Binding LigandBis a compound selected from: . In certain embodiments ASGPR Binding LigandBis a compound selected from: . In an alternative aspect, ASGPR Binding LigandBis a compound selected from: , , , . In other embodiments ASGPR Binding LigandBis selected from: Non-limiting examples of ASGPR Binding LigandBinclude: , , . In certain embodiments, ASGPR Binding LigandBis selected from: In other embodiments, the ASGPR Binding Ligand or ASGPR Binding LigandBis selected from: In alternative embodiments, the ASGPR Binding Ligand or ASGPR Binding LigandBis selected from: . In alternative embodiments, the ASGPR Binding Ligand or ASGPR Binding LigandBis selected from:

[0041] In other embodiments, the ASGPR Binding Ligand or ASGPR Binding LigandBis selected from: In alternative embodiments, the ASGPR Binding Ligand or ASGPR Binding LigandBis selected from: . In alternative embodiments, the ASGPR Binding Ligand or ASGPR Binding LigandBis selected from: In other embodiments, the ASGPR Binding LigandBis selected from: . In other embodiments, the ASGPR Binding LigandBis selected from: In other embodiments, the ASGPR Binding LigandBis selected from:

[0042] In other embodiments, the ASGPR Binding LigandBis selected from: In alternative embodiments the ASGPR Binding Ligand is selected from:

[0043] iii) heterocycle substituted with one R1substituent and optionally substituted with n substituents independently selected from R75; cycloalkyl; aryl or heteroaryl; and wherein all other variables are as defined herein. In certain embodiments, heteroaryl is a 6-membered heteroaryl, for example a nitrogen containing 6-membered heteroaryl. In certain embodiments, heteroaryl is a 5-membered heteroaryl. In certain embodiments, the 5-membered heteroaryl contains one nitrogen atom. In certain embodiments, the 5-membered heteroaryl contains two nitrogen atoms. In certain embodiments, the 5-membered heteroaryl contains one nitrogen atom and one oxygen atom. In certain embodiments, the 5-membered heteroaryl contains two nitrogen atoms and one oxygen atom. In certain embodiments, the 5- membered heteroaryl contains one nitrogen atom and one sulfur atom. In certain embodiments, the 5-membered heteroaryl contains two nitrogen atoms and one sulfur atom. In certain embodiments, the 5-membered heteroaryl contains three nitrogen atoms. In certain embodiments, heteroaryl is selected from pyridine, pyrimidine, pyrazine, and pyridazine. In certain embodiments, heteroaryl is selected from the group consisting of: . In certain embodiments heteroaryl is selected from the group consisting of , In certain embodiments heteroaryl is selected from the group consisting of: . In certain embodiments the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is selected from: or a pharmaceutically acceptable salt thereof. In certain embodiments, the protein degrading compound of the invention is:

[0044] or a pharmaceutically acceptable salt thereof. In certain embodiments, the protein degrading compound of the invention is:

[0045] or a pharmaceutically acceptable salt thereof. In certain embodiments, the protein degrading compound of the invention is:

[0046] or a pharmaceutically acceptable salt thereof. In certain embodiments, the protein degrading compound of the invention is:

[0047] or a pharmaceutically acceptable salt thereof. In certain embodiments, the protein degrading compound of the invention is:

[0048] pharmaceutically acceptable salt thereof. In certain embodiments, . In certain embodiments, . In certain embodiments, . In certain embodiments, .

[0049] In certain embodiments, . In certain embodiments, . In certain embodiments, . In certain aspects the compound of the present invention is a compound of Formula I:

[0050] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I:

[0051] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I:

[0052] or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I

[0053] or a pharmaceutically acceptable salt thereof. In other aspects the compound of the present invention is a compound of Formula II: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula II:

[0054] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula:

[0055] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula:

[0056] or a pharmaceutically acceptable salt thereof. COMPOUND TERMINOLOGY Extracellular protein degraders are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All of the extracellular protein degraders described herein include independently the enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and / or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The present invention includes extracellular protein degraders with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Examples of isotopes that can be incorporated into extracellular protein degraders, of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,14C,15N,17O,18O,18F31P,32P,35S,36Cl, and125I respectively. In certain embodiments, isotopically labelled into extracellular protein degraders can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Isotopically labeled into extracellular protein degraders of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by using a readily available isotopically labeled reagent instead of a non-isotopically labeled reagent. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may optionally be used anywhere in described structures that achieves the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In certain embodiments, the isotopic substitution is accomplished by replacing hydrogen with a deuterium at one or more locations on the molecule to improve the performance of the drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in a location of bond breakage during metabolism (an α-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a β-deuterium kinetic isotope effect). Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial isotopic substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 80, 85, 90, 95 or 99% or more enriched in an isotope at any location of interest. In certain embodiments deuterium is 80, 85, 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance, and in an embodiment is enough to alter a detectable property of the drug in a human. The extracellular protein degraders of the present invention may form a solvate with solvents (including water). Therefore, in certain embodiments, the invention includes a solvated form of the active extracellular protein degrader. The term "solvate" refers to a molecular complex of an extracellular protein degrader of the present invention (including a salt thereof) with one or more solvent molecules. Nonlimiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising an extracellular protein degrader of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO. A solvate can be in a liquid or solid form. A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, implant, and the like. “Pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. The present invention includes pharmaceutical compositions of the described extracellular protein degraders. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms. A “pharmaceutically acceptable salt” is a derivative of the disclosed extracellular protein degrader in which the parent extracellular protein degrader is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present extracellular protein degraders can be synthesized from a parent extracellular protein degrader that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these extracellular protein degraders with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these extracellular protein degraders with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Salts of the present extracellular protein degraders further include solvates of the extracellular protein degraders and of the extracellular protein degrader salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts which are acceptable for human consumption and the quaternary ammonium salts of the parent extracellular protein degrader formed, for example, from inorganic or organic acids. Examples, of such salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)1-4- COOH, and the like, or using an acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). The term “carrier” applied to pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle with which an active extracellular protein degrader is provided. A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition / combination that is generally safe, acceptable for human consumption, and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In certain embodiments, an excipient is used that is acceptable for veterinary use. A “patient” or “host” or “subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein. Typically, the host, patient, or subject is a human. A “patient” or “host” or “subject” also refers to for example, a mammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mice, bird, and the like. A “therapeutically effective amount” of an extracellular protein degrader, pharmaceutical composition, or combination of this invention means an amount that when administered to a host provides a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom occurs within any variable group. For example, when any variable group is, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in nonlimiting embodiments, CDH2, CD2H, CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). In certain other embodiments, a variable group has a “ ‘ “ or an “a” designation, which in certain embodiments can be deuterated. The term “immunoglobulin,” typically refers to a large Y-shaped protein (e.g. an antibody) that identifies and neutralizes a foreign compound or object such as a pathogen or disease tissue. Non-limiting examples of immunoglobulin proteins include IgA, IgD, IgE, IgG, and IgM. An immunoglobulin as used herein may also include a binding fragment as known to the skilled worker. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2 is attached through carbon of the keto (C=O) group. The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded and the resulting compound is stable. The term “percent (%) identity”, “percent (%) homology”, “percent (%) homologous to” “sequence identity”, “sequence homology”, “percent sequence identity”, “percent sequence homology”, “percent identical” or the like in the context of nucleic acid sequences or amino acid sequences refers to the residues in the two sequences which are the same when aligned for correspondence. As provided herein, the terms “homology,” “homologous,” “identity,” “identical,” and the like are used interchangeably to indicate similarity between two sequences. Percent sequence homology or identity is calculated by determining the number of matched positions in aligned sequences, dividing the number of matched positions by the length of an aligned sequence, and multiplying by 100. A matched position refers to a position in which identical amino acids or nucleic acids occur at the same position in aligned sequences. Unless otherwise specified, it is to be understood that a percentage of identity is a minimum level of identity and encompasses all higher levels of identity up to 100% identity to the reference sequence. For example, “95% identity” and “at least 95% identity” may be used interchangeably and include 95, 96, 97, 98, 99 up to 100% identity to the referenced sequence, and all fractions therebetween. The length of sequence identity comparison may be over the full-length of an amino acid sequence or a fragment of an amino acid sequence. Generally, when referring to “identity”, “homology”, or “similarity” between two different sequences, “identity”, “homology” or “similarity” is determined in reference to “aligned” sequences. “Aligned” sequences or “alignments” refer to more than one nucleic acid sequences or amino acid sequences, often containing corrections for missing or additional bases or amino acids as compared to a reference sequence. Multiple sequence alignment programs are also available for nucleic acid sequences and amino acid sequences. Examples of such programs include, “Clustal Omega”, “Clustal W”, “CAP Sequence Assembly”, “BLAST”, “MAP”, and “MEME”, which are accessible through Web Servers on the internet. Other sources for such programs are known to those skilled in the art. The percent sequence identity between a particular nucleic acid or amino acid sequence and a sequence referenced by a particular sequence homology or identification number (e.g., SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, etc.) can be determined as follows. First, a nucleic acid or amino acid sequence is compared to the sequence set forth in a particular sequence identification number using the BLAST 2 Sequences (Bl2seq) program from the stand-alone version of BLASTZ containing BLASTN version 2.0.14 and BLASTP version 2.0.14. This stand-alone version of BLASTZ can be obtained online at fr.com / blast or at ncbi.nlm.nih.gov. Instructions explaining how to use the Bl2seq program can be found in the readme file accompanying BLASTZ. Bl2seq performs a comparison between two sequences using either the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. Once aligned, the number of matches is determined by counting the number of positions where an identical nucleotide or amino acid residue is presented in both sequences. The percent sequence identity is determined by dividing the number of matches by the length of the sequence set forth in the identified sequence (e.g., SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, etc.), followed by multiplying the resulting value by 100. “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group. In certain embodiments, the alkyl contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, from 1 to about 4 carbon atoms, or from 1 to 3 carbon atoms. In certain embodiments, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5or C1-C6.The specified ranges as used herein indicate an alkyl group which is considered to explicitly disclose as individual species each member of the range described as a unique species. For example, the term C1-C6 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and also a carbocyclic alkyl group of 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C0-Cn alkyl is used herein in conjunction with another group, for example, (C3-C7cycloalkyl)C0-C4 alkyl, or –C0-C4alkyl(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms as in –O-C0-C4alkyl(C3-C7cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and hexyl. When a term is used that includes “alk” it should be understood that “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenloxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. “Alkenyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain. Nonlimiting examples are C2-C8alkenyl, C2-C7alkenyl, C2-C6alkenyl, C2-C5alkenyl and C2-C4alkenyl. The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2- C8alkynyl or C2-C6alkynyl. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl. “Alkoxy” is an alkyl group as defined above covalently bound through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly an “alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In certain embodiments, the alkoxy group is optionally substituted as described above. “Haloalkyl” indicates both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2- fluoroethyl, and penta-fluoroethyl. “Aryl" indicates an aromatic group containing only carbon in the aromatic ring or rings. In certain embodiments, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. The term “aryl” includes groups where a saturated or partially unsaturated carbocycle group is fused with an aromatic ring. The term “aryl” also includes groups where a saturated or partially unsaturated heterocycle group is fused with an aromatic ring so long as the attachment point is the aromatic ring. Such compounds may include aryl rings fused to a 4 to 7 or a 5 to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2 or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In certain embodiments, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. The term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, and O. The term “heterocycle” includes monocyclic 3-12 membered rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro, bicyclic ring systems). It does not include rings containing - O-O- or -S-S- portions. Examples of saturated heterocycle groups include saturated 4- to 7- membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4 to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4- tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a- hexahydro-lH-3-aza-fluorenyl, 5,6,7- trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H- benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3- dihydro-lH-lλ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. “Bicyclic heterocycle” includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. “Bicyclic heterocycle” also includes heterocyclic radicals that are fused or bridged with a carbocycle radical. For example partially unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms. Non-limiting examples of bicyclic heterocycles include: Unless otherwise drawn or clear from the context, the term “bicyclic heterocycle” includes cis and trans diastereomers. Non-limiting examples of chiral bicyclic heterocycles include: In certain alternative embodiments the term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, O, B, Si, and P. “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O, S, B or P with remaining ring atoms being carbon. In certain embodiments, the only heteroatom is nitrogen. In certain embodiments, the only heteroatom is oxygen. In certain embodiments, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 or 6 ring atoms. In some embodiments bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is, groups containing 8 or 10 ring atoms in which one 5, 6, or 7-member aromatic ring is fused to a second aromatic or non-aromatic ring wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, tetrahydrofuranyl, and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. “Heteroaryloxy” is a heteroaryl group as described bound to the group it substituted via an oxygen, -O-, linker. “Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein. “Arylalkyl” is an alkyl group as described herein substituted with an aryl group as described herein. “Heterocycloalkyl” is an alkyl group as described herein substituted with a heterocyclo group as described herein. In certain embodiments, when compounds are “optionally substituted” they may be substituted as allowed by valence by groups selected from alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, cyano, nitro, C(O)R3, wherein the optional substituent is selected such that a stable compound results. For example could be substituted with 1 or 2 groups independently selected from alkyl, alkenyl, alkynyl, haloalkyl, -OR6, F, Cl, Br, I, -NR6R7, cyano, nitro, C(O)R3so long as a stable compound results but only one group selected from , , , , so long as a stable compound results. on the other hand could only be substituted with 1 or 2 groups selected from . Non-limiting examples of optionally substituted CH2groups include: Non-limiting examples of optionally substituted -S- groups include: Embodiments of “alkyl” In certain embodiments “alkyl” is a C1-C10alkyl, C1-C9alkyl, C1-C8alkyl, C1-C7alkyl, C1-C6alkyl, C1-C5alkyl, C1-C4alkyl, C1-C3alkyl, or C1-C2alkyl. In certain embodiments “alkyl” has one carbon. In certain embodiments “alkyl” has two carbons. In certain embodiments “alkyl” has three carbons. In certain embodiments “alkyl” has four carbons. In certain embodiments “alkyl” has five carbons. In certain embodiments “alkyl” has six carbons. Non-limiting examples of “alkyl” include: methyl, ethyl, propyl, butyl, pentyl, and hexyl. Additional non-limiting examples of “alkyl” include: isopropyl, isobutyl, isopentyl, and isohexyl. Additional non-limiting examples of “alkyl” include: sec-butyl, sec-pentyl, and sec-hexyl. Additional non-limiting examples of “alkyl” include: tert-butyl, tert-pentyl, and tert-hexyl. Additional non-limiting examples of “alkyl” include: neopentyl, 3-pentyl, and active pentyl. In an alternative embodiment the “alkyl” group is optionally substituted. In an alternative embodiment the “alkenyl” group is optionally substituted. In an alternative embodiment the “alkynyl” group is optionally substituted. Embodiments of “haloalkyl” In certain embodiments “haloalkyl” is a C1-C10haloalkyl, C1-C9haloalkyl, C1-C8haloalkyl, C1-C7haloalkyl, C1-C6haloalkyl, C1-C5haloalkyl, C1-C4haloalkyl, C1-C3haloalkyl, and C1- C2haloalkyl. In certain embodiments “haloalkyl” has one carbon. In certain embodiments “haloalkyl” has one carbon and one halogen. In certain embodiments “haloalkyl” has one carbon and two halogens. In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. In certain embodiments “haloalkyl” has three carbons. In certain embodiments “haloalkyl” has four carbons. In certain embodiments “haloalkyl” has five carbons. In certain embodiments “haloalkyl” has six carbons. Non-limiting examples of “haloalkyl” include: , , . Additional non-limiting examples of “haloalkyl” include: Additional non-limiting examples of “haloalkyl” include: . Additional non-limiting examples of “haloalkyl” include: , , and . Embodiments of “heteroaryl” Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: In certain embodiments “heteroaryl” is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl). Non-limiting examples of 6 membered “heteroaryl” groups with 1 or 2 nitrogen atoms include: , In certain embodiments “heteroaryl” is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . In certain embodiments “heteroaryl” is azaindole or benzimidazole. In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: Embodiments of “heterocycle” In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms. In certain embodiments “heterocycle” refers to a cyclic ring with one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms. Non-limiting examples of “heterocycle” include aziridine, oxirane, thiirane, azetidine, 1,3- diazetidine, oxetane, and thietane. Additional non-limiting examples of “heterocycle” include pyrrolidine, 3-pyrroline, 2- pyrroline, pyrazolidine, and imidazolidine. Additional non-limiting examples of “heterocycle” include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane. Additional non-limiting examples of “heterocycle” include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocyclic ring. Bicyclic and tricyclic substituents described herein are attached through the named functional group. For example, if an R substituent is a bicyclic heterocycle the attachment point is on a heterocyclic ring. For example, is a “heterocycle” group. However, group. Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: .Additional non-limiting examples of “heterocycle” include: .Non-limiting examples of “heterocycle” also include: . Non-limiting examples of “heterocycle” also include: Additional non-limiting examples of “heterocycle” include: Additional non-limiting examples of “heterocycle” include: . Aryl In certain embodiments “aryl” is a 6 carbon aromatic group (phenyl). In certain embodiments “aryl” is a 10 carbon aromatic group (naphthyl). In certain embodiments “aryl” is a 6 carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. For example group. However, le” group. Embodiments of “arylalkyl” Non-limiting examples of “arylalkyl” include: . In certain embodiments the “arylalkyl” refers to a 2 carbon alkyl group substituted with an aryl group. Non-limiting examples of “arylalkyl” include: . I. EXTRACELLULAR PROTEIN DEGRADATION A wide range of well-known and characterized extracellular proteins can cause, modulate, or amplify diseases in vivo, such as abnormal cellular proliferation such as tumors and cancer, autoimmune disorders, inflammation and aging-related diseases. For example, extracellular proteins such as growth factors, cytokines, and chemokines bind to cell surface receptors, often initiate aberrant signaling in multiple diseases such as cancer and inflammation. An extracellular protein degrader described herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable compositions can be used to treat a disorder which is mediated by the Target Extracellular Protein that binds to the Extracellular Protein Targeting Ligand. The described degraders are capable of targeting specific Extracellular Proteins that mediate pathological disorders for lysosomal degradation. The Target Extracellular Protein may modulate a disorder in a human via a mechanism of action such as modification of a biological pathway, pathogenic signaling, or modulation of a signal cascade or cellular entry. In certain embodiments, the Target Extracellular Protein is a protein that is not druggable in the classic sense in that it does not have a binding pocket or an active site that can be inhibited or otherwise bound, and cannot be easily allosterically controlled. In another embodiment, the Target Extracellular Protein is a protein that is druggable in the classic sense, yet for therapeutic purposes, degradation of the protein is preferred to inhibition. The Target Extracellular Protein is recruited with an Extracellular Protein Targeting Ligand, which is a ligand for the Target Extracellular Protein. Typically, the Extracellular Protein Targeting Ligand binds the Target Extracellular Protein in a non-covalent fashion. In an alternative embodiment, the Target Extracellular Protein is covalently bound to the Extracellular Protein Targeting Ligand in a covalent manner that can be irreversible or reversible. Accordingly, in some embodiments, a method to treat a host with a disorder mediated by a Target Extracellular Protein is provided that includes administering an effective amount of a degrader targeting the Target Extracellular Protein to the host, typically a human, optionally in a pharmaceutically acceptable composition. The Target Extracellular Protein can be any amino acid sequence to which the degrader comprising an Extracellular Protein Targeting Ligand can be bound which through degradation thereof, results in a beneficial therapeutic effect. In certain embodiments, the Target Extracellular Protein is a non-endogenous peptide such as that from a pathogen or toxin. In another embodiment, the Target Extracellular Protein can be an endogenous protein that mediates a disorder. The endogenous protein can be either the normal form of the protein or an aberrant form. For example, the Target Extracellular Protein can be an extracellular mutant protein, or a protein, for example, where a partial, or full, gain-of-function or loss-of-function is encoded by nucleotide polymorphisms. In some embodiments, the degrader targets the aberrant form of the protein and not the normal form of the protein. In certain embodiments, an amino acid of a peptide Extracellular Protein Targeting Ligand described herein is mutated to histidine. Histidine is a basic amino acid and can be protonated in acidic compartments of the body or cells, for example the endolysosome. In certain embodiments, the peptide Extracellular Protein Targeting Ligand carrying a histidine mutation has a different binding affinity for the Target Protein at neutral pH, for example at pH 7.4 than at more acidic pH, for example at a pH less than 6.5. The decreased affinity for the Target Protein may allow the compound of the invention to dissociate from the Target Protein once internalized by ASGPR. The dissociation of the compound of the invention before maturation of the lysosome may allow the compound of the invention to exit the cell. This process can enable one molecule of the compound of the invention to traffic multiple Target Protein molecules to the liver, and thus the lysosome. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has a binding affinity for the target molecule that is calcium dependent and / or pH dependent In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has higher binding affinity for extracellular target molecule at neutral pH than at low pH. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has a higher binding affinity for the target molecule extracellularly than intraendosomally. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has a higher binding affinity for the target molecule at an extracellular pH than at an intraendosomal pH. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has a pH 6.0: 7.4 KD ratio for the target molecule of between 2: 1 and 10,000: 1. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has a higher koff rate for the target molecule intraendosomally than extracellularly. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein binds FcRn intraendosomally. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein facilitates externalization from the cell via FcRn. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has one or more mutations that impart pH-dependent binding affinity for the target molecule. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein has been mutated with one or more histidine substitutions. In certain embodiments, an amino acid residue selected from D, L, N, P, Q, R, and Y is replaced by histidine in a peptide Extracellular Protein Targeting Ligand described herein. In certain embodiments, a peptide Extracellular Protein Targeting Ligand described herein wherein the one or more histidine substitutions are located in the binding or CDR region of the peptide, antibody, or antibody fragment. In certain aspects a D, L, N, P, Q, R, or Y amino acid in a sequence listing described herein is replaced by histidine, for example a D, L, N, P, Q, R, or Y amino acid in a CDR1, CDR2, or CDR3 region of an antibody described herein. In certain embodiments a D amino acid is replaced by histidine. In certain embodiments an L amino acid is replaced by histidine. In certain embodiments a N amino acid is replaced by histidine. In certain embodiments a P amino acid is replaced by histidine. In certain embodiments a Q amino acid is replaced by histidine. In certain embodiments an R amino acid is replaced by histidine. In certain embodiments a Y amino acid is replaced by histidine. The Extracellular Protein Targeting Ligand is a ligand which covalently or non-covalently binds to a Target Extracellular Protein which has been selected for lysosomal degradation. In certain embodiments the Extracellular Protein Targeting Ligand is a small molecule or moiety (for example a peptide, nucleotide, antibody fragment, aptamer, biomolecule, or other chemical structure) that binds to a Target Extracellular Protein, and wherein the Target Extracellular Protein is a mediator of disease in a host as described in detail below. Exemplary Extracellular Protein Targeting Ligands are provided herein and in the Figures. In certain embodiments, the Extracellular Protein Targeting Ligand is selected from Extracellular Protein Targeting LigandA. In certain embodiments, the Extracellular Protein Targeting Ligand is selected from Extracellular Protein Targeting LigandB. In alternative embodiments, the Extracellular Protein Targeting Ligand or Extracellular Protein Targeting LigandBidentified by a SEQ ID NO is in cyclic form. For example, a cyclic form of a peptide sequence described herein can be a head to tail cyclized from wherein the first amino acid in the sequence is covalently bound to the last amino acid in the sequence. In alternative embodiments, the cyclic form of a peptide sequence described herein is a side chain cyclized form, wherein two amino acid side chains are covalently bound together (including but not limited to a disulfide, amide, ester, or ether bond between side chains). For example, a peptide sequence with two cysteine residues includes the peptide wherein the cysteine residues are bound together via a disulfide bond. In alternative embodiments, the cyclic form of a peptide sequence described herein includes a stapled form of the peptide sequence. In alternative embodiments, Extracellular Protein Targeting LigandBis selected from Extracellular Protein Targeting LigandA. Anchor Bond The Extracellular Protein Targeting Ligand (“EPTL”) is covalently bound to Linker in the ASGPR-binding extracellular protein degrader compound through the Anchor Bond (which is the chemical bond between the EPTL and either Linker B, Linker C or Linker D). This bond can be placed at any location on the ligand that does not unacceptably disrupt the ability of the EPTL to bind to the Target Extracellular Protein. The Anchor Bond is depicted on the nonlimiting examples of Extracellular Protein Targeting Ligands in the figures as: A number of exemplary Target Extracellular Proteins for medical therapy described below have characterizing structural information in the well-known Protein Data Bank (“PDB”), which is a database for the three-dimensional structural information for large biological molecules such as proteins and nucleic acids. PDB includes x-ray crystallography and other information submitted by scientists around the world, and is freely accessible. See for example www.rcsb.org; www.wwpdb.org and www.uniprot.org. Using the PDB codes for example provided in Section ** or in the Data Bank itself, and technical references provided herein or otherwise publicly available, the skilled artisan can determine appropriate locations where the EPTL can be linked through an Anchor Bond to Linker B, Linker C or Linker D to the ASGPR-binding moiety. For many of these proteins, published references describe how a range of ligands bind to the Target Extracellular Proteins, and from this information, one can determine reasonable Anchor Bond locations. For example, the skilled artisan can use available visualization tools, including those available on the PDB website, to determine where the Extracellular Protein Targeting Ligand docks into to the Target Extracellular Protein. The skilled artisan can also import the crystal structure and the selected Extracellular Protein Targeting Ligand of interest into modeling software (including for example PyMOL, Glide, Maestro, RasMol, Visual Molecular Dynamics, Jmol, and AutoDock) to determine what portion of the Extracellular Protein Targeting Ligand is bound to the Target Extracellular Protein. The ASGPR ligand is then bound through the Linker and the Anchor Bond at a point that does not unduly adversely affect binding to the Target Extracellular Protein. Optional Substituents In certain embodiments an Extracellular Protein Targeting Ligand described herein, for example in one of the figures, is optionally substituted with 1, 2, 3, or 4 optional substituents independently selected from alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, cyano, nitro, C(O)R3, wherein the optional substituent is selected such that a stable compound results. In certain embodiments the Target Extracellular Protein is selected from IgA, IgG, IgE, TNF-alpha, IL-1, IL-2, IL-6, IFN-γ, VEGF, TGF-β1, PCSK-9, CPB2, ChE, CCL2, Factor VII, Factor IX, CD40L,Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, FGF1, FGF2, FN1, IL-5, IL-8, IL-10, IL-21, IL-22, Kallikrein 1, LPL, MMP1, MIF, GIF, L-dopachrome isomerase, or phenylpyruvate tautomerase, neutrophil elastase, Prothrombin, KLKB1, PLG, PAI-1, endothelial plasminogen activator inhibitor, serpin E1, phospholipases A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), Transforming growth factor beta 2 (TGF-β2, TGFB2), thrombospondin 1, Urokinase, Urokinase-type plasminogen activator, complement factor B, complement factor D, target complement factor H, and complement component 5. In certain embodiments, where the Target Extracellular Protein has a receptor the Target Extracellular Protein can be used to degrade the receptor. In certain embodiments the Extracellular Protein Targeting Ligand is a ligand for a protein selected from IgA, IgG, IgE, TNF-alpha, IL-1, IL-2, IL-6, IFN-γ, VEGF, TGF-β1, PCSK-9, CPB2, ChE, CCL2, Factor VII, Factor IX, CD40L,Factor Xa, Factor XI, Factor XIa, Factor XII, Factor XIII, FGF1, FGF2, FN1, IL-5, IL-8, IL-10, IL-21, IL-22, Kallikrein 1, LPL, MMP1, MIF, GIF, L- dopachrome isomerase, or phenylpyruvate tautomerase, neutrophil elastase, Prothrombin, KLKB1, PLG, PAI-1, endothelial plasminogen activator inhibitor, serpin E1, phospholipases A2, PLA2, PA21B, PLA2G1B, PLA2-IB, PLA2, PLA2A, PA2IIA, PLA2G2A, PLA2-IIA, PGF, plasminogen activator, tissue type (tPA, PLAT), Transforming growth factor beta 2 (TGF-β2, TGFB2), thrombospondin 1, Urokinase, Urokinase-type plasminogen activator, complement factor B, complement factor D, target complement factor H, and complement component 5. In other embodiments the Extracellular Protein Targeting Ligand is a ligand for anti-B1AR antibodies. Amino Acids In certain embodiments the Extracellular Protein Targeting Ligand comprises one or more amino acids. The invention contemplates using natural amino acids, unnatural amino acids, or any combination thereof to achieve desired targeting ligand properties. The term “natural amino acid” refers to an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments a natural amino acid is replaced with a corresponding unnatural amino acid for example substituting a phenylalanine for a 4-chloro-phenylalanine. Non-limiting examples of unnatural amino acids include: 4-chloro-phenylalanine, 3-fluoro-phenalalanine, 4- trifluoromethyl-phaenylalanine, 3,4-dichloro-phenylalanine, 4-phenyl-phenylalanine, N- methylalanine, N-methylglutamic acid, N-methylphenylalanine, and homoserine. Additional examples of non-natural amino acids include:

[0057] In certain embodiments the Extracellular Protein Targeting Ligand is a sequence of amino acids. In certain embodiments the amino acid sequence is connected to the Linker portion of the molecule by a bond to a terminal amine. In certain embodiments the amino acid sequence is connected to the Linker portion of the molecule by a bond to a terminal carboxylic acid (e.g. an ester or amide). In certain embodiments the peptide includes an amine, hydroxyl, or carboxylic acid side chain and the linker may be bound to one of these sidechains. For example, when the amino acid sequence is SEQ ID NO: 1 MLKKIE non-limiting examples of locations wherein the peptide may be attached to the linker include:

[0058] The amino acid sequence can be attached to the Linker with chemistry described herein and as otherwise known in the art. For example, when the desired linking group is an amide the linker can end with a carboxylic acid, acyl chloride, anhydride, ester, or other amide precursor and an amine of the targeting ligand can be attached with an amide coupling reaction such as a HATU or HBTU coupling reaction. The amide bond can also be formed from an amine in the Linker reacting with a carboxylic acid, acyl chloride, anhydride, ester, or other amide precursor in the Targeting Ligand. In certain aspects the Linker is attached to the Extracellular Protein Targeting Ligand through an amide. In certain embodiments the Linker is attached to the C-terminus of an amino acid sequence described herein, for example through the reaction of an amine of the Linker with a carboxylic acid or ester of the Targeting Ligand. In other embodiments the Linker is attached to the N-terminus of an amino acid sequence described herein, for example through the reaction of an amine in the Targeting Ligand with a carboxylic acid, acyl chloride, anhydride, ester, or other amide precursor of the Linker. In certain embodiments the amide is formed using the Schotten Baumenn reaction or a condensation reaction. When the desired linking group is an amine the linker can end with a halogen, aldehyde, or other electrophilic group and an amine of the Targeting Ligand can be attached with a nucleophilic substitution reaction, for example a SNAr, SN1, or SN2 reaction or by reductive amination. The amine bond can also be formed from an amine in the Linker reacting with a halogen, aldehyde, or other electrophilic group in the Targeting Ligand. In certain aspects the Linker is attached to the Extracellular Protein Targeting Ligand through an amine. In certain embodiments the Linker is attached to the N-terminus of an amino acid sequence described herein, for example through the reaction of an amine in the Targeting Ligand with a halogen, aldehyde, or other electrophilic group of the Linker. In certain embodiments the amine bond is formed through an SNAr, SN1, or SN2 reaction. When the desired linking group is an ether the linker can end with a halogen or other electrophilic group and hydroxyl of the Targeting Ligand can be attached with an nucleophilic substitution reaction, for example a SNAr, SN1, or SN2 reaction. The ether bond can also be formed from a hydroxyl in the Linker reacting with a halogen or other electrophilic group in the Targeting Ligand. When the desired linking group is a triazole the linker can end with an alkyne and an azide of the Targeting Ligand can be attached through a click reaction. The triazole can also be formed from azide in the Linker reacting with an alkyne in the Targeting Ligand. In certain embodiments the alkyne is a terminal alkyne. In other embodiments the alkyne is an internal alkyne. Non- limiting examples of alkynes for use in the click reaction include: , , In certain aspects the Linker is attached to the Extracellular Protein Targeting Ligand through a triazole. In certain embodiments the Linker is attached to the N-terminus of an amino acid sequence described herein, for example through the reaction of an azide in the Targeting Ligand with an alkyne in the Linker. In certain aspects the azide in the Targeting Ligand is first formed by converting the terminal amine in an amino acid sequence described herein into an azide. In other aspects the azide is formed through other reactions as known to the skilled artisan or a different sequence of synthetic steps. When the desired linking group is a succinimide the linker can end with an maleimide and a thiol, amino, or hydroxyl of the Targeting Ligand can be attached through a Michael addition reaction. Non-limiting examples of Extracellular Protein Targeting Ligands that are a sequence of amino acids include aptamers, antibodies, and peptides. In certain embodiments the left most amino acid listed in the sequence listing is the C-terminus. In other embodiments the right most amino acid listed in the sequence listing is the C-terminus. In certain embodiments the amino acid sequence refers to a sequence without specified chirality. In other embodiments the amino acid sequence is all D-, all L-, or a mixture of D- and L- amino acids. When peptides are denoted by an amino acid sequence in a structure drawn herein the left side of the peptide is typically the N-terminus and the right side is typically the C-terminus unless excluded by context. For example, the proline in PIESESLK is attached through the nitrogen of the N-terminus to the linker in the structure below. For clarity the NH that is part of the amide is part of proline and the CO is part of the linker. When the lysine in PIESESLK is attached through the carbonyl of the C-terminus to the linker in the structure below.

[0059] For clarity the NH that is bound to the lysine is part of the linker and the lysine is bound to the NH by the carbonyl that is part of the C-terminus. In certain embodiments, the Extracellular Targeting LigandAor Extracellular Targeting LigandBis a targeting ligand that has at least 80%, 85%, 90%, 95%, or 98% sequence identity to a sequence described herein. For example, in certain embodiments the Extracellular Targeting LigandAor Extracellular Targeting LigandBis an amino acid sequence that has at least 95% sequence identity to SEQ ID NO: 1. In certain embodiments an ASGPR Binding Ligand or ASGPR Binding LigandBis conjugated to an Extracellular Protein Targeting LigandAor Extracellular Protein Targeting LigandBthat is a peptide (for example an antibody or fragment thereof) by using a bioconjugate technique. According to this technique, a small molecule moiety (that is, linker plus ASGPR Binding Ligand or ASGPR Binding LigandB) is connected to the antibody through formation of a covalent bond, such as disulfide bond or amide bond. The existence of lysine and cysteine residues on antibodies provides accessible reaction sites for conjugation. In the case of amide coupling, an active carboxylic acid ester (when available in the linker) may be used to connect payloads to lysine residues on the antibody. For conjugation through lysines, the primary amine on lysine side chain provides a convenient reactive group for conjugation chemistry. Cysteine based reaction provides another means of coupling. After reduction, the disulfide bond of the antibody can transform to cysteine residues which are accessible for coupling reaction. In certain embodiments other reactive sites are first protected and then the disulfide bond of the antibody is reduced to a cysteine residue for selective coupling (for example, a thiol maleimide coupling reaction). Antibodies can have both interchain disulfide bonds and intrachain disulfide bonds. The interchain disulfide bonds are exposed on the outside of the antibody and are easy to be reduced to expose free cysteine residues, providing the available sites for conjugation to the antibodies. The advantage of conjugation through cysteines is the relatively mild condition for reduction and conjugation. Non-limiting examples of conjugation techniques are provided in Zhiwen Fu et al. “Antibody drug conjugate: the “biological missile” for targeted cancer therapy”. Signal Transduction and Targeted Therapy (2022), vol. 7, article number: 93; and Yang Feng et al. “Conjugates of Small Molecule Drugs with Antibodies and Other Proteins”. Biomedicines (2014), 2(1): 1–13. In certain embodiments the Linker contains moieties which are capable of reacting with lysine amine groups or cysteine sulfhydryl groups. For example, linker may include a maleimide group that reacts with sulfhydryl group to form stable thioether bond, or active carboxylic acid ester group that reacts with lysine primary amine to form an amide bond. In certain embodiments the amide bond reaction utilizes a coupling reagent for example HATU, HUTU HOAt, HBTU, DCC, DIC, or EDC. II. EXTRACELLULAR PROTEIN DEGRADATION A wide range of well-known and characterized extracellular proteins can cause, modulate, or amplify diseases in vivo, such as abnormal cellular proliferation such as tumors and cancer, autoimmune disorders, inflammation and aging-related diseases. For example, extracellular proteins such as growth factors, cytokines, and chemokines bind to cell surface receptors, often initiate aberrant signaling in multiple diseases such as cancer and inflammation. An extracellular protein degrader described herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable compositions can be used to treat a disorder which is mediated by the Target Extracellular Protein that binds to the Extracellular Protein Targeting Ligand. The described degraders are capable of targeting specific Extracellular Proteins that mediate pathological disorders for lysosomal degradation. The Target Extracellular Protein may modulate a disorder in a human via a mechanism of action such as modification of a biological pathway, pathogenic signaling, or modulation of a signal cascade or cellular entry. In certain embodiments, the Target Extracellular Protein is a protein that is not druggable in the classic sense in that it does not have a binding pocket or an active site that can be inhibited or otherwise bound, and cannot be easily allosterically controlled. In another embodiment, the Target Extracellular Protein is a protein that is druggable in the classic sense, yet for therapeutic purposes, degradation of the protein is preferred to inhibition. The Target Extracellular Protein is recruited with an Extracellular Protein Targeting Ligand, which is a ligand for the Target Extracellular Protein. Typically, the Extracellular Protein Targeting Ligand binds the Target Extracellular Protein in a non-covalent fashion. In an alternative embodiment, the Target Extracellular Protein is covalently bound to the Extracellular Protein Targeting Ligand in a covalent manner that can be irreversible or reversible. Accordingly, in some embodiments, a method to treat a host with a disorder mediated by a Target Extracellular Protein is provided that includes administering an effective amount of a degrader targeting the Target Extracellular Protein to the host, typically a human, optionally in a pharmaceutically acceptable composition. IIA. EXTRACELLULAR PROTEIN TARGETING LIGANDBAnti-citrullinated Protein Antibodies (ACPA) In certain embodiments, the Extracellular Protein Targeting LigandBbinds anti- citrullinated protein antibodies (ACPA). In certain embodiments, a Targeted Protein Degrader that degrades ACPA can be used in the treatment of autoimmune diseases such as rheumatoid arthritis. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from SEQ ID NO: 2-4 (Khatri, S. et al “Cyclic Citrullinated Peptide Aptamer Treatment Attenuates Collagen-Induced Arthritis” Biomacromolecules 2022, 23, 2126-2137). In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclized form of SEQ ID NO: 2-4. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide selected from SEQ ID NO: 2-4. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide of SEQ ID NO 2-4 with one, two, three, or four amino acids modified with citrulline. SEQ ID NO: 2 CHHPGIAEFPS-Cit-GKSYSYSKQFC

[0060] SEQ ID NO: 3 EEEECHHPGIAEFPS-Cit-GKSYSYSKQFC SEQ ID NO: 4 C6-CHHPGIAEFPS-Cit-GKSYSYSKQFC-OH In certain embodiments, the Extracellular Protein Targeting LigandBis a nanoparticle prepared according to Khatri, S. et al “Cyclic Citrullinated Peptide Aptamer Treatment Attenuates Collagen-Induced Arthritis” Biomacromolecules 2022, 23, 2126-2137. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from SEQ ID NO: 5-24 (Khatri, S. et al. “Antibodies to synthetic citrullinated peptide epitope correlate with disease activity and flares in rheumatoid arthritis” PLoS ONE 15(4): e0232010). SEQ ID NO: 5 HHPGIAEFPS(Cit)GKSSSYSKQF SEQ ID NO: 6 HHPGIAEFPS(Cit)GKSYSYS KQF SEQ ID NO: 7 HGP GIA EFP S(Cit)G PSY SYS KQF SEQ ID NO: 8 AEGGGV(Cit)GPRVVE SEQ ID NO: 9 ASSGGV(Cit)GPRIVE SEQ ID NO: 10 KDLLPS(Cit)D(Cit)QHLPLIK SEQ ID NO: 11 QMRMELE(Cit)PGGNEIT(Cit)GGSTSYG SEQ ID NO: 12 NVSPGT(Cit)(Cit)EYHTEK SEQ ID NO: 13 ST(Cit)SVSSSSY(Cit)(Cit)MFGG SEQ ID NO: 14 VYAT(Cit)SSAV(Cit)L(Cit)SSVP SEQ ID NO: 15 A(Cit)TKQTA(Cit)KSTGGKAP SEQ ID NO: 16 AA(Cit)KSAPSTGGVKKPH SEQ ID NO: 17 Y(Cit)PGTVAL(Cit)EIKKYQKS SEQ ID NO: 18 LI(Cit)KLPFQ(Cit)LV(Cit)EIAQDFK SEQ ID NO: 19 LCAIHAK(Cit)VTIMPKDI SEQ ID NO: 20 A(Cit)GLTG(Cit)PGDA SEQ ID NO: 21 SHQEST(Cit)G(Cit)S(Cit)GRSGRSGS SEQ ID NO: 22 T(Cit)GRS SEQ ID NO: 23 T(Cit)G(Cit)S SEQ ID NO: 24 TRG(Cit)S In certain embodiments, the Extracellular Protein Targeting LigandBis selected from SEQ ID NO: 25-34 (Fernandes-Cerqueira et al. Targeting of anti-citrullinated protein / peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens Arthritis Research & Therapy (2015) 17:155). In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclized form of SEQ ID NO: 25-34. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide selected from SEQ ID NO: 25-34. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide of SEQ ID NO 25-34 with one, two, three, or four amino acids replaced with citrulline. SEQ ID NO: 25 HHP GIA EFP SRG KSS SYS KQF SEQ ID NO: 26 HHP GIA EFP SXG KSS SYS KQF (wherein X is citrulline) SEQ ID NO: 27 SKQ FTS STS YNR GDS TFE SKS SEQ ID NO: 28 SKQ FTS STS YNX GDS TFE SKS (wherein X is citrulline) SEQ ID NO: 29 APP PIS GGG YRA RPA KAA AT SEQ ID NO: 30 APP PIS GGG YXA RPA KAA AT (wherein X is citrulline) SEQ ID NO: 31 APP PIS GGG YRA XPA KAA AT (wherein X is citrulline) SEQ ID NO: 32 cyclo-CHHP GIA EFP SXG KSS SYS KQF (wherein X is citrulline) SEQ ID NO: 33 GIA EFP SXG KSS SYS (wherein X is citrulline) SEQ ID NO: 34 A EFP SXG KSS S (wherein X is citrulline) In certain embodiments, the Extracellular Protein Targeting LigandBbinds anti- citrullinated protein antibodies (ACPA). In certain embodiments, a Targeted Protein Degrader that degrades ACPA can be used in the treatment of autoimmune diseases such as rheumatoid arthritis. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 2 In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to SEQ ID NO: 2. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 2. In certain embodiments, the compound of the invention is of the formula:

[0061] or or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 5. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to SEQ ID NO: 5. In certain embodiments, the compound of the invention is of the formula:

[0062] ; or a pharmaceutically acceptable salt thereof. In alternative embodiments, the compound of the invention is or a pharmaceutically acceptable salt thereof. In alternative embodiments, the compound of the invention is or a pharmaceutically acceptable salt thereof. In alternative embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 35 HQCHQEST(Cit)GRSRGRCGRSGS In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to SEQ ID NO: 35. In certain embodiments, SEQ ID NO: 35 is a cyclic peptide. In certain embodiments, SEQ ID NO: 35 is the structure . In certain embodiments, the compound of the invention is of the formula

[0063] or a pharmaceutically acceptable salt thereof. In alternative embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 36 HSKRGHAKSRPV(Cit)GHQCHQEST(Cit)GRSRGRCGRSGS In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to SEQ ID NO: 36. In certain embodiments, SEQ ID NO: 36 is a cyclic peptide. In certain embodiments, SEQ ID NO: 36 is the structure In certain embodiments, the compound of the invention is of the formula

[0064] or a pharmaceutically acceptable salt thereof. In alternative embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 37 HSTKRGHAKSRPV(Cit)GHQCHQEST(Cit)GRSRGRCGRSGS In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to SEQ ID NO: 37. In certain embodiments, SEQ ID NO: 37 is a cyclic peptide. In certain embodiments, SEQ ID NO: 37 is the structure . In certain embodiments, the compound of the invention is of the formula:

[0065] or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide described in Perez et al. J. Med. Chem.2007, 50, 3573-3584. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from

[0066] wherein X is absent or selected from glycine, alanine, phenylalanine, and cysteine. In certain embodiments, one X is cysteine. In certain embodiments, two X are cysteine. In certain embodiments, one or more arginine residues in any one of SEQ ID NO: 38-153 can be replaced with a citrulline. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 38-153. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide of SEQ ID NO: 38-153 in cyclized form. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide of SEQ ID NO: 38-153 in a head-to-tail cyclized form, for example the peptide head-to-tail cyclized to form . In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide of SEQ ID NO: 38-153 wherein two amino acid side chains are covalently bound to form a cyclic peptide, such as a disulfide bond between cysteines. For example, the peptide can be a cyclic form of the structure . In certain embodiments, In certain embodiments, the Extracellular Protein Targeting LigandBis selected from In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 154-161. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 154-161. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 154-161, for example the peptide ARGH(Cit)PLDKKREEAPSL(Cit)PAD can be . In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 154-161, for example GFFCARGH(Cit)PLDKKREEAPCL(Cit)PA can be . In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide described in Schellekens, G. Arthritis and Rheumatism, 2000, 43(1), 155-163. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from

[0067] In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic version of a peptide of SEQ ID NO: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 162-305, for example the peptide SEQ ID NO: 35 HQCHQEST(Cit)GRSRGRCGRSGS can be . In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 162-305, for example the peptide SEQ ID NO: 35 HQCHQEST(Cit)GRSRGRCGRSGS can be . In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric peptide comprising a fragment of the protein fibrin and a fragment of the protein filaggrin. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein α-fibrin and one or more fragments of the protein filaggrin, for example a fragment comprising an amino acid selected from SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein α-fibrin comprising an amino acid selected from SEQ ID NOs: 38-61 that are operatively arranged with one or more fragments of the protein filaggrin comprising an amino acid selected from SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein α-fibrin comprising an amino acid sequence with at least about 80% homology to one of SEQ ID NOs: 38-61 that are operatively arranged with one or more fragments of the protein filaggrin comprising an amino acid sequence with at least 80% homology to one of SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising a one or more fragments of the protein α-fibrin comprising an amino acid selected from SEQ ID NOs: 96-119 that are operatively arranged with one or more fragments of the protein filaggrin comprising an amino acid selected from SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein α-fibrin comprising an amino acid sequence with at least about 80% homology to one of SEQ ID NOs: 96-119 that are operatively arranged with one or more fragments of the protein filaggrin comprising an amino acid sequence with at least 80% homology to one of SEQ ID NOs: 162-305. For example, a chimeric peptide comprising SEQ ID NO: 55 and 276 is a peptide of the sequence: SEQ ID NO: 306 HSTKRGHAKSRPV(Cit)HQCHQESTRG(Cit)SRGRCGRSGS In certain embodiments the chimeric peptide comprising SEQ ID NO: 113 and 275 is a peptide of the sequence: SEQ ID NO: 307 XXXHCTKRGHAKCRPV(Cit)GXXXHQCHQEST(Cit)GRSRGRCGRSGS In certain embodiments, the chimeric peptide is in a cyclized form, for example one or both of the fragments contains a cycle (including head-to-tail cyclization or side chain cyclization as described herein). For example, the peptide of the sequence SEQ ID NO 306 can be , . In certain embodiments, the peptide of the sequence SEQ ID NO 307 can be , , , , , or ; wherein X is absent or selected from glycine, alanine, phenylalanine, and cysteine. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric peptide comprising one or more fragments of the protein β-fibrin and one or more fragments of the protein filaggrin, for example a fragment comprising an amino acid selected from SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein β-fibrin comprising an amino acid selected from SEQ ID NO: 62-95 and one or more fragments of the protein filaggrin comprising an amino acid selected from SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein β-fibrin comprising an amino acid sequence with at least about 80% homology to any one of SEQ ID NOs: 62-95 and one or more fragments of the protein filaggrin comprising an amino acid sequence with at least about 80% homology to any one of SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein β-fibrin comprising an amino acid selected from SEQ ID NOs: 120-153 and one or more fragments of the protein filaggrin comprising an amino acid selected from SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a chimeric polypeptide comprising one or more fragments of the protein β-fibrin comprising an amino acid sequence with at least about 80% homology to any one of SEQ ID NOs: 120-153 and one or more fragments of the protein filaggrin comprising an amino acid sequence with at least about 80% homology to any one of SEQ ID NOs: 162-305. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide selected from SEQ ID NO: 308-319. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 308-319. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 308-319. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 308-319. In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 308-319, for example cyclized through a disulfide bond between two cysteine amino acids. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide selected from SEQ ID NO: 320-359. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a peptide sequence selected from SEQ ID NO: 320-359. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 320-359. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 320-359. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 320-359. In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 320-359, for example cyclized through a disulfide bond between two cysteine amino acids.

[0068] In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 275. In certain embodiments, the compound of the invention is of the formula:

[0069] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula:

[0070] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide selected from SEQ ID NO: 360-371. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 360-371. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 360-371. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 360-371. In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 360-371, for example cyclized through a disulfide bond between two cysteine amino acids. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 359. In certain embodiments, the compound of the invention is of the formula:

[0071] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclized form of SEQ ID NO: 359. In certain embodiments, the compound of the invention is of the formula:

[0072] ; or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide selected from SEQ ID NO: 372-383. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 372-383. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 372-383. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 372-383. In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 372-383, for example cyclized through a disulfide bond between two cysteine amino acids.

[0073] In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 306. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclized form of SEQ ID NO: 306. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the invention is of the formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide selected from SEQ ID NO: 384-406. In certain embodiments, the Extracellular Protein Targeting LigandB is an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 384-406. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 384-406. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 384-406. In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 384-406, for example cyclized through a disulfide bond between two cysteine amino acids. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide selected from SEQ ID NO: 407-414. In certain embodiments, the Extracellular Protein Targeting LigandBis an amino acid sequence having at least about 80% sequence homology to any one of SEQ ID NO: 407-414. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic form of a peptide of SEQ ID NO: 407-414. In certain embodiments, the Extracellular Protein Targeting LigandBis a head-to-tail cyclized version of a peptide of SEQ ID NO: 407-414. In certain embodiments, the Extracellular Protein Targeting LigandBis a side chain cyclized version of a peptide of SEQ ID NO: 407-414, for example cyclized through a disulfide bond between two cysteine amino acids. Anti-THSR Autoantibodies In certain embodiments the Extracellular Protein Targeting LigandBbinds to autoantibodies that bind to thyrotropin-TSH receptor (TSHR). In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that binds to anti-THSR autoantibodies. In certain embodiments the Extracellular Protein Targeting LigandBis CHQEEDFRVTC (SEQ ID NO: 415). In certain embodiments, the Extracellular Protein Targeting LigandAis TKLDAVYLNKNKG (SEQ ID NO: 416). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence CHQEEDFRVTC. In certain embodiments the Extracellular Protein Targeting LigandBis cyclo(x(i)CHQEEDFRVTCz(j)) (Formula TSHR-I, SEQ ID NO: 417); or In certain embodiments the Extracellular Protein Targeting LigandBis cyclo(x(k)TKLDAVYLNKNKG) (Formula TSHR-II, SEQ ID NO: 418); wherein x and z are at each occurrence individually selected from an amino acid; i is an integer from 0 to 4, j is an integer from 0 to 4, wherein i+j≤4, preferably i=j=0; and k is an integer of 0 to 2, preferably k=0. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence cyclo(x(i)CHQEEDFRVTCz(j)) (SEQ ID NO: 417) or cyclo(x(k)TKLDAVYLNKNKG) (SEQ ID NO: 418). The cyclization of the anti-THSR autoantibody Extracellular Protein Targeting LigandBmay occur by a linkage which is a covalent binding selected from the group comprising S—S linkages, peptide bonds, carbon bonds such as C—C or C═C, ester bonds, ether bonds, azo bonds, C—SC linkages, C—N—C linkages and C═N—C linkages. In one embodiment the S—S linkage is formed by two Cys residues of the peptide. The latter is preferred for the peptide of formula (I), wherein preferably i=0 and j=0. In case the cyclisation in the peptide of Formula TSHR-I is via an S—S linkage of the two Cys residues of the peptide, x(i) and y(j) represent side chains of the cyclic peptide linked via peptide bonds to the peptide backbone. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence SPPCECHQEEDFRVTCKDIQRIPS (SEQ ID NO: 419). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence LPPSTQTLKLIETHLRTIPSHAFS (SEQ ID NO: 420). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence SNLPNISRIYVSIDVTL (SEQ ID NO: 421). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence YNLSKVTHIEIRNTRNLTYIDPDA (SEQ ID NO: 422). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence LKELPLLKFLGIFNTGLKMFPDLT (SEQ ID NO: 423). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence KVYSTDIFFILEITDNP (SEQ ID NO: 424). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence NAFQGLCNETLTLKLYNNGFTSVQ (SEQ ID NO: 425). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence KDAFGGVYSGPSLLDVSQTS (SEQ ID NO: 426). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence PSKGLEHLKELIARNTWTLKKLPL (SEQ ID NO: 427). In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that binds to anti-THSR autoantibodies described in Ungerer 2018 Front BioSci. In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that binds to anti-THSR autoantibodies described in EP3369743A1. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence GYAFNGTKLDAVYLNKNKYLTVID (SEQ ID NO: 428) or a fragment or derivative thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence XaaXaaXaaXaaXaaXaaGYAFNGTKLDAVYLNKNKYLTVID (SEQ ID NO: 429) or a fragment or derivative thereof, wherein Xaa is independently absent or independently selected at each occurrence from an amino acid. In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence GYAFNGTKLDAVYLNKNKYLTVID (SEQ ID NO: 428) or a fragment or derivative thereof, wherein the cyclic peptide is head-to-tail cyclized. In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that is or comprises a fragment of the thyrotropin receptor (TSHR), for example the leucine rich domain. In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that is or comprises amino acids 22-260 of TSHR. In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that is or comprises a peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with amino acids 22-260 of TSHR. In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that is or comprises amino acids 22-260 of TSHR comprising one or more mutations selected from Asp43Ala, Glu61Ala, Glu157Ala, Glu178Ala, Asp203Ala, Asp232Ala, Arg255Ala, and Trp258Ala. In certain embodiments the Extracellular Protein Targeting LigandBis a peptide ligand that is or comprises a stabilized fragment of the thyrotropin receptor (TSHR). In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 430 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLRQRKSVNALNSPLHQ EYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQEDEIIGFGQELKNPQEETLQAFDSH YDYTICGDSEDMVCTPKSDEFNPCEDIMG In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 431 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLRQRKSVNGQELKNPQ EETLQAFDSHYDYTICGDSEDMVCTPKSDEFNPCEDIMG In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 432 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLRQRKSVN In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 433 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYP In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 434 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLK In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 435 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLALYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYP In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 436 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLRLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYP In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 437 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKKLIARNTWTLKKLP LSLSFLHLTRADLSYP In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 438 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV YLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARNTWTLKKLP LSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLRQRKSVNGQELKNPQ In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 439 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT KVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQGYAFNGTKLDAV In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 440 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV SIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKFLGIFNTGLKMFPDLT In certain embodiments, the Extracellular Protein Targeting LigandBis a cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide of the sequence: SEQ ID NO: 441 GMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHLRTIPSHAFSNLPNISRIYV Anti-β1AR Autoantibody Targeting LigandBIn certain embodiments the anti-β1AR autoantibody Targeting Ligand is SEQ ID NO: 442 DCCKPDNYCR, wherein each amino acid is a D-amino acid. In certain embodiments, the anti- β1AR autoantibody Extracellular Protein Targeting Ligand has about 99%, 98%, 95%, 93%, 90%, 88%, 85%, 83%, or 80% sequence identity with SEQ ID NO: 442. In certain embodiments the anti-β1AR autoantibody Targeting Ligand is SEQ ID NO: 443 RRCYND. In certain embodiments, the anti-β1AR autoantibody Extracellular Protein Targeting Ligand has about 99%, 98%, 95%, 93%, 90%, 88%, 85%, 83%, or 80% sequence identity with SEQ ID NO: 443. In certain embodiments, the anti-β1AR autoantibody Targeting Ligand is SEQ ID NO: 443, cyclized from N-terminus to C-terminus. In certain embodiments the anti-β1AR autoantibody Extracellular Protein Targeting LigandBis SEQ ID NO: 444 ADEARRCYNDPKCSDFVQ. In certain embodiments, the anti- β1AR autoantibody Targeting LigandBhas about 98%, 95%, 93%, 90%, 88%, 85%, 83%, or 80% sequence identity with SEQ ID NO: 444. In certain embodiments, the anti-β1AR autoantibody Targeting LigandBis SEQ ID NO: 444, cyclized from N-terminus to C-terminus. In certain embodiments, the anti-β1AR autoantibody Targeting LigandBis SEQ ID NO: 444, with a disulfide bond between the cysteine residues. In certain aspects an extracellular protein degrading compound of Formula: or

[0074] or a pharmaceutically acceptable salt thereof. In certain aspects an extracellular protein degrading compound is of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: or a pharmaceutically acceptable salt thereof. In certain aspects the compound of the present invention is a compound of Formula I: or a pharmaceutically acceptable salt thereof. In other aspects the compound of the present invention is a compound of Formula II: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula II:

[0075] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula:

[0076] In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof. In certain aspects an extracellular protein degrading compound of Formula:

[0077] or a pharmaceutically acceptable salt thereof. In certain aspects an extracellular protein degrading compound is of Formula:

[0078] or a pharmaceutically acceptable salt thereof. IL-17 In some embodiments, the Target Extracellular Protein is human interleukin-17 (IL-17) (UniProtKB – Q16552 (IL17_HUMAN)). Interleukin-17 is a 35 kDa homodimeric glycoprotein and is an important cytokine for the inflammatory response. IL-17 is secreted by a distinct class of Helper T cells (known as Th17 cells) which mediates tissue inflammation. A characteristic effect of IL-17 production is the expansion of neutrophils, and in healthy tissue it is responsible for neutrophil homeostasis. IL-17 has been implicated as a major factor in psoriasis as well as other autoimmune diseases. Other diseases where IL-17 therapies may be of benefit include but are not limited to asthma, rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, and inflammatory bowel disease. Inflammation caused by IL-17 has been shown to hamper recovery post-stroke. In certain embodiments IL-17 Targeting Ligand is of Formula: wherein selected from (i) an optionally substituted C3-12 carbocycle and optionally substituted 3- to 12- membered heterocycle wherein substituents on Ring AF are independently selected at each occurrence from halogen, -ORF11, -SRF11, -N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, N(RF11)C(O)RF11, -N(RF11)S(O)2RF11, -C(O)ORF11, -OC(O)RF11, -S(O)RF11, -S(O)2RF11, -NO2, =O, =S, =N(RF11), -CN; and (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF11, -SRF11, -N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, N(RF11)C(O)RF11, -C(O)ORF11, -OC(O)RF11, -S(O)RF11, -S(O)2RF11, -NO2, =O, =S, =N(RF11), -CN, C3-10 carbocycle and 3- to 10- membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF11, N(RF11)2, -C(O)RF11, -C(O)N(RF11)2, -N(RF11)C(O)RF11, -C(O)ORF11, -OC(O)RF11, -NO2, =O, =NRF11and -CN; selected from (i) an optionally substituted C3-10 carbocycle and optionally substituted 3- to 12- membered heterocycle each substituent on Ring BF is independently selected at each occurrence from halogen, -ORF12, -SRF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, -N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -S(O)RF12, -S(O)2RF12, -NO2, =O, =S, =N(RF12), -CN; and (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF12, -SRF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -S(O)RF12, -S(O)2RF12, -NO2, =O, =S, =N(RF12), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, -N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -NO, =O, =N(RF11) and -CN; in certain embodiments, each substituent on Ring BF is independently selected from (i) halogen, haloalkyl, -ORF12, -SRF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, -N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -S(O)RF12, -S(O)2RF12, -NO2, =O, =S, =N(RF12), -CN; and (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF12, -SRF12, -N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, -S(O)RF12, -S(O)2RF12, -NO2, =O, =S, =N(RF12), -CN, C3-10 carbocycle, and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF12,N(RF12)2, -C(O)RF12, -C(O)N(RF12)2, -N(RF12)C(O)RF12, -C(O)ORF12, -OC(O)RF12, - NO, =O, =N(RF11) and -CN;· RF4is selected from -C(O)N(RF23)(RF24) and C(O)heterocycle, wherein heterocycle is optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, -ORF13, -SRF13, -N(RF13)2, -C(O)RF13, -C(O)N(RF13)2, -N(RF13)C(O)RF13, -C(O)ORF13, -OC(O)RF13, -S(O)RF13, -S(O)2RF13, -NO2, =O, =S, =N(RF13) -CN; and C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF13, -SRF13, -N(RF13)2, -C(O)RF13, -C(O)N(RF13)2, N(RF13)C(O)RF13, -C(O)ORF13, -OC(O)RF13, -S(O)RF13, -S(O)2RF13, -NO2, =O, =S, =N(RF13), -CN, C3-10carbocycle and 3- to 10-membered heterocycle, wherein the C3-10carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF13,-N(RF13)2, -C(O)RF13, -C(O)N(RF13)2, -N(RF13)C(O)RF13, -C(O)ORF13, -OC(O)RF13, -NO2, =O, =N(RF13), and -CN; LFis bond or selected from -O- and -NH-; RFAis independently selected at each occurrence from hydrogen, halogen, -ORF14, -N(RF14)2, -C(O)RF14, -C(O)N(RF14)2, N(RF14)C(O)RF14, -C(O)ORF14, -OC(O)RF14, -NO2, -CN, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from: halogen, ORF14,-N(RF14)2, -C(O)RF14, NO2, =O, and -CN; or RFAis independently selected at each occurrence from hydrogen, halogen, haloalkyl, - ORF14, -N(RF14)2, -C(O)RF14, -C(O)N(RF14)2, N(RF14)C(O)RF14, -C(O)ORF14, -OC(O)RF14, -NO2, - CN, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from: halogen, ORF14,-N(RF14)2,-C(O)RF14, NO2, =O, and -CN; RFBis selected from hydrogen, halogen, -ORF15, -N(RF15)2, -C(O)RF15, -C(O)N(RF15)2, N(RF15)C(O)RF15, -C(O)ORF15, -OC(O)RF15, -NO2, -CN, and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents selected from: halogen, ORF15,-N(RF15)2, -C(O)RF15, NO2, =O, and -CN, wherein at least one of RAor RBis not hydrogen; RF' and RF'' are independently selected from: hydrogen, halogen, -ORF16, and C1-6 alkyl; wherein the C1-6 alkyl is optionally substituted with one or more substituents selected from: halogen, -ORF16, -N(RF16)2, -C(O)RF16, -NO2, =O, and -CN; RF1is selected from -ORF21, -N(RF21)(RF22), -N(RF21)C(O)RF22, -N(RF21)C(O)ORF22, -N(RF21)C(O)N(RF21)(RF22), -N(RF21)S(=O)2N(RF21)(RF22), and -N(RF21)S(=O)2(RF22); each RF2and RF3are independently selected from: hydrogen, halogen, -ORF17, C1-6 alkyl, and C3-6 cycloalkyl; wherein the C1-6 alkyl and C3-6 cycloalkyl are optionally substituted with one or more substituents selected from: halogen, -ORF17, -N(RF17)2, -C(O)RF17, -NO2, =O, and -CN; or RF2and RF3bound to the same carbon come together to form a C3-6 cycloalkyl optionally substituted with one or more substituents selected from halogen, -ORF17, -N(RF17)2, -C(O)RF17, -NO2, =O, and -CN; RF21is independently selected at each occurrence from hydrogen and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen, -ORF17, -N(RF17)2, -C(O)RF17, -NO2, =O, and -CN; RF22is selected from: C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF18, -SRF18, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF18, -N(RF18)2, -C(O)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(O)ORF18, - OC(O)RF18, -NO2, =O, =N(RF18), and -CN; and C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF18, -SRF18, - N(RF18)2, -C(O)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(O)ORF18, -OC(O)RF18, -S(O)RF18, - S(O)2RF18, -NO2, =O, =S, =N(RF18), -CN; and C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF18, -SRF18, -N(RF18)2, -C(O)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(O)ORF18, -OC(O)RF18, -S(O)RF18, -S(O)2RF18, -NO2, =O, =S, =N(RF18), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF18, N(RF18)2, -C(O)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(O)ORF18, -OC(O)RF18, - NO =O, =N(RF18), and -CN; and C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF18, -N(RF18)2, -C(O)RF18, -C(O)N(RF18)2, -N(RF18)C(O)RF18, -C(O)ORF18, -OC(O)RF18, -NO2, =O, =N(RF18), and -CN; RF23is selected from: C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -ORF19, -SRF19, -N(RF19)2, -NO2, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -ORF19, -N(RF19)2, =O, C1-C6 alkyl, C1-C6 haloalkyl, and -CN; and C3-12carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -ORF19, -N(RF19)2, =O, C1-C6 alkyl, C1-C6 haloalkyl, and-CN; RF24is selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -ORF19, -SRF19, -N(RF19)2, -NO2, -CN, C3-6 carbocycle and 3- to 6-membered heterocycle; RF11, RF12, RF13, RF14, RF15, RF16, RF17, RF18, and RF19are independently selected at each occurrence from (i) hydrogen; and (ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN, C3-10carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents selected from: halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl, -NH2, -NO2, =O, and -CN; and (iii) C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, - O-C1-C6 alkyl, -O-C1-C6haloalkyl -NH2, -NO2, =O, -CN; and (iv) C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-C6 alkyl, -O-C1-C6 haloalkyl -NH2, -NO2, =O, and -CN; nFis selected from 0 and 1; and mFis selected from 0, 1, and 2. In certain embodiments IL-17 Targeting Ligand is of Formula:

[0079] In certain embodiments IL-17 Targeting Ligand is of Formula: wherein, RG1is selected from the group consisting of 5- or 6-membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C1-C6)alkyl, phenyl-(C1-C4)alkyl, (C3-C7)cycloalkyl, 4-6-membered heterocycloalkyl and -NRGCRGD, wherein said 5- or 6-membered heteroaryl, 9- or 10-membered bicyclic heteroaryl, phenyl, (C1-C6)alkoxy, (C3-C7)cycloalkoxy, (C1-C6)alkyl, phenyl-(C1-C4)alkyl, (C3-C7)cycloalkyl and 4-6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from RGA; RGArepresents deuterium, halogen, hydroxy, -NRGCRGD, (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or, 4-6-membered heterocycloalkyl, wherein said (C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C3-C7)cycloalkyl, phenyl, 5- or 6-membered heteroaryl or 4-6-membered heterocycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxy, cyano, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, -SO2-(C1-C4)alkyl and -NRGCRGD; RG2is selected from the group consisting of 5- or 6-membered heteroaryl, wherein said 5- or 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from RGB, wherein said 5- or 6-membered heteroaryl may optionally contain -CO- as a ring member and wherein when said 5-membered heteroaryl contains nitrogen as a ring atom said nitrogen may optionally be substituted with a substituent selected from RG8; RGBrepresents deuterium, halogen, cyano, hydroxy, -NRGCRGD, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-CO-O-(CH2)n- or (C3-C7)cycloalkyl, wherein n is 1-4, and wherein said (C1-C6)alkyl, (C1-C6)alkoxy or (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, -NRGCRGDand (C1-C4)alkoxy; RGCand RGDeach independently are selected from the group consisting of hydrogen and (C1-C6)alkyl, or RGCand RGDtogether form pyrrolidinyl or piperidinyl, wherein said (C1-C6)alkyl, pyrrolidinyl or piperidinyl is optionally substituted with one or more substituents independently selected from halogen, cyano and hydroxy; RG8is selected from the group consisting of -LG-PO(OH)2and -CHRGG-O-(CO-A-NRGH)(0 or 1)-CO-A-NRGHRGI; LGis selected from the group consisting of a bond or -CHRGGO-; wherein each -CO-A-NRGH- independently represents an amino acid residue wherein the amino acid residue is selected from the natural amino acids either in D or L-form or as mixtures of the D and L form, and wherein said amino acid residue may be substituted on the a-amino group with a substituent RGH; RGG, RGH, and RGIare independently selected from hydrogen and (C1-C6) alkyl; RG3is selected from the group consisting of hydrogen, deuterium, hydroxy and halogen; RG4is selected from the group consisting of hydrogen, deuterium and halogen; RG5is selected from the group consisting of -CHRG6RG7, (C3-C10)cycloalkyl and GG, wherein said (C3-C10)cycloalkyl and GG are optionally substituted with one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, (C1-C4)alkyl and halo(C1-C4)alkyl; GG represents RG6and RG7each independently represents hydrogen, phenyl, (C1-C6)alkyl, or (C3- C7)cycloalkyl, wherein said phenyl, (C1-C6)alkyl or (C3-C7)cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy and (C1- C4)alkyl. In certain embodiments IL-17 Targeting Ligand is of Formula: wherein: RH1is a 5-10-membered heteroaryl group, optionally substituted with 1 or more substituents independently chosen from hydroxyl, halogen, cyano, and C1-C6alkyl, wherein one or more CH2group of the C1-C6 alkyl is replaced by an NH, N(C1-C4alkyl), O, or S, and wherein C1-C6alkyl is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, and amino, additionally, RH1is optionally substituted with 0 or l substituents chosen from C3-C7cycloalkyl. phenyl, and 5-6-membered heterocycloalkyl having l or 2 heteroatoms independently chosen from N, O, and S, and RH1is covalently bound to LinkerB, LinkerC, or LinkerD; RH2is a 5-membered heteroaryl group, optionally substituted with l or more substituents independently chosen from hydroxyl, halogen, cyano, and C1-C6alkyl, wherein one or more CH2group of the C1-C6 alkyl is optionally replaced by an NH, N(C1-C4alkyl), O, S, or SO2, and wherein C1-C6alkyl is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, and amino, and RH2is optionally substituted with one cyclopropyl or cyclopropyl hydroxyl group; RH3and RH4are independently chosen from hydrogen, hydroxyl, halogen, cyano, amino, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; and RH5is CHRH6RH7, C3-C8cycloalkyl, adamantyl, phenyl, or , wherein the C3-C7cycloalkyl and are optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, amino. C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; is selected from: ; RH6and RH7are each independently chosen from hydrogen, C1-C4alkyl, C1-C2haloalkyl. phenyl, C1-C6alkyl, and C3-C7cycloalkyl, wherein the phenyl, C1-C6alkyl, and C3-C7cycloalkyl are optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, and C1- C4alkyl, where one of RH6and RH7is not hydrogen. In certain embodiments IL-17 Targeting Ligand is of Formula: . In certain embodiments IL-17 Targeting Ligand is of Formula: . In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is of Formula:

[0080] wherein RF5is independently selected at each occurrence from RFA, or when taken together with the carbon atom which they are both attached, represents a C3-9cycloalkyl or a C3-7heterocycle, either of which may be optionally substituted by 1, 2, or 3 substituents selected from R21. In certain embodiments the IL-17 Targeting Ligand is: . Non-limiting examples of IL-17 Targeting Ligands include: . In certain embodiments the IL-17 Targeting Ligand is: . Non-limiting examples of IL-17 Targeting Ligands include: .

[0081] . In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is of Formula: . Non-limiting examples of IL-17 Targeting Ligands include: a

[0082] In certain embodiments IL-17 Targeting Ligand is of Formula: . . In certain embodiments IL-17 Targeting Ligand is of Formula: . In certain embodiments IL-17 Targeting Ligand selected from: . In certain embodiments IL-17 Targeting Ligand is selected from: In certain embodiments IL-17 Targeting Ligand is of Formula: In certain embodiments IL-17 Targeting Ligand is selected from:

[0083] In certain embodiments IL-17 Targeting Ligand is selected from: . In certain embodiments IL-17 Targeting Ligand is of Formula: In certain embodiments IL-17 Targeting Ligand is selected from: In certain embodiments IL-17 Targeting Ligand is of Formula: . In certain embodiments IL-17 Targeting Ligand is selected from: In certain embodiments IL-17 Targeting Ligand is of Formula: In certain embodiments IL-17 Targeting Ligand is selected from: In certain embodiments IL-17 Targeting Ligand is of Formula:

[0084] wherein RF7is a bond or -CRF7ARF7B-; wherein RF7Aand RF7Bare each independently selected at each occurrence from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, each of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from halogen, -OH, alkyl, alkoxy, alkyloxy-alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; Cy2 is a 5-6 membered aromatic ring, said ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said ring is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, alkyl, alkoxy, cycloalkyl, or -CN; n3 is independently 0, 1, 2, or 3; Cy3 is a 4-8 membered saturated or partially or completely unsaturated ring, said ring comprising 0-3 heteroatoms independently selected from N, O, S, S(O), and S(O)2; wherein said ring is optionally substituted with 1, 2, or 3 substituents selected from R21; wherein Cy2 and Cy3 are fused with each other; n1 is 0 or 1; n2 is 0, 1, or2; wherein n1 and n2 are not 0 at the same time; and X20is N or CH. In certain embodiments the IL-17 Targeting Ligand is: . Non-limiting examples of IL-17 Targeting Ligands include: ,

[0085] ,

[0086] In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is of Formula: n4 is 0, 1, or 2; RF9and RF10are each independently H, alkyl, cycloalkyl, alkoxy-alkyl, wherein each alkyl, cycloalkyl, and alkoxy-alkyl is optionally substituted with 1, 2, or 3 substituents selected from R21; or RF9and RF10together with the carbon atom to which they are attached form a spiro cycloalkyl or spiro heterocycle. In certain embodiments IL-17 Targeting Ligand is of Formula: . In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is: . In certain embodiments IL-17 Targeting Ligand is: In certain embodiments IL-17 Targeting Ligand is: Immunoglobulin G In some aspects of the invention, the Extracellular Protein Targeting Ligand targets an immunoglobulin, for example IgG, IgA, IgM, or IgE. The immunoglobulin degrading compounds described herein degrade a target immunoglobulin, for example IgG, IgA, IgM, or IgE, by linking a ligand for the selected immunoglobulin to a potent ASGPR binder through specific linking groups. In certain embodiments of the present invention, the selected immunoglobulin degrader degrades

[0087] or a pharmaceutically acceptable salt thereof; wherein: IgG Targeting Ligand is a Ligand that binds to immunoglobulin G. In certain embodiments, the IgG Targeting Ligand binds an antibody to either a foreign antigen or an autologous antigen (i.e. an autoantibody). In certain embodiments, the IgG Targeting Ligand binds an autoantibody. The IgG Targeting Ligand can bind a certain subclass of IgG, including IgG1, IgG2, IgG3, and IgG4, or a combination thereof. For example, a pan-IgG degrading compound could bind all subclasses of IgG. In certain embodiments, the IgG Targeting Ligand binds IgG1 and IgG2. In certain embodiments, the IgG Targeting Ligand binds IgG1, IgG2, and IgG4. In some aspects of the present invention an IgG degrader of the present invention uses a 1:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In other aspects of the present invention an IgG degrader of the present invention uses a 2:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In other aspects of the present invention an IgG degrader of the present invention uses a 3:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In certain embodiments the IgG Targeting Ligand is a peptide. In certain embodiments, the peptide IgG Targeting Ligand is a cyclic or linear peptide. In certain embodiments, the peptide IgG Targeting Ligand comprises one or more, or is entirely D-amino acids. In certain embodiments Extracellular Protein Targeting LigandBbinds IgG. In certain embodiments, Extracellular Protein Targeting LigandBis selected from: Ig-AMP-1 (VGECVRGRCSKISCCSQFGYCGKGPKYCG) SEQ ID NO: 445 Ig-EET-1 (GCQAHYWYRVWFCKQDSDCLAGCVCGPNGFCG) SEQ ID NO: 446 Ig-CON-5 (ECKGKGAKCSSISIHDAHCCTGSCRSGKC) SEQ ID NO: 447 SEQ ID NO: 449. In certain embodiments, the IgG Targeting Ligand is a targeting ligand that has at least 80%, 85%, 90%, 95%, or 98% sequence identity to a sequence described herein. For example, in certain embodiments the IgG Targeting Ligand is an amino acid that has at least 95% sequence identity to SEQ ID NO: 447. In certain embodiments, the IgG Targeting Ligand is a targeting ligand that has at least 80%, 85%, 90%, 95%, or 98% sequence identity to any one of SEQ ID NOs: 455-459. In certain embodiments, the IgG Targeting Ligand is a targeting ligand that has at least 80%, 85%, 90%, 95%, or 98% sequence identity to any one of SEQ ID NOs: 450-611. In certain embodiments, the IgG Targeting Ligand is selected from

[0088]

[0089] In certain embodiments, the Extracellular Protein Targeting LigandBis an immunoglobulin binding small molecule described in U.S. Patent 9,745,339. In certain embodiments, the Extracellular Protein Targeting LigandBis an immunoglobulin binding small molecule of the formula: wherein Am is an amide group —NR6—C(O)—, and wherein either NR6is attached to Arx1and — C(O)— is attached to Arx2, or —C(O)— is attached to Arx1and -NR6- is attached to Arx2; and Arx1is a 5-, 6- or 7-membered mononuclear aromatic ring or partially saturated aromatic ring, optionally: (a) attached to a further 5- or 6-membered mononuclear aromatic ring via a chemical bond; or (b) fused to a mononuclear or binuclear aromatic ring as part of a multinuclear ring system; wherein Arx1is directly connected to Am via a chemical bond present on the said 5-, 6- or 7-membered aromatic ring constituting Arx1, or indirectly via a chemical bond which is either present at the further 5- or 6-membered aromatic ring attached to Arx1, or on the further 5- or 6- membered aromatic ring fused to Arx1; and wherein Arx1is either not further substituted or attached to at least one substituent selected from C1-C4 alkyl; C3-C4 cycloalkyl; C2-C4 alkenyl; C2-C4 alkynyl; a halogen; C1-C4 haloalkyl; hydroxyl-substituted C1-C4 alkyl; C1-C4 alkoxy; hydroxyl-substituted C1-C4 alkoxy; halogen- substituted C1-C4 alkoxy; C1-C4 alkylamino; C1-C4 alkylthio; —NO2; ═O; ═S; ═NH; —OH; and combinations thereof; Arx2is a 5- or 6-membered mononuclear aromatic ring which is unsubstituted, or via a chemical bond attached to at least one substituent selected from C1-C6 alkyl; C3-C6 cycloalkyl; C2- C6 alkenyl; C5-C6 cycloalkenyl; C2-C6 alkynyl; a halogen; C1-C6 haloalkyl; hydroxyl-substituted C1-C6 alkyl; C1-C6 alkoxy; hydroxyl-substituted C1-C6 alkoxy; halogen-substituted C1-C6 alkoxy; C1-C6 alkylamino; C1-C6 alkylthio; carbamoyl; C1-C4 alkylenedioxy, preferably methylenedioxy and ethylenedioxy; —OH; —SH; a 5- or 6-membered mononuclear aromatic ring; and combinations thereof; and wherein Arx2optionally, further to the substituents to which it may be attached via a chemical bond as cited above, is fused to a 5- or 6-membered mononuclear aromatic ring as part of a multinuclear ring system. In certain embodiments, the Extracellular Protein Targeting LigandAis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide described herein. In certain embodiments, Extracellular Protein Targeting LigandAis at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a peptide described herein with one or more or all of the amino acids in the D-configuration. IgG Fc Region Binding Targeting Ligands In certain embodiments, the Extracellular Protein Targeting LigandBhas the structure: (Formula A-I); wherein Ra1, Ra2, and Ra3are independently −La−R’; each of La1and La2is independently La; each Lais independently a covalent bond, or an optionally substituted bivalent group selected from C1-C20 alkyl or C1-C20 heteroalkyl having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each −Cy− is independently an optionally substituted bivalent monocyclic, bicyclic or polycyclic wherein each monocyclic ring is independently selected from a C3-20 cycloaliphatic ring, a C6-20 aryl ring, a 5-20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, and sulfur; each R’ is independently −R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30 aliphatic, C1-30 heteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30 aryl, C6-30 arylaliphatic, C6-30 arylheteroaliphatic having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon. In certain embodiments Formula A-I binds the Fc region of IgG. In certain embodiments the Extracellular Protein Targeting LigandBof Formula A-I is attached to the Linker through the nitrogen . In other embodiments the Extracellular Protein Targeting LigandBof Formula A-I is attached to the Linker through the carbonyl . In certain embodiments, the Extracellular Protein Targeting LigandBhas the structure or a salt form thereof, wherein: each of RA1, RA3and RA5is independently hydrogen or an optionally substituted group selected from C1-6alkyl, a C3-8cycloalkyl, aryl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: RA1and RA1’are optionally taken together with their intervening carbon atom to form a 3- 8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; RA3and RA3’are optionally taken together with their intervening carbon atom to form a 3- 8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; an RA5group and the RA5’group attached to the same carbon atom are optionally taken together with their intervening carbon atom to form a 3-8 membered optionally substituted saturated or partially unsaturated spirocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated spirocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two RA5groups are optionally taken together with their intervening atoms to form a C1-10alkyl, C2-10alkenyl, C2-10alkynyl wherein 1-3 methylene units of the chain are independently and optionally replaced with –S–, –SS–, –N(R)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –C(O)N(R)–, –N(R)C(O)–, –S(O)–, – S(O)2–, or –Cy1–, wherein each –Cy1– is independently a 5-6 membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of RA1’, RA3’and RA5’is independently hydrogen or optionally substituted C1-3alkyl; each of RA2, RA4and RA6is independently hydrogen, or optionally substituted C1-4alkyl, or: RA2and RA1are optionally taken together with their intervening atoms to form a 4-8 membered, optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; RA4and RA3are optionally taken together with their intervening atoms to form a 4-8 membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an RA6group and its adjacent RA5group are optionally taken together with their intervening atoms to form a 4-8 membered optionally substituted saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R22Bis a trivalent linker moiety; and each of m and n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, Extracellular Protein Targeting LigandBis or comprises a peptide moiety, e.g., a moiety having the structure of Rc−(Xaa)z− or a salt form thereof, wherein each of Rc, z and Xaa is independently as described herein. In some embodiments, one or more Xaa are independently an unnatural amino acid residue. In some embodiments, side chains of two or more amino acid residues may be linked together to form bridges. For example, in some embodiments, side chains of two cysteine residues may form a disulfide bridge comprising −S−S− (which, as in many proteins, can be formed by two −SH groups). In some embodiments, Extracellular Protein Targeting LigandB, is or comprises a cyclic peptide moiety, e.g., a moiety having the structure of or a salt form thereof, wherein: each Xaa is independently a residue of an amino acid or an amino acid analog; t is 0-50; z is 1-50; each RCis independently −La−R’; each La is independently a covalent bond, or an optionally substituted bivalent group selected from C1-20alkyl or C1-20heteroalkyl having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−; each −Cy− is independently an optionally substituted bivalent monocyclic, bicyclic or polycyclic group wherein each monocyclic ring is independently selected from a C3-20cycloalkyl ring, a C6-20aryl ring, a 5- 20 membered heteroaryl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and a 3-20 membered heterocyclyl ring having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; each R’ is independently −R, −C(O)R, −CO2R, or −SO2R; each R is independently −H, or an optionally substituted group selected from C1-30alkyl, C1-30heteroalkyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, C6-30aryl, C6-30arylalkyl, C6-30arylheteroalkyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, 5-30 membered heteroaryl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, and 3-30 membered heterocyclyl having 1-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon, or two R groups are optionally and independently taken together to form a covalent bond, or: two or more R groups on the same atom are optionally and independently taken together with the atom to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the atom, 0-10 heteroatoms independently selected from oxygen, nitrogen, sulfur, phosphorus and silicon; or two or more R groups on two or more atoms are optionally and independently taken together with their intervening atoms to form an optionally substituted, 3-30 membered, monocyclic, bicyclic or polycyclic ring having, in addition to the intervening atoms, 0-10 heteroatoms. In some embodiments, Extracellular Protein Targeting LigandBis a peptide unit. In some embodiments, a peptide unit comprises R. In some embodiments, at least one Xaa is R. In some embodiments, a peptide unit is or comprises APAR. In some embodiments, a peptide unit is or comprises RAPA. In some embodiments, a peptide unit comprises an amino acid residue that has a side chain comprising an aromatic group (“aromatic amino acid residue”, XaaA). In some embodiments, a peptide unit comprises a positively charged amino acid residue and an aromatic amino acid residue. In some embodiments, a peptide unit comprises W. In some embodiments, a peptide unit comprises a positively charged amino acid residue (XaaP) and an aromatic amino acid residue. In some embodiments, a peptide unit is or comprises XaaAXaaXaaPXaaP. In some embodiments, a peptide unit is or comprises XaaPXaaPXaaXaaA. In some embodiments, a peptide unit is or comprises XaaPXaaAXaaP. In some embodiments, a peptide unit is or comprises two or more XaaPXaaAXaaP. In some embodiments, a peptide unit is or comprises XaaPXaaAXaaPXaaXaaPXaaAXaaP. In some embodiments, a peptide unit is or comprises XaaPXaaPXaaAXaaAXaaP. In some embodiments, a peptide unit is or comprises XaaPXaaPXaaPXaaA. In some embodiments, a peptide unit is or comprises two or more XaaAXaaAXaaP. In some embodiments, a peptide residue comprises one or more proline residues. In some embodiments, a peptide unit is or comprises HWRGWA. In some embodiments, a peptide unit is or comprises WGRR. In some embodiments, a peptide unit is or comprises RRGW. In some embodiments, a peptide unit is or comprises NKFRGKYK. In some embodiments, a peptide unit is or comprises NRFRGKYK. In some embodiments, a peptide unit is or comprises NARKFYK. In some embodiments, a peptide unit is or comprises NARKFYKG. In some embodiments, a peptide unit is or comprises HWRGWV. In some embodiments, a peptide unit is or comprises KHFRNKD. In some embodiments, a peptide unit comprises a positively charged amino acid residue, an aromatic amino acid residue, and an amino acid residue, e.g., a residue of an amino acid of formula A-I, that has a negatively charged side chain (e.g., at physiological pH about 7.4, “negatively charged amino acid residue”, XaaN). In some embodiments, a peptide unit comprises RHRFNKD. In some embodiments, a peptide unit is RHRFNKD. In some embodiments, a peptide unit comprises TY. In some embodiments, a peptide unit is TY. In some embodiments, a peptide unit comprises TYK. In some embodiments, a peptide unit is TYK. In some embodiments, a peptide unit comprises RTY. In some embodiments, a peptide unit is RTY. In some embodiments, a peptide unit comprises RTYK. In some embodiments, a peptide unit is RTYK. In some embodiments, a peptide unit is or comprises a sequence selected from PAM. In some embodiments, a peptide unit comprises WHL. In some embodiments, a peptide unit is WHL. In some embodiments, a peptide unit is or comprises WXL, wherein X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit comprises WDL. In some embodiments, a peptide unit is WDL. In some embodiments, a peptide unit comprises ELVW. In some embodiments, a peptide unit is ELVW. In some embodiments, a peptide unit comprises GELVW. In some embodiments, a peptide unit is GELVW. In some embodiments, a peptide unit is or comprises a sequence selected from AWHLGELVW. In some embodiments, a peptide unit is or comprises AWHLGELVW. In some embodiments, a peptide unit is or comprises a sequence selected from AWDLGELVW. In some embodiments, a peptide unit is or comprises AWDLGELVW. In some embodiments, a peptide unit is or comprises AWXLGELVW, wherein X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises a sequence selected from DCAWHLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises DCAWHLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from DCAWXLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins, and X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises DCAWXLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins, and X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, X comprises −COOH or a salt or activated form thereof in its side chain. In some embodiments, a peptide unit is or comprises a sequence selected from DCAWDLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises DCAWDLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from Fc-III. In some embodiments, a peptide unit is or comprises Fc-III. In some embodiments, a peptide unit is or comprises a sequence selected from DPLPAWXLGELVW, wherein X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises DPLPAWXLGELVW, wherein X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises a sequence selected from DPLPAWDLGELVW. In some embodiments, a peptide unit is or comprises DPLPAWDLGELVW. In some embodiments, a peptide unit is or comprises a sequence selected from DPLPAWHLGELVW, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises DPLPAWHLGELVW (e.g., FcBP-1), wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from FcBP-1. In some embodiments, a peptide unit is or comprises a sequence selected from DPLPDCAWXLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins, and X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises DPLPDCAWXLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins, and X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises a sequence selected from DPLPDCAWHLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises DPLPDCAWHLGELVWCT (e.g., FcBP-2), wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from DPLPDCAWDLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises DPLPDCAWDLGELVWCT, wherein the two cysteine residues can form a disulfide bond as found in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from FcBP-2. In some embodiments, a peptide unit is or comprises a sequence selected from CDCAWXLGELVWCTC, wherein the first and the last cysteines, and the two cysteines in the middle of the sequence, can each independently form a disulfide bond as in natural proteins, and X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises CDCAWXLGELVWCTC, wherein the first and the last cysteines, and the two cysteines in the middle of the sequence, can each independently form a disulfide bond as in natural proteins, and X is an amino acid residue as described herein, e.g., one suitable for connection with another moiety (e.g., an amino acid residue comprising −COOH or a salt or activated form thereof such as D, E, etc.). In some embodiments, a peptide unit is or comprises a sequence selected from CDCAWHLGELVWCTC, wherein the first and the last cysteines, and the two cysteines in the middle of the sequence, can each independently form a disulfide bond as in natural proteins. In some embodiments, a peptide unit is or comprises CDCAWHLGELVWCTC, wherein the first and the last cysteines, and the two cysteines in the middle of the sequence, can each independently form a disulfide bond as in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from CDCAWDLGELVWCTC, wherein the first and the last cysteines, and the two cysteines in the middle of the sequence, can each independently form a disulfide bond as in natural proteins. In some embodiments, a peptide unit is or comprises CDCAWDLGELVWCTC, wherein the first and the last cysteines, and the two cysteines in the middle of the sequence, can each independently form a disulfide bond as in natural proteins. In some embodiments, a peptide unit is or comprises a sequence selected from Fc-III-4c. In some embodiments, a peptide unit is or comprises a sequence selected from FcRM. In some embodiments, a peptide unit is or comprises a cyclic peptide unit. In some embodiments, a cyclic peptide unit comprises amide group formed by an amino group of a side chain and the C-terminus −COOH. It is appreciated by those skilled in the art that in various embodiments, when a peptide unit is connected to another moiety, an amino acid residue of a peptide unit may be connected through various positions, e.g., its backbone, its side chain, etc. In some embodiments, an amino acid residue is modified for connection. In some embodiments, an amino acid residue is replaced with another suitable residue for connection while maintaining one or more properties and / or activities a peptide unit (e.g., binding to an antibody as described herein). For example, in some embodiments, an amino acid residue is replaced with an amino acid residue with a side chain comprising −COOH or a salt or activated form thereof (e.g., side chain being −CH2−COOH or a salt or activated form thereof). As exemplified herein, in various sequences H may be replaced with D (e.g., in various peptide units comprising WHL). In some embodiments, a peptide unit is connected to another moiety through −COOH or a salt or activated form thereof, e.g., through formation of e.g., −CON(R’)−. In some embodiments, R’ is −H. In some embodiments, −COOH is in a side chain of an amino acid residue. In some embodiments, in a sequence described herein (e.g., DCAWHLGELVWCT), 1-5 (e.g., 1, 2, 3, 4, or 5) amino acid residues may be independently and optionally replaced with another amino acid residue, 1-5 (e.g., 1, 2, 3, 4, or 5) amino acid residues may be independently and optionally deleted, and / or 1-5 (e.g., 1, 2, 3, 4, or 5) amino acid residues may be independently and optionally inserted. In some embodiments, a peptide moiety is connected to the rest of a molecule through its N- terminus. In some embodiments, it is connected to the rest of a molecule through its C-terminus. In some embodiments, it is connected to the rest of a molecule through a side chain of an amino acid residue (e.g., various X residues as described in the present disclosure). In some embodiments, two cysteine residues may independently and optionally form a disulfide bond. In some embodiments, the total number of replacements, deletions and insertions is no more than 10 (e.g., 0, or no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, the total number is 0. In some embodiments, the total number is no more than 1. In some embodiments, the total number is no more than 2. In some embodiments, the total number is no more than 3. In some embodiments, the total number is no more than 4. In some embodiments, the total number is no more than 5. In some embodiments, the total number is no more than 6. In some embodiments, the total number is no more than 7. In some embodiments, the total number is no more than 8. In some embodiments, the total number is no more than 9. In some embodiments, the total number is no more than 10. In some embodiments, there are no insertions. In some embodiments, there are no deletions. In some embodiments, an antibody binding moiety comprises or has the structure of DCAWHLGELVWCT or a salt form thereof, wherein the two C residues are linked by a −S−S−. In some embodiments, an antibody binding moiety comprises or has the structure of DCAWHLGELVWCT or a salt form thereof, wherein the N-terminus is capped with R−C(O)−. In some embodiments, wherein R is methyl. In some embodiments, an antibody binding moiety is connected to the rest of a molecule through its C-terminus. In some embodiments, −(Xaa)z− is or comprises [X1]p1[X2]p2-X3X4X5X6X7X8X9X10X11X12-[X13]p13- [X14]p14[X15]p15[X16]p16, wherein each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15and X16is independently an amino acid residue, e.g., of an amino acid of formula A-I, and each of p1, p2, p13, p14, p15 and p16 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15and X16is independently an amino acid residue of an amino acid of formula A-I. In some embodiments, each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15and X16is independently a natural amino acid residue. In some embodiments, one or more of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15and X16are independently an unnatural amino acid residue as described in the present disclosure. In some embodiments, a peptide unit comprises a functional group in an amino acid residue that can react with a functional group of another amino acid residue. In some embodiments, a peptide unit comprises an amino acid residue with a side chain which comprises a functional group that can react with another functional group of the side chain of another amino acid residue to form a linkage. In some embodiments, one functional group of one amino acid residue is connected to a functional group of another amino acid residue to form a linkage (or bridge). Linkages are bonded to backbone atoms of peptide units and comprise no backbone atoms. In some embodiments, a peptide unit comprises a linkage formed by two side chains of non- neighboring amino acid residues. In some embodiments, a linkage is bonded to two backbone atoms of two non- neighboring amino acid residues. In some embodiments, both backbone atoms bonded to a linkage are carbon atoms. In some embodiments, a linkage has the structure of Lb, wherein Lb is La as described in the present disclosure, wherein La is not a covalent bond. In some embodiments, La comprises −Cy−. In some embodiments, La comprises −Cy−, wherein −Cy− is optionally substituted heteroaryl. In some embodiments, In some embodiments, In some embodiments, such an La can be formed by a −N3 group of the side chain of one amino acid residue, and the −≡− of the side chain of another amino acid residue. In some embodiments, a linkage is formed through connection of two thiol groups, e.g., of two cysteine residues. In some embodiments, La comprises −S−S−. In some embodiments, La is −CH2−S−S−CH2−. In some embodiments, a linkage is formed through connection of an amino group (e.g., −NH2 in the side chain of a lysine residue) and a carboxylic acid group (e.g., −COOH in the side chain of an aspartic acid or glutamic acid residue). In some embodiments, La comprises −C(O)−N(R’)−. In some embodiments, La comprise −C(O)−NH−. In some embodiments, La is −CH2CONH−(CH2)3−. In some embodiments, La comprises −C(O)−N(R’)−, wherein R’ is R, and is taken together with an R group on the peptide backbone to form a ring. In some embodiments, La is −(CH2)2−N(R’)−CO−−(CH2)2−. In some embodiments, −Cy− is optionally substituted phenylene. In some embodiments, −Cy− is optionally substituted 1,2-phenylene. In some embodiments, In some embodiments, . In some embodiments, La is optionally substituted bivalent C2-20 alkyl. In some embodiments, La is optionally substituted −(CH2)9−CH=CH−(CH2)9−. In some embodiments, La is −(CH2)3−CH=CH−(CH2)3−. In some embodiments, each of X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15and X16is independently an amino acid residue of the Formula A-1. In some embodiments, X5is an amino acid residue whose side chain comprises an optionally substituted saturated, partially saturated or aromatic ring. In some embodiments, X5is In some embodiments, X6is XaaA. In some embodiments, X6is XaaP. In some embodiments, X6is His. In some embodiments, X12is XaaA. In some embodiments, X12is XaaP. In some embodiments, X9is Asp. In some embodiments, X9is Glu. In some embodiments, .In some embodiments, .In some embodiments, each of X7, X10, and X11is independently an amino acid residue with a hydrophobic side chain (“hydrophobic amino acid residue”, XaaH). In some embodiments, X7 is XaaH. In some embodiments, X7 is , some embodi 7 ments, X is Val.In some embodiments, X10is XaaH. In some embodiments, X10is Met. In some In some embodiments, X8is Gly. In some embodiments, X4is Pro. In some embodiments, X3is Lys. In some embodiments, the −COOH of X12forms an amide bond with the side chain amino group of Lys (X3), and the other amino group of the Lys (X3) is connected to Linker. In some embodiments, −(Xaa)z− is or comprises −X3X4X5X6X7X8X9X10X11X12−, wherein: each of X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12is independently an amino acid residue; at least two amino acid residues are connected through one or more linkages Lb; Lb is an optionally substituted bivalent group selected from C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms; X6is XaaAor XaaP; X9is XaaN; and X12is XaaAor XaaP. In some embodiments, each of X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12is independently an amino acid residue of an amino acid of Formula A-I as described in the present disclosure. In some embodiments, two non-neighboring amino acid residues are connected by Lb. In some embodiments, X5and X10are connected by Lb. In some embodiments, there is one linkage Lb. In some embodiments, X6is XaaA. In some embodiments, X6is XaaP. In some embodiments, X6is His. In some embodiments, X9is Asp. In some embodiments, X9is Glu. .

[0090] . In some embodiments each of X4, X7, and X11is independently XaaH. In some embodiments, X4is XaaH. In some embodiments, X4is Ala. In some embodiments, X7is XaaH. In some embodiments, . In some embodiments,X11 is XaaH. In some Embodiments, X11 is , , . In someembodiments, X8is Gly. In some embodiments, X3is Lys. In some embodiments, the −COOH of X12forms an amide bond with the side chain amino group of Lys (X3), and the other amino group of the Lys (X3) is connected to a linker moiety and then an antibody binding moiety. In some embodiments, .In some embodiments, Lb connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, both X5and X10are Cys, and the two −SH groups of their side chains form −S−S− (Lb is −CH2−S−S−CH2−). In some embodiments, −(Xaa)z− is or comprises −X2X3X4X5X6X7X8X9X10X11X12−, wherein: each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12is independently an amino acid residue; at least two amino acid residues are connected through one or more linkages Lb; Lb is an optionally substituted bivalent group selected from C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms; X4is XaaA; X5is XaaAor XaaP; X8is XaaN; and X11is XaaA. In some embodiments, each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12is independently an amino acid residue of an amino acid of Formula A-I as described in the present disclosure. In some embodiments, two non-neighboring amino acid residues are connected by Lb. In some embodiments, there is one linkage Lb. In some embodiments, X2and X12are connected by Lb. In some embodiments, Lb is −CH2−S−S−CH2−. In some embodiments, Lb is −CH2−CH2−S−CH2−. In some embodiments, Lb is −CH2CH2CO−N(R’)−CH2CH2−. In some embodiments, R’ are taken together with an R group on the backbone atom that −N(R’)−CH2CH2− is bonded to form a ring, e.g., In some embodiments, a formed ring is 3-, 4-, 5-, 6-, 7- or 8-membered. In some embodiments, a formed ring is monocyclic. In some embodiments, a formed ring is saturated. In some embodiments, .In some embodiments, Lb connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, X4is XaaA. In some embodiments, X4is Tyr. In some embodiments, X5is XaaA. In some embodiments, X5is XaaP. In some embodiments, X5is His. In some embodiments, X8is Asp. In some embodiments, X8is Glu. X11is Tyr. In some embodiments, both X2and X12are Cys, and the two −SH groups of their side chains form −S−S− (Lb is −CH2−S−S−CH2−). In some embodiments, each of X3, X6, X9, and X10is independently XaaH. In some embodiments, X3is XaaH. In some embodiments, X3is Ala. In some embodiments, X6is XaaH. In some embodiments, X6is Leu. In some embodiments, X9is XaaH. In some embodiments,X9 is Leu. In some embodiments, X9 is In someembodiments, X10is XaaH. In some embodiments, X10is Val. In some embodiments, X10is In some embodiments, X7is Gly. In some embodiments, p1 is 1. In some embodiments, X1is Asp. In some embodiments, p13 is 1. In some embodiments, p14, p15 and p16 are 0. In some embodiments, X13is an amino acid residue comprising a polar uncharged side chain (e.g., at physiological pH, “polar uncharged amino acid residue”, XaaL). In some embodiments, X13is Thr. In some embodiments, X13is Val. In some embodiments, p13 is 0. In some embodiments, RCis −NHCH2CH(OH)CH3. In some embodiments, RCis (R)−NHCH2CH(OH)CH3. In some embodiments, RCis (S)−NHCH2CH(OH)CH3. In some embodiments, −(Xaa)z− is or comprises −X2X3X4X5X6X7X8X9X10X11X12−, wherein: each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12is independently an amino acid residue; at least two amino acid residues are connected through one or more linkages Lb; Lb is an optionally substituted bivalent group selected from C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms; X5is XaaAor XaaP; X8is XaaN; and X11is XaaA. In some embodiments, each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, and X12is independently an amino acid residue of an amino acid of formula A-I as described in the present disclosure. In some embodiments, two non-neighboring amino acid residues are connected by Lb. In some embodiments, there is one linkage Lb. In some embodiments, there are two or more linkages Lb. In some embodiments, there are two linkages Lb. In some embodiments, X2and X12are connected by Lb. In some embodiments, X4and X9are connected by Lb. In some embodiments, X4and X10are connected by Lb. In some embodiments, Lb is −CH2−S−S−CH2−. In some In some embodiments, both X2and X12are Cys, and the two −SH groups of their side chains form −S−S− (Lb is −CH2−S−S−CH2−). In some embodiments, both X4and X10are Cys, and the two −SH groups of their side chains form −S−S− (Lb is −CH2−S−S−CH2−). In someembodiments, X4 and X9 are connected by Lb, wherein Lb or . In some embodiments, X5is XaaA. In some embodiments, X5is XaaP. In some embodiments, X5is His. In some embodiments, X8is Asp. In some embodiments, X8is Glu. In

[0091] Lb, wherein Lb is −CH2−S−CH2CH2−. In some embodiments, Lb connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, each of X3, X6, and X9is independently XaaH. In some embodiments, X3is XaaH. In some embodiments, X3is Ala. In some embodiments, X6is XaaH. In some embodiments, X6is Leu. In some embodiments, X6is embodiments, X9is Leu. In some embodiments, . In some embodiments, X10is XaaH. In some embodiments, X10is Val. In some embodiments, X7is Gly. In some embodiments, p1 is 1. In some embodiments, X1is XaaN. In some embodiments, X1is Asp. In some embodiments, X1is Glu. In some embodiments, p13 is 1. In some embodiments, p14, p15 and p16 are 0. In some embodiments, X13is XaaL. In some embodiments, X13is Thr. In some embodiments, X13is Val. In some embodiments, −(Xaa)z− is or comprises −X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16−, wherein: each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, and X16is independently an amino acid residue; at least two amino acid residues are connected through a linkage Lb; Lb is an optionally substituted bivalent group selected from C1-C20 aliphatic or C1-C20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with −C(R’)2−, −Cy−, −O−, −S−, −S−S−, −N(R’)−, −C(O)−, −C(S)−, −C(NR’)−, −C(O)N(R’)−, −N(R’)C(O)N(R’)−, −N(R’)C(O)O−, −S(O)−, −S(O)2−, −S(O)2N(R’)−, −C(O)S−, or −C(O)O−, wherein Lb is bonded to a backbone atom of one amino acid residue and a backbone atom of another amino acid residue, and comprises no backbone atoms; X3is XaaN; X6is XaaA; X7is XaaAor XaaP; X9is XaaN; and X13is XaaA. In some embodiments, each of X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, and X16is independently an amino acid residue of an amino acid of Formula A-I as described in the present disclosure. In some embodiments, two non-neighboring amino acid residues are connected by Lb. In some embodiments, there is one linkage Lb. In some embodiments, there are two or more linkages Lb. In some embodiments, there are two linkages Lb. In some embodiments, X2is connected to X16by Lb. In some embodiments, X4is connected to X14by Lb. In some embodiments, both X2and X16are Cys, and the two −SH groups of their side chains form −S−S− (Lb is −CH2−S−S−CH2−). In some embodiments, both X4and X14are Cys, and the two −SH groups of their side chains form −S−S− (Lb is −CH2−S−S−CH2−). In some embodiments, Lb connects two alpha-carbon atoms of two different amino acid residues. In some embodiments, X3is Asp. In some embodiments, X3is Glu. In some embodiments, X5is XaaH. In some embodiments, X5is Ala. In some embodiments, X6is XaaA. In some embodiments, X6is Tyr. In some embodiments, X7is XaaA. In some embodiments, X7is XaaP. In some embodiments, X7is His. In some embodiments, X8is XaaH. In some embodiments, X8is Ala. In some embodiments, X9is Gly. In some embodiments, X10is Asp. In some embodiments, X10is Glu. In some embodiments, X11is XaaH. In some embodiments, X11is Leu. In some embodiments, X12is XaaH. In some embodiments, X12is Val. In some embodiments, X13is XaaA. In some embodiments, X13is Tyr. In some embodiments, X15is XaaL. In some embodiments, X15is Thr. In some embodiments, X15is Val. In some embodiments, p1 is 1. In some embodiments, In some embodiments, X1is XaaN. In some embodiments, X1is Asp. In some embodiments, X1is Glu. As appreciated by those skilled in the art, an amino acid residue may be replaced by another amino acid residue having similar properties, e.g., one XaaH(e.g., Val, Leu, etc.) may be replaced with another XaaH(e.g., Leu, Ile, Ala, etc.), one XaaAmay be replaced with another XaaA, one XaaPmay be replaced with another XaaP, one XaaNmay be replaced with another XaaN, one XaaLmay be replaced with another XaaL, etc. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from:

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] and . In certain embodiments, the Extracellular Protein Targeting LigandBis selected from:

[0103]

[0104]

[0105] . Immunoglobulin A (IgA) Aberrant expression of immunoglobulin A (IgA) mediates a range of autoimmune and immune-mediated disorders, including IgA nephropathy (also known as Berger’s disease), celiac disease, Crohn’s disease, Henoch-Schönlein purpura (HSP) (also known as IgA vasculitis), IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic liver cirrhosis, acquired immunodeficiency syndrome, IgA multiple myeloma, α-chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, and primary glomerulonephritis, among others. In certain embodiments, Extracellular Protein Targeting LigandBis an IgA1 binding ligand in US20090317381A1; US20210301019A1; US4757134; US5210183; US5644030; US5714334; US5723303; US5869047; Ramsland, P. et al. “Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1” PNAS 2007, 104:38, 15051-15056; and Herr, A. et al. “Insights into IgA-mediated immune responses from the crystal structures of human FcaRI and its complex with IgA1-Fc” Nature 2003, 423, 614-620. In certain embodiments, Extracellular Protein Targeting LigandBis an IgA Targeting Ligand selected from SEQ ID NO: 612 *(Ac)-FVPTTX(N-Me)AX(N-Me)AEAPC* SEQ ID NO: 613 *(Ac)-FVDTTS(N-Me)FX(N-Me)ENSPC* SEQ ID NO: 614 *(Ac)-FVSTTX(N-Me)AX(N-Me)ADRPC* SEQ ID NO: 615 *(Ac)-FVDTTS(N-Me)FX(N-Me)ANSPC* SEQ ID NO: 616 *(Ac)-FVDSTT(N-Me)AX(N-Me)ANHPC* SEQ ID NO: 617 *(Ac)-FVDTTS(N-Me)FX(N-Me)AESPC* SEQ ID NO: 618 *(Ac)-FVDTTS(N-Me)F(4CF3)F(N-Me)AESPC* SEQ ID NO: 619 *(Ac)-FVDTTS(N-Me)AX(N-Me)AKSPC* SEQ ID NO: 620 *(Ac)-FVSTTX(N-Me)AX(N-Me)ADSPC* SEQ ID NO: 621 *(Ac)-FVSTTS(N-Me)FX(N-Me)ADRPC* SEQ ID NO: 622 *(Ac)-FVDTTX(N-Me)AX(N-Me)AESPC* SEQ ID NO: 623 *(Ac)-FVSTT(4CF3)F(N-Me)A(4CF3)F(N-Me)AERPC* SEQ ID NO: 624 *(Ac)-FVSTTS(N-Me)FX(N-Me)AESPC* SEQ ID NO: 625 *(Ac)-FVSTTX(N-Me)FX(N-Me)AESPC* SEQ ID NO: 626 *(Ac)-FVSTTX(N-Me)A(3,4diCl)F(N-Me)ADRPC* SEQ ID NO: 627 *(Ac)-FVSTTX(N-Me)A(3Fl)F(N-Me)ADRPC* SEQ ID NO: 628 *(Ac)-FVDTTA(N-Me)FX(N-Me)AEAPC* SEQ ID NO: 629 *(Ac)-FVDTTF(N-Me)AX(N-Me)AESPC* SEQ ID NO: 630 *(Ac)-FVDTTA(N-Me)FX(N-Me)AQAPC* SEQ ID NO: 631 *(Ac)-FVPTTX(N-Me)AX(N-Me)ADRPC* SEQ ID NO: 632 *(Ac)-FVSTTX(N-Me)AX(N-Me)APSPC* SEQ ID NO: 633 *(Ac)-FVPTTA(N-Me)FX(N-Me)AEAPC* SEQ ID NO: 634 *(Ac)-FVATTF(N-Me)AX(N-Me)AKAPC* SEQ ID NO: 635 *(Ac)-FVNTTF(N-Me)AX(N-Me)AKAPC* SEQ ID NO: 636 *(Ac)-FVSTTF(N-Me)AX(N-Me)AEAPC* SEQ ID NO: 637 *(Ac)-FVSTTX(N-Me)AX(N-Me)AESPC* SEQ ID NO: 638 *(Ac)-FVDTTX(N-Me)A(3,4diCl)F(N-Me)AESPC* SEQ ID NO: 639 *(Ac)-FENTTF(N-Me)AX(N-Me)AASPC* SEQ ID NO: 640 *(Ac)-FVPTTF(N-Me)A(4Cl)F(N-Me)APAPC* SEQ ID NO: 641 *(Ac)-FVPTTF(N-Me)A(4Cl)F(N-Me)ADAPC* SEQ ID NO: 642 *(Ac)-FV-Hse-TTF(N-Me)A(4CI)F(N-Me)ADAPC* SEQ ID NO: 643 *(Ac)-FVATTF(N-Me)A(4Cl)F(N-Me)ANAPC* SEQ ID NO: 644 *(Ac)-FVPTTV(N-Me)A(4Cl)F(N-Me)AEAPC* SEQ ID NO: 645 *(Ac)-FVNTTF(N-Me)AX(N-Me)A(N-Me)EAPC* SEQ ID NO: 646 *(Ac)-FVPTTF(N-Me)AX(N-Me)AEAPC* SEQ ID NO: 647 *(Ac)-FVPTTX(N-Me)AX(N-Me)AAAPC* In some aspects of the present invention an IgA degrader uses a 1:1 ratio of ASGPR Binding Ligands to IgA Binding Ligand. In some aspects of the present invention an IgA degrader uses a 2:1 ratio of ASGPR Binding Ligands to IgA Binding Ligand. In some aspects of the present invention an IgA degrader uses a 3:1 ratio of ASGPR Binding Ligands to IgA Binding Ligand. The selective targeting of IgA can be particularly beneficial when the present invention is used in the treatment of a disease known to be caused primarily by IgA, such as Henoch-Schönlein purpura, also known as IgA vasculitis. Additional disorders mediated by IgA include cryoglobulinemia, granulomatosis with polyangiitis, thrombocytopenia, peripheral neuropathy, MGUS, IgA nephropathy, and Henoch Schönlein purpura Immunoglobulin A1 (IgA1) Immunoglobulin A is a class of antibodies which is commonly found in secretions, but is also present in serum. IgA contains four heavy chains and four light chains, in a dimeric form. IgA exists in two isotypes, IgA1 and IgA2. IgA1 contains more repeats in the hinge region and is the predominant form found in serum. While production of IgA maintains strong mucosal immunity and defending against pathogens, it can become toxic. IgA nephropathy, also known as Berger’s disease, is the pathological buildup of IgA antibodies which reduces kidney function. The etiology of the disease remains unclear, however it has been suggested that the glycosylation pattern on the hinge region plays a role. As proper kidney function is important for overall health, IgA nephropathy is associated with systemic diseases such as liver failure, cancer, celiac disease, systemic lupus erythematosus, rheumatoid arthritis, heart failure, reactive arthritis, and ankylosing spondylitis. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises an epitope that is recognized by IgAl, gd-IgAl, and / or anti-gd-IgA1. In certain embodiments, an epitope is a linear epitope. In certain embodiments, an epitope is a conformational epitope. In certain embodiments, an epitope is or comprises a single continuous epitope. In certain embodiments, an epitope comprises one or more additional amino acid residues, e.g., on the 5' end and / or the 3' end of the epitope. In certain embodiments, an epitope comprises one or more sequences separated by one or more intervening amino acid sequences configured such that the one or more sequences form a single epitope, e.g., spatially form an epitope when expressed and folded into a polypeptide conformation. In certain embodiments, an intervening amino acid sequence comprises a linker and / or a spacer. For example, an epitope comprising one or more sequences separated by one or more intervening amino acid sequences has the following structure: Xn-[A1]-Xn-[A2]-Xn, wherein Alis a first portion of an epitope and A2is a second portion of an epitope which together form a spatial epitope that is recognized by IgAl, gd-IgAl, and / or anti-gd-IgA1, and X denotes intervening amino acid sequences with n being an integer from 0-20. In certain embodiments, an intervening amino acid sequence is a spacer or a linker, e.g., as described herein. In certain embodiments, an epitope that is formed by one or more sequences can be broken up into 3, 4, 5, or more fragments. For example, in such embodiments, the Extracellular Protein Targeting LigandBmay comprise the following structure: Xn-[Al]-Xn-[A2]-Xn-[An]-Xn, wherein Alis a first portion of an epitope, A2is a second portion of an epitope, and An is the n-th portion of an epitope which together form a spatial epitope that is recognized by IgAl, gd-IgAl, and / or anti-gd-IgA1, and X denotes intervening amino acid sequences with n being an integer from 0-20. In certain embodiments, an intervening amino acid sequence is a spacer or a linker, e.g., as described herein. CD89, also known as immunoglobulin alpha Fc receptor (FcaRl), is a human myeloid IgA Fc receptor and binds to both IgAl and IgA2 subclasses of IgA (Morton HC and Brandtzaeg P (2001) Arch Immunol Ther Exp (Warsz) 49(3):217-29. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises CD89 polypeptides or fragments thereof, for example soluble CD89 (sCD89), which specifically bind to IgA1. An exemplary human CD89 polypeptide sequence is provided herein as SEQ ID NO: 648 (comprising the signal sequence of SEQ ID NO: 649), SEQ ID NO: 650 (comprising the signal sequence of SEQ ID NO: 649), SEQ ID NO: 651 (comprising the signal sequence of SEQ ID NO: 652), SEQ ID NO: 653, and SEQ ID NO: 654. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from SEQ ID NOs 648-654, or a fragment thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide sequence with at least about 80%, 85%, 90%, or even 95% homology with a sequence selected from SEQ ID NOs 648-654, or a fragment thereof In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a soluble form of CD89 of a variant or a fragment thereof. Soluble CD89 is described e.g., in van Zandbergen G et al., (1999) J Immunology 163, pp.5806-5812; and in van Der Boog PJM et al., (2002) J Immunology 168.3 pp.1252-1258, the entire contents of each of which are hereby expressly incorporated by reference. In certain embodiments, a CD89 polypeptide comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100 % sequence identity with SEQ ID NO: 648. In certain embodiments, a CD89 polypeptide is or comprises SEQ ID NO: 648 or SEQ ID NO: 650. In certain embodiments, a CD89 polypeptide is or comprises SEQ ID NO: 648 or SEQ ID NO: 650 without the signal peptide of SEQ ID NO: 649. In certain embodiments, the Extracellular Protein Targeting LigandBcomprising a CD89 polypeptide comprises a sequence having at least 85% identity to SEQ ID NO: 648 without the signal peptide of SEQ ID NO: 649. In certain embodiments, a CD89 polypeptide comprises a sequence having at least 85% identity to SEQ ID NO: 650 without the signal peptide of SEQ ID NO: 649. In certain embodiments, the Extracellular Protein Targeting LigandBcomprising a CD89 polypeptide comprising a sequence having at least 85% identity to SEQ ID NO: 648 without the signal peptide of SEQ ID NO: 649, further comprises a signal peptide selected from the group consisting of SEQ ID NOs: 655-658. In certain embodiments, the Extracellular Protein Targeting LigandBcomprising a CD89 polypeptide comprising a sequence having at least 85% identity to SEQ ID NO: 650 without the signal peptide of SEQ ID NO: 649, further comprises a signal peptide selected from the group consisting of SEQ ID NOs: 655-658. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a plurality of CD89 fragments that bind to IgAl, e.g., the same or different CD89 fragments that bind to IgAl. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a plurality of the same CD89 fragments that bind to IgAl. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a plurality of different CD89 fragments that bind to IgAl. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an IgAl antibody comprises a contiguous chain of amino acids comprising at least 5%, at least 10%, 15%, at least 20%, at least 25%, at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, of the amino acid of SEQ ID NO: 648 or SEQ ID NO: 650. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an IgAl antibody comprises a contiguous chain of amino acids comprising at least 5%, at least 10%, 15%, at least 20%, at least 25%, at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, of the amino acid of SEQ ID NO: 648 or SEQ ID NO: 650 without the signal peptide. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an IgAl antibody comprises a contiguous chain of amino acids comprising at least 5%, at least 10%, 15%, at least 20%, at least 25%, at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, of the amino acid of SEQ ID NO: 651. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an IgAl antibody comprises a contiguous chain of amino acids comprising at least 5%, at least 10%, 15%, at least 20%, at least 25%, at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, of the amino acid of SEQ ID NO: 652. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an IgAl antibody comprises a contiguous chain of amino acids comprising at least 5%, at least 10%, 15%, at least 20%, at least 25%, at least 30 %, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, of the amino acid of SEQ ID NO: 654. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an IgAl antibody comprises a full length CD89 protein, e.g., as provided in SEQ ID NO: 648 with or without the signal peptide. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an anti- IgAl antibody comprises a variant of a CD89 polypeptide. In certain embodiments, a variant is an inactive variant as compared to a wild-type CD89 polypeptide. In certain embodiments, a variant comprises a CD89 polypeptide or a fragment thereof having one or more mutations at a glycosylation site. In certain embodiments, a mutation is at an Asparagine residue such that a glycosylation site is altered. In certain embodiments, a mutation comprises a mutation at Asparagine 141, Asparagine 177, Asparagine 186 and / or Asparagine 198. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a CD89 polypeptide or a fragment thereof having one or more native glycosylation sites. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a CD89 polypeptide or a fragment thereof having two native glycosylation sites. In certain embodiments, a native glycosylation site comprises N65 and / or N79. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a CD89 polypeptide or a fragment thereof comprising native glycosylation sites: N65 and N79. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a CD89 polypeptide or a fragment thereof having one or more engineered glycosylation sites. In certain embodiments, an engineered glycosylation site is or comprises the sequence of SEQ ID NO: 659. In certain embodiments, the Extracellular Protein Targeting LigandBcomprises a CD89 polypeptide or a fragment thereof having two native glycosylation sites: N65 and N79, and one engineered glycosylation site having the sequence of SEQ ID NO: 659. Anti-gd-IgAl autoantibodies and peptides that bind to anti-gd-IgAl In IgA nephropathy autoimmunity, a gd-IgAl autoantigens produces anti-gd-IgAl autoantibodies. In certain embodiments, anti-gd-IgAl autoantibodies or immune complexes comprising the same form deposits in one or more tissues or organs. In certain embodiments, anti- gd-IgAl autoantibodies or immune complexes comprising the same contribute to and / or result in IgA nephropathy. In certain embodiments, an anti-gd-IgAl autoantibody is an IgG antibody. In certain embodiments, an anti-gd-IgAl autoantibody is an IgA antibody. In certain embodiments, an anti- gd-IgAl autoantibody is an IgM antibody. In certain embodiments, an anti-gd-IgAl autoantibody is an IgD antibody. In certain embodiments, an anti-gd-IgAl autoantibody is an IgE antibody. In certain embodiments, a gd-IgAl autoantigen is a gd-IgAl polypeptide or a variant or fragment thereof. In certain embodiments, a gd-IgAl autoantigen is a glycan profile found on gd- IgAl. In certain embodiments, an anti-gd-IgAl autoantibody, a fragment, or a complex thereof is characterized in that it binds to a gd-IgAl polypeptide or a variant or fragment thereof. In certain embodiments, an anti-gd-IgAl autoantibody, a fragment, or a complex thereof is characterized in that it binds to one or more glycans on gd-IgAl. In certain embodiments, an anti-gd-IgAl antibody specifically binds to a glycan profile on gd-IgAl. In certain embodiments, a glycan profile bound by an anti-gd-IgAl is not present on a reference IgAl, e.g., an IgAl from a healthy individual or an individual who is not at risk of developing IgAN. In certain embodiments, a glycan profile bound by an anti-gd-IgAl is a gd-IgAl glycan profile described herein. In certain embodiments, the Extracellular Protein Targeting LigandAdisclosed herein comprises one or more peptides that specifically bind to one or more idiotopes of an anti-gd-IgAl autoantibody, or a fragment thereof. In certain embodiments, the one or more peptides comprise an anti-idiotypic antibody or a fragment (e.g., an antigen binding fragment) thereof. In certain embodiments, an anti-gd-IgAl IgG comprises a mutation in a complementarity determining region 3 (CDR3) of an Ig heavy chain (IgH) variable region. In certain embodiments, the mutation comprises an Alanine to Serine mutation. In certain embodiments, the Alanine to Serine mutation occurs in a YCAR amino acid sequence or a YCAK amino acid sequence of a CDR3 IgH. Exemplary mutations in anti-gd-IgAl autoantibodies are disclosed in U.S. Patent 9,655,963, the entire contents of which are hereby incorporated by reference. In certain embodiments, the Extracellular Protein Targeting LigandBdisclosed herein comprises one or more peptides that specifically bind to a CDR3 IgH region of an anti-gd-IgAl autoantibody or to a fragment thereof. In certain embodiments, a CDR3 IgH region of an anti-gd- IgAl autoantibody comprises a mutation, e.g., as described herein. In certain embodiments, the Extracellular Protein Targeting LigandBdisclosed herein comprises one or more peptides that specifically bind to a mutation in a CDR3 IgH region of an anti-gd-IgAl autoantibody. In certain embodiments, the one or more peptides bind to a YCAR amino acid sequence in a CDR3 IgH in which the Alanine is substituted for a Serine. In certain embodiments, the one or more peptides bind to a YCAK amino acid sequence in a CDR3 IgH in which the Alanine is substituted for a Serine. In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an anti- gd-IgAl autoantibody binds to an IgG protein, or a fragment or a variant thereof. In certain embodiments, the IgG is an IgGl, an IgG2, an IgG3, or an IgG4. In certain embodiments, the IgG protein has a mutation in a CDR3 region. Phospholipase A2Receptor-1 (PLA2R) Autoantibodies In some embodiments, the Target Extracellular Protein is an autoantibody that binds PLA2R. Phospolipase A2 Receptor-1 (PLA2R) is a major target in autoimmune membranous nephropathy. Membranous nephropathy is one of the leading causes of nephrotic syndrome, with most patients progressing to end-stage renal disease. Current treatment regimes with anti-CD20 antibodies can be ineffective at generating a complete remission. PLA2R is a transmembrane glycoprotein with a cysteine-rich N-terminal extracellular domain. This domain contains the epitope where autoantibodies bind. Reduction of autoantibody levels may provide relief to patients and complete elimination of the autoantibodies could be required to produce a durable remission. In certain embodiments a compound is provided of Formula:

[0106] ; or a pharmaceutically acceptable salt thereof; wherein PLA2R Autoantibody Binding Ligand is any PLA2R Autoantibody Binding Ligand described in WO2019 / 081912. In certain embodiments PLA2R Autoantibody Binding Ligand is a peptide of Formula XV1- LinkerZ-XV2wherein: XV1is selected from SEQ ID NO: 660-662; SEQ ID NO: 660 SVLTXV3ENXV3; SEQ ID NO: 661 SVLTXV3ENCK; SEQ ID NO: 662 XV3IXV3XV3EXV3LK; wherein XV3is independently at each occurrence any natural amino acid or other amino acid described herein; XV2is SEQ ID NO: 663-664; SEQ ID NO.663: PIXV4XV5ES; SEQ ID NO.664: VIXV4XV5ES; wherein: XV4is selected from aspartic acid, glutamic acid, asparagine, and glutamine; XV5is selected from serine, cysteine, threonine, aspartic acid, and glutamic acid; the peptide is linked to a LinkerB, LinkerCor LinkerDdescribed herein at a terminal amine or carboxylic acid; and LinkerZis selected from a peptide of SEQ ID NOs 665-696, and a polyethylene glycol polymer wherein the number of monomers is from one to about twenty. SEQ ID NO: 665 GGGSGGGSGGGS

[0107] In certain embodiments, SVLTXV3ENXV3is SVLTEENC (SEQ ID NO.697). In certain embodiments, SVLTXV3ENXV3is SVLTEENS (SEQ ID NO.698). In certain embodiments, SVLTXV3ENXV3is SVLTLENC (SEQ ID NO.699). In certain embodiments, PIXV4XV5ES is PIESES (SEQ ID NO.700). In certain embodiments, PIXV4XV5ES is PIDDES (SEQ ID NO.701). In certain embodiments, VIXV4XV5ES is VIQSES (SEQ ID NO.702). In certain embodiments, the PLA2R Autoantibody Binding Ligand is a sequence comprising VIQSES (SEQ ID NO: 702) and SVLTLENC (SEQ ID NO: 699) linked by a LinkerZgroup comprising five glycine residues ((Gly)5; SEQ ID NO: 694). In certain embodiments, the PLA2R Autoantibody Binding Ligand is a sequence comprising VIQSES (SEQ ID NO: 702) and SVLTLENC (SEQ ID NO: 699) linked by a LinkerZselected from SEQ ID NOs 665-696. In certain embodiments, LinkerZis a polyethylene glycol polymer wherein the number of monomers is from about 1 to about 20. In certain embodiments the PLA2R Autoantibody Binding Ligand is PIESES-LinkerZ- SVLTEENC In certain embodiments, the PLA2R Autoantibody Binding Ligand is VIQSES-LinkerZ- SVLTLENC In certain embodiments, the PLA2R Autoantibody Binding Ligand is VIQSES-LinkerZ- SVLTEENC In certain embodiments, the PLA2R Autoantibody Binding Ligand is PIDDES-LinkerZ- SVLTLENC In certain embodiments, the PLA2R Autoantibody Binding Ligand is PIDDES-LinkerZ- SVLTEENC In certain embodiments, the Extracellular Protein Targeting LigandAis an antibody that binds PLA2R autoantibody. Membranous nephropathy (MN) is an autoimmune disease of the kidneys wherein antibodies deposit on the glomerular walls. These protein deposits can lead to kidney failure. The most common autoantigen for the autoantibodies associated with MN is PLA2R. Additional autoantigens include NELL-1, NEP, EXT1 / EXT2, semaphorin 3B, protocadherin 7, FAT1, NDNF, THSDA7, and HTRA1. In certain embodiments, the Extracellular Protein Targeting LigandBbinds to an autoantibody to an autoantigen associated with MN. In certain embodiments, the Extracellular Protein Targeting LigandBis capable of binding to any one, or all, or a combination of: an anti-PLA2R autoantibody or a fragment or a complex thereof; an anti- THSD7A autoantibody or a fragment or a complex thereof; an anti-NELL autoantibody or a fragment or a complex thereof; an anti-NEP autoantibody or a fragment or a complex thereof; an anti-EXTl autoantibody or a fragment or a complex thereof; and an anti-EXT2 autoantibody or a fragment or a complex thereof. In certain embodiments, the autoantigen associated with MN comprises: PLA2R, THSD7A, NEP, NELLI, EXT1, EXT2, SEMA3B, NCAM1, PCDH7, or a combination thereof. In certain embodiments, the autoantigen associated with MN is a PLA2R polypeptide, or a variant or fragment thereof. In certain embodiments, an Extracellular Protein Targeting LigandBis or comprises a PLA2R polypeptide or a fragment thereof. In certain embodiments, an Extracellular Protein Targeting LigandBis or comprises SEQ ID NO: 703 or a fragment thereof. In certain embodiments, an Extracellular Protein Targeting LigandBis or comprises a polypeptide with at least about 80%, 85%, 90%, or even 95% sequence homology with SEQ ID NO: 703 or a fragment thereof. In certain embodiments, the autoantigen associated with MN is a PLA2R polypeptide, or a variant or fragment thereof. In certain embodiments, an Extracellular Protein Targeting LigandBis or comprises a PLA2R polypeptide or a fragment thereof. In certain embodiments, an Extracellular Protein Targeting LigandBis or comprises SEQ ID NO: 704 or a fragment thereof. In certain embodiments, an Extracellular Protein Targeting LigandBis or comprises a polypeptide with at least about 80%, 85%, 90%, or even 95% sequence homology with SEQ ID NO: 704 or a fragment thereof.

[0108] In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide that is or comprises one or more of the following PLA2R domains: (i) an N-terminal cysteine rich (CysR) domain or a fragment or variant thereof; (ii) a fibronectin 2 domain or a fragment or variant thereof; (iii) a CTLD1 domain, or a fragment or variant thereof; (iv) a CTLD2 domain, or a fragment or variant thereof; (v) a CTLD3 domain, or a fragment or variant thereof; (vi) a CTLD4 domain, or a fragment or variant thereof; (vii) a CTLD5 domain, or a fragment or variant thereof; (viii) a CTLD6 domain, or a fragment or variant thereof; (ix) a CTLD7 domain, or a fragment or variant thereof; (x) a CTLD8 domain, or a fragment or variant thereof; (xi) any combination of (i)-(x). In certain embodiments, the Extracellular Protein Targeting LigandBis a PLA2R polypeptide comprising: (i) an N-terminal cysteine rich (CysR) domain or a fragment or variant thereof; (ii) a fibronectin 2 domain or a fragment or variant thereof; (iii) a CTLD1 domain, or a fragment or variant thereof; and (iv) a CTLD2 domain, or a fragment or variant thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a PLA2R polypeptide that is or comprises a CysR domain having the amino acid sequence of SEQ ID NO: 705. In certain embodiments, the Extracellular Protein Targeting LigandBis a PLA2R polypeptide that is or comprises a CysR domain having an amino acid that is at least about 80%, 85%, 90%, or 95% homologous to SEQ ID NO: 705. In certain embodiments, the Extracellular Protein Targeting LigandAis a PLA2R polypeptide or a fragment thereof having one or more native glycosylation sites. In certain embodiments, the Extracellular Protein Targeting LigandAis a PLA2R polypeptide or a fragment thereof having five native glycosylation sites. In certain embodiments, a native glycosylation site comprises N93, N315, N433, N454 or N473. Anti-Neutrophil Antibodies Anti-neutrophil autoantibodies are commonly found in autoimmune diseases such as Anti- neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and are often implicated in disease pathogenesis. Neutrophils are the most common type of white blood cells. An antineutrophil autoantibody is an antibody that specifically binds to an antigen endogenous to neutrophils (e.g., a neutrophil autoantigen). A neutrophil autoantigen is encoded by a nucleic acid sequence that is naturally occurring in the genome of neutrophils. In certain embodiments, a neutrophil autoantigen is expressed in a neutrophil, e.g., in the cytoplasm, nucleus, peri-nucleus, or in a compartment in a cell. In certain embodiments, a neutrophil autoantigen is expressed on the cell surface of neutrophils. Anti-neutrophil autoantibodies are detected in a number of autoimmune disorders. In certain embodiments, anti-neutrophil autoantibodies may cause neutrophil activation leading to vascular endothelial injury to small and / or medium blood vessels. In certain embodiments, anti- neutrophil autoantibodies contribute to and / or result in vasculitis. In certain embodiments, anti- neutrophil autoantibodies contribute to and / or result in anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. In certain embodiments, an anti-neutrophil autoantibody is an IgG antibody. In certain embodiments, an anti-neutrophil autoantibody is an IgA antibody. In certain embodiments, an anti- neutrophil autoantibody is an IgM antibody. In certain embodiments, an anti-neutrophil autoantibody is an IgD antibody. In certain embodiments, an anti-neutrophil autoantibody is an IgE antibody. Exemplary neutrophil autoantigens include, but are not limited to, proteinase 3 (PR3) or a variant or fragment thereof; myeloperoxidase (MPO) or a variant or fragment thereof; lysosomal membrane protein-2 (LAMP2) or a variant or fragment thereof; pentraxin-3 (PTX3) or a variant or fragment thereof. In certain embodiments, anti-neutrophil autoantibodies may specifically bind neutrophil autoantigens (e.g., cytoplasmic granule proteins), such as PR3, MPO, LAMP2 and / or PTX3. The peptide sequence of human PR3 is designated by UNIPROT protein number P24158. The peptide sequence of human MPO is designated by UNIPROT protein number P05164. The peptide sequence of human LAMP2 is designated by UNIPROT protein number P13473. The peptide sequence of human PTX3 is designated by UNIPROT protein number P26022. These peptide sequences, as well as other information available via the UNIPROT database are incorporated herein by reference. ANCA vasculitis ANCA vasculitis is a systemic disease that may involve ears, nose and throat, lungs, kidneys, heart, digestive system, nervous system, eyes, skin, musculoskeletal tract and, infrequently, other organs (Hilhorst, M. et al. J Am Soc Neprhol, 2015). ANCA vasculitis may be induced by autoimmunity (e.g., anti-neutrophil autoantibodies) to neutrophil granule proteins (e.g., neutrophil autoantigens), such as myeloperoxidase (MPO) or proteinase 3 (PR3) as described herein. Anti-neutrophil autoantibodies against PR3 or MPO can alone or in combination result in vasculitis (e.g., small to medium-vessel vasculitis). In certain embodiments, anti-neutrophil autoantibodies that specifically bind to PR3 and / or MPO cause ANCA vasculitis. Additional anti- neutrophil autoantibodies have been identified in subjects with ANCA vasculitis, which may be causative of or contribute to development or severity of a neutrophil autoantibody associated disease, including LAMP-2 and PTX3. Current treatments for ANCA vasculitis include cyclophosphamide, RITUXIMAB, methotrexate, mycophenolate mofetil, steroids, and plasma exchange. In certain embodiments, one or more additional treatments (e.g., one or more current treatments listed above) may be administered prior to, substantially simultaneously with, or subsequent to administration of the compound of the invention. Microscopic Polyangiitis (MPA) / perinuclear ANCA Autoimmunity to MPO (e.g., generation of anti-MPO autoantibodies) is strongly associated with Microscopic Polyangiitis (MPA) / perinuclear ANCA. MPA is often characterized by vasculitis limited to the kidneys. Studies have shown that 1 out of 3 patients with MPA progress to dialysis or kidney transplantation (Hilhorst, M. et al. J Am Soc Neprhol, 2015). In certain embodiments, ANCA vasculitis is Microscopic Polyangiitis (MPA) / perinuclear ANCA. Current treatments for MPA vasculitis include immune suppression therapy using glucocorticoids (e.g., methyl prednisone), cyclophosphamide, RITUXIMAB, methotrexate, mycophenolate mofetil, azathioprine, steroids, and plasma exchange. In certain embodiments, one or more additional treatments (e.g., one or more current treatments listed above) may be administered prior to, substantially simultaneously with, or subsequent to administration of the compound of the invention. Granulomatosis with Polyangiitis (GPA) / cytoplasmic ANCA Autoimmunity to PR3 (e.g., generation of PR3 autoantibodies) is strongly associated with Granulomatosis with Polyangiitis (GPA) / cytoplasmic ANCA (Formerly called Wegener’s Granulomatosis). GPA if often characterized by granulomatous inflammation of the respiratory tract, necrotizing small-vessel vasculitis, and glomerulonephritis. A hallmark of GPA is granulomatous inflammation. Granuloma formation is thought to be initiated by small aggregates of neutrophils surrounding necrotic areas (microabscess) (Hilhorst, M. et al. J Am Soc Neprhol, 2015). In certain embodiments, ANCA vasculitis is Granulomatosis with Polyangiitis (GPA) / cytoplasmic ANCA. In certain embodiments, an anti-neutrophil autoantibody is an anti-Proteinase 3 (PR3) autoantibody or a fragment or a complex thereof. In certain embodiments, an anti-PR3 autoantibody binds to PR3, or a variant or fragment thereof. In certain embodiments, an anti-PR3 autoantibody binds to PR3 in complex with one or more proteins. In certain embodiments, the one or more proteins in complex with PR3 comprises CD 177. In certain embodiments, an anti-neutrophil autoantibody is an anti-Myeloperoxidase (MPO) autoantibody or a fragment or a complex thereof. In certain embodiments, an anti-MPO autoantibody binds to MPO, or a variant or fragment thereof. In certain embodiments, a glycoengineered polypeptide is capable of binding to: an anti- PR3 autoantibody or a fragment or a complex thereof, and an anti-MPO autoantibody or a fragment or a complex thereof. In certain embodiments, a glycoengineered polypeptide is capable of binding to one or more anti-neutrophil autoantibodies, in addition to an anti-PR3 autoantibody and / or an anti-MPO autoantibody. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 706 or a fragment thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 707 or a fragment thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 708 or a fragment thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide with at least about 80%, 85%, 90%, or even 95% homology with SEQ ID NO: 706. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide with at least about 80%, 85%, 90%, or even 95% homology with SEQ ID NO: 707. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide with at least about 80%, 85%, 90%, or even 95% homology with SEQ ID NO: 708. PR3 epitopes that may be recognized by anti-PR3 autoantibodies are disclosed in Van Der Geld YM et al., (2004) Clin Exp Immunol, Vol 137, pp.451-459, the entire contents of which are hereby incorporated by reference. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises one or more epitopes disclosed in Van Der Geld et al., 2004 (SEQ ID NOs: 709-723) In certain embodiments, the Extracellular Protein Targeting LigandBthat binds to an anti- PR3 autoantibody comprises a variant of a PR3 polypeptide, for example, a variant of SEQ ID NO: 724. In certain embodiments, a variant is an inactive variant as compared to a wild-type PR3 polypeptide. In certain embodiments, a variant comprises a mutation at the Valine residue at position 119, the Alanine residue at position 135, the Threonine residue at position 136, or a combination thereof. In certain embodiments, a variant comprises a mutation at one or more or all of amino acids 71 (His), 118 (Asp) and 203 (Ser) of SEQ ID NO: 724. In certain embodiments, a variant comprises a mutation at amino acid 71 (His), of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 71 (His), further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acid 118 (Asp) of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 118 (Asp) further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acid 203 (Ser) of SEQ ID NO: 724. In certain embodiments, a variant comprises a Serine to Alanine mutation at position 203 of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 203 (Ser) further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acids 71 (His), 118 (Asp) and 203 (Ser) of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acids 71 (His), 118 (Asp) and 203 (Ser) of SEQ ID NO: 724further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at one or more or all of amino acids 180 (Phe), 181 (Phe), 228 (Leu), or 229 (Phe) of SEQ ID NO: 724. In certain embodiments, a variant comprises a mutation at amino acid 180 (Phe) of SEQ ID NO: 724. In certain embodiments, a variant comprises a Phenylalanine to Alanine mutation at position 180 of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 180 (Phe) further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acid 181 (Phe) of SEQ ID NO: 724. In certain embodiments, a variant comprises a Phenylalanine to Alanine mutation at position 181 of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 181 (Phe) further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acid 228 (Leu) of SEQ ID NO: 724. In certain embodiments, a variant comprises a Leucine to Alanine mutation at position 228 of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 228 (Leu) further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acid 229 (Phe) of SEQ ID NO: 724. In certain embodiments, a variant comprises a Phenylalanine to Alanine mutation at position 229 of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation at amino acid 229 (Phe) further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. In certain embodiments, a variant comprises a mutation at amino acids 180 (Phe), 181 (Phe), 228 (Leu), or 229 (Phe) of SEQ ID NO: 724. In certain embodiments, a variant comprising a mutation, e.g., into an Alanine, at amino acids 180 (Phe), 181 (Phe), 228 (Leu), or 229 (Phe) of SEQ ID NO: 724further comprises one or more additional mutations to SEQ ID NO: 724, e.g., as described herein. Integrins In some embodiments, the Target Extracellular Protein is an integrin. Integrins are a family of cell adhesion molecules that is known to be mediators of tissue fibrosis. A molecule capable of degrading integrins may treat, prevent, or mitigate the progression of fibrotic disease. In certain embodiments, the Extracellular Protein Targeting LigandBis an integrin binder described in WO 2024 / 047655. In certain embodiments, the Extracellular Protein Targeting LigandBis an integrin binder that specifically binds to activated integrin beta-2 (Itgβ2), for example ADWA11, ADWA16, C6D4, 37E11, HuC6D4F12, CL7290 or a humanized version thereof. In some embodiments, the humanized version is ADWA11-2.1, ADWA11-2.2, ADWA11-2.3, ADWA11-2.4, ADWA16-1, ADWA16-2, ADWA16-3, ADWA16-3.2, ADWA16- 4, ADWA16hugraft, Ab1, Ab2, or Ab3. In certain embodiments, the Extracellular Protein Targeting LigandBis an integrin binder described in WO 2024 / 083086. In certain embodiments, the Extracellular Protein Targeting LigandBis a compound of the formula , wherein RIntY1is selected from -C1-6alkyl-, -O-, -C1-6alkyl-O-, -NH-, and -C1-6alkyl-NH-; RIntY2is selected from -C1-6alkyl-, -O-, -C1-6alkyl-O-, -NH-, and -C1-6alkyl-NH-; RInt1is substituted or unsubstituted 6-10 membered aromatic ring or a substituted or unsubstituted 5-8 membered heteroaromatic ring; RInt2is a hydrogen atom, substituted or unsubstituted 6-10 membered aromatic ring or a substituted or unsubstituted 5-8 membered heteroaromatic ring, or a substituted or unsubstituted 8-16 membered fused ring; RIntXis oxygen or nitrogen; wherein when RIntXis an oxygen, RInt3ais a hydrogen atom, -C1-6alkyl, a substituted or unsubstituted 6-10-membered aromatic ring, and RInt3bdoes not exist; or when RIntXis nitrogen, RInt3ais a hydrogen atom, -C1-6alkyl, a substituted or unsubstituted 6-10-membered aromatic ring, and RInt3bis hydrogen; is a substituted or unsubstituted spirocyclic or fused ring. In certain embodiments, the Extracellular Protein Targeting LigandBis an integrin binder described in WO 2024 / 173572 or WO 2024 / 175570. In certain embodiments, the Extracellular Protein Targeting LigandBis a compound of the formula: RIntZis -CH(R21)-, -O-, or -NR6-; each of RInt1a, RInt1b, RInt1c, RInt1d, RInt1e, or RInt1fis independently selected from -H, -C1-4alkyl, -C1-4alkoxy, -OH, -C1-4alkyl-OH, -C1-4alkyl-C1-4alkoxy, -CF3, -CF2H, -CFH2, -CN, -NO2, -NH2, -NR6R7; RInt5is independently selected at each instance from -H, -C1-4alkyl, -C1-4alkoxy, -OH, -C1-4alkyl-OH, -C1-4alkyl-C1-4alkoxy, -CF3, -CF2H, -CFH2, -O(C1-4)haloalkyl, -CN, -NO2, -NH2, -NR6R7; each RInt7is independently -F or -H; m is independently 0, 1, or 2. In certain embodiments, the Extracellular Protein Targeting LigandBis an integrin binder described in WO 2024 / 175907. In certain embodiments, the Extracellular Protein Targeting LigandBis a compound of the formula:

[0109] Wherein RIntLLis a C3-8alkyl, C3-8alkene, or C3-8alkynyl group, optionally substituted by 1, 2, 3, or 4 groups independently selected from R21; RInt8is a 4-10-membered heterocycyl, 5-10-membered heteroaryl, aryl, C3-10cycloalkyl, or are independently N oInt22 r CR ; RInt22is independently selected at each occurrence from H, halo, cyano, hydroxyl, C1-5alkyl, C1-5alkoxy, C1-5haloalkyl, C1-5haloalkoxy, C1-5alkylene-O-C1-5alkylene, C3-6cycloalkyl, and 4-6-membered heterocycle. Anti-Aquaporin Autoantibodies In certain embodiments, the Extracellular Protein Targeting LigandBis an anti-AQP4 autoantibody binding peptide described in WO 2015 / 179360. In certain embodiments, the Extracellular Protein Targeting LigandBis a fragment of AQP4 extracellular loop c or a derivative thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising LVTPPSVVGGLGVTMVHGN (SEQ ID NO: 725), or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with SEQ ID NO: 725). Anti-Acetylcholine Receptor (AChR) Autoantibodies AChR is a pentameric, transmembrane protein composed of five subunits in a stoichiometry of α2, β, v, and δ. In adults, the receptor y subunit is replaced by the ε- subunit. AChR are located at high density in the postsynaptic membrane of the neuromuscular junction (NMJ). After binding of acetylcholine (ACh), released by the nerve terminal, AChR facilitate the depolarisation of the postsynaptic membrane, leading to the contraction of muscle fibers. Anti- AChR antibodies induce a loss of AChR, leading to an impaired neuromuscular transmission. This results in fluctuating skeletal muscle weakness that worsens with use, and improves with rest. If the concentration of AChR is very low, the effects can also be measured by electrophysiology, showing a decrementing response of the compound muscle action potential (CMAP) after repetitive nerve stimulation. IgG1 autoantibodies against the AChR are common in Myasthenia gravis (MG), a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal muscles of the body. In certain embodiments, the Extracellular Protein Targeting LigandBbinds anti-AChR autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBbinds IgG1 anti-AChR autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis an anti-AChR autoantibody binding peptide described in WO 2023 / 112028 or WO 2024 / 127398. In certain embodiments, the Extracellular Protein Targeting LigandBis an acetylcholine receptor subunit or a fragment thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis an acetylcholine receptor subunit, or fragment thereof, comprising at least one mutation that decreases aggregation of the fragment, wherein said fragment is selected from: (i) a fragment of ACHRA and comprises a mutation selected from: deletion of N141, F100G, W149R, V155A, Y93F, Y93H, Y93R and a combination thereof within a wild- type AChRa comprising SEQ ID NO: 726 or a AChRa with increased solubility comprising SEQ ID NO: 727; (ii) a fragment of ACHRG and comprises a mutation selected from: M84S, Y105E, Y117E, Y117R, and a combination thereof within a wild-type AChRa comprising SEQ ID NO: 728 or a AChRa with increased solubility comprising SEQ ID NO: 729; and (iii) a fragment of ACHRD and comprises a mutation selected from: C108A, C108I, Y119R, deletion of N141, L151E and a combination thereof within a wild-type AChRa comprising SEQ ID NO: 730 or a AChRa with increased solubility comprising SEQ ID NO: 731. In certain embodiments, the Extracellular Protein Targeting LigandBis an acetylcholine receptor subunit selected from acetylcholine receptor subunit alpha (ACHRA), acetylcholine receptor subunit beta (ACHRB), acetylcholine receptor subunit gamma (ACHRG), acetylcholine receptor subunit delta (ACHRD) and acetylcholine receptor subunit epsilon (ACHRE), or a fragment thereof. According to some embodiments, the acetylcholine receptor subunit is selected from: an alpha subunit comprising the amino acid sequence provided in SEQ ID NO: 727, a beta subunit comprising the amino acid sequence provided in SEQ ID NO: 732, a gamma subunit comprising the amino acid sequence provided in SEQ ID NO: 729, a delta subunit comprising the amino acid sequence provided in SEQ ID NO: 731, and an epsilon subunit comprising the amino acid sequence provided in SEQ ID NO: 733. According to some embodiments, an analog or derivative thereof comprises at least 80% identity to the human protein. In some embodiments, at least 80% is at least 85%. In certain embodiments, the Extracellular Protein Targeting LigandBis an acetylcholine receptor subunit comprising one or more mutations that decrease the affinity of natural acetylcholine receptor ligands, for example to more selectively bind the anti-AChR autoantibodies. In certain embodiments, the acetylcholine receptor subunit, or fragment thereof, comprises a tyrosine to phenylalanine mutation, for example, a mutation of tyrosine 190 in SEQ ID NO: 726 to phenylalanine. In certain embodiments, the acetylcholine receptor subunit, or fragment thereof, comprises a mutation selected from V8E, W149R, and V155A. In certain embodiments, the acetylcholine receptor subunit, or fragment thereof, comprises two mutations selected from V8E, W149R, and V155A. SEQ ID NO: 726 SEHETRLVAK LFKDYSSVVR PVEDHRQVVE VTVGLQLIQL INVDEVNQIV TTNVRLKQQW VDYNLKWNPD DYGGVKKIHI PSEKIWRPDL VLYNNADGDF AIVKFTKVLL QYTGHITWTP PAIFKSYCEI IVTHFPFDEQ NCSMKLGTWT YDGSVVAINP ESDQPDLSNF MESGEWVIKE SRGWKHSVTY SCCPDTPYLD ITYHFVMQRL P SEQ ID NO: 727 SEHETRLVAK LFKDYSSVVR PVEDHRQVVE VTVGLQLIQL INVDEVNQIV TTNVRLKQQW VDYNLKWNPD DYGGVKKIHI PSEKIWRPDL VLYNNADGDF AIVKFTKVLL QYTGHITWTP PAIFKSYCDV SGVDTESGAT NCSMKLGTWT YDGSVVAINP ESDQPDLSNF MESGEWVIKE SRGWKHSVTY SCCPDTPYLD ITYHFVMQRL P SEQ ID NO: 728 RNQEERLLAD LMQNYDPNLR PAERDSDVVN VSLKLTLTNL ISLNEREEAL TTNVWIEMQW CDYRLRWDPR DYEGLWVLRV PSTMVWRPDI VLENNVDGVF EVALYCNVLV SPDGCIYWLP PAIFRSACSI SVTYFPFDWQ NCSLIFQSQT YSTNEIDLQL SQEDGQTIEW IFIDPEAFTE NGEWAIQHRP AKMLLDPAAP AQEAGHQKVV FYLLIQRKP SEQ ID NO: 729 RNQEERLLAD LMQNYDPNLR PAERDSDVVN VSLKLTLTNL ISLNEREEAL TTNVWIEMQW CDYRLRWDPR DYEGLWVLRV PSTMVWRPDI VLENNVDGVF EVALYCNVLV SPDGCIYWLP PAIFRSACDV SGVDTESGAT NCSLIFQSQT YSTNEIDLQL SQEDGQTIEW IFIDPEAFTE NGEWAIQHRP AKMLLDPAAP AQEAGHQKVV FYLLIQRKP SEQ ID NO: 730 LNEEERLIRH LFQEKGYNKE LRPVAHKEES VDVALALTLS NLISLKEVEE TLTTNVWIEH GWTDNRLKWN AEEFGNISVL RLPPDMVWLP EIVLENNNDG SFQISYSCNV LVYHYGFVYW LPPAIFRSSC PISVTYFPFD WQNCSLKFSS LKYTAKEITL SLKQDAKENR TYPVEWIIID PEGFTENGEW EIVHRPARVN VDPRAPLDSP SRQDITFYLI IRRKP SEQ ID NO: 731 LNEEERLIRH LFQEKGYNKE LRPVAHKEES VDVALALTLS NLISLKEVEE TLTTNVWIEH GWTDNRLKWN AEEFGNISVL RLPPDMVWLP EIVLENNNDG SFQISYSCNV LVYHYGFVYW LPPAIFRSSC DVSGVDTESG ATNCSLKFSS LKYTAKEITL SLKQDAKENR TYPVEWIIID PEGFTENGEW EIVHRPARVN VDPRAPLDSP SRQDITFYLI IRRKP SEQ ID NO: 732 SEAEGRLREKLFSGYDSSVRPAREVGDRVRVSVGLILAQLISLNEKDEEMSTKVYL DLEWTDYRLSWDPAEHDGIDSLRITAESVWLPDVVLLNNNDGNFDVALDISVVVS SDGSVRWQPPGIYRSSCSIQVTYFPFDWQNCTMVFSSYSYDSSEVSLQTGLGPDGQ GHQEIHIHEGTFIENGQWEIIHKPSRLIQPPGDPRGGREGQRQEVIFYLIIRRKP SEQ ID NO: 733 KNEELRLYHHLFNNYDPGSRPVREPEDTVTISLKVTLTNLISLNEKEETLTTSVWIGI DWQDYRLNYSKDDFGGIETLRVPSELVWLPEIVLENNIDGQFGVAYDANVLVYEG GSVTWLPPAIYRSVCAVEVTYFPFDWQNCSLIFRSQTYNAEEVEFTFAVDNDGKTI NKIDIDTEAYTENGEWAIDFCPGVIRRHHGGATDGPGETDVIYSLIIRRKP In certain embodiments, the Extracellular Protein Targeting LigandBis an acetylcholine receptor subunit comprising one or more mutations that increase the solubility of the compound. In certain embodiments, the Extracellular Protein Targeting LigandBis an acetylcholine receptor subunit wherein a cys loop within the subunit is replaced with CDVSGVDTESGATNC (SEQ ID NO: 734). In certain embodiments, the Extracellular Protein Targeting LigandBis ACHRA and the cys loop consists of CEIIVTHFPFDEQNC (SEQ ID NO: 735). In certain embodiments, the Extracellular Protein Targeting LigandBis ACHRG and the cys loop consists of CSISVTYFPFDWQNC (SEQ ID NO: 736). In certain embodiments, the Extracellular Protein Targeting LigandBis ACHRD and the cys loop consists of CPISVTYFPFDWQNC (SEQ ID NO: 737). Anti-Aquaporin-4 (AQP4) Autoantibodies Neuromyelitis Optica (NMO) is an inflammatory disease of the central nervous system (CNS) that is characterized by severe attacks of optic neuritis (ON) and longitudinally extensive (transverse) myelitis (LE(T)M). Recent developments have led to the discovery of a disease- specific autoantibody, NMO-immunoglobulin G (NMO-lgG), and subsequent identification of the main target autoantigen, Aquaporin-4 (AQP4). Other autoimmune diseases with anti-AQP4 antibody seropositive patients include, for example, systemic lupus erythematosus and Sjogren syndrome. In certain embodiments, the Extracellular Protein Targeting LigandBis an anti-AQP4 autoantibody binding peptide described in WO 2023 / 275108. In certain embodiments, the Extracellular Protein Targeting LigandBis a fragment of AQP4 or a derivative thereof. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 19-33, for example a peptide comprising one of SEQ ID NO 738-753, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 738-753. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 64-77, for example a peptide comprising one of SEQ ID NO, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 754-769.

[0110] wherein when present in any one of these epitope sequences, the residue [CS] stands for a single cysteine (C) or a single serine (S) residue. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 101-114, for example a peptide comprising one of SEQ ID NO 770-780, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 770-780. wherein when present in any one of these epitope sequences, the residue [CS] stands for a single cysteine (C) or a single serine (S) residue. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 107-121, for example a peptide comprising one of SEQ ID NO 781-796, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 781-796.

[0111] wherein when present in any one of these epitope sequences, the residue [CS] stands for a single cysteine (C) or a single serine (S) residue. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 161-174, for example a peptide comprising one of SEQ ID NO 797-808, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 171-185, for example a peptide comprising one of SEQ ID NO 809-824, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 809-824. wherein when present in any one of these epitope sequences, the residue [CS] stands for a single cysteine (C) or a single serine (S) residue. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 202-216, for example a peptide comprising one of SEQ ID NO 825-840, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 825-840. SEQ ID NO: 837INYTGASMNPAR In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 249-263, for example a peptide comprising one of SEQ ID NO 841-856, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 841-856. wherein when present in any one of these epitope sequences, the residue [CS] stands for a single cysteine (C) or a single serine (S) residue. In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide comprising a fragment of AQP4 region 284-298, for example a peptide comprising one of SEQ ID NO 857-872, or peptide with at least about 80%, 85%, 90%, 92%, 95%, 98%, or 99% sequence homology with one of SEQ ID NO 857-872.

[0112] Integrins In certain embodiments, the Extracellular Protein Targeting LigandBis a peptide described in Kimura RH et al. Engineered cystine knot peptides that bind alphavbeta3, alphavbeta5, and alpha5beta1 integrins with low-nanomolar affinity. Proteins.2009 Nov 1;77(2):359-69. In certain embodiments, the Extracellular Protein Targeting LigandBis selected from In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 881 SEQ ID NO: 881 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 882 SEQ ID NO: 882 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 883 SEQ ID NO: 883 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO:884 SEQ ID NO: 884 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 885 SEQ ID NO: 885 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 886 SEQ ID NO: 886 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 887 SEQ ID NO: 887 In certain embodiments, the Extracellular Protein Targeting LigandBis SEQ ID NO: 888 SEQ ID NO: 888 Desmoglein-2 (DSG-2) Autoantibodies In certain embodiments, the Extracellular Protein Targeting LigandBbinds a desmoglein- 2 (DSG-2) autoantibody. In certain embodiments, a Targeted Protein Degrader that degrades autoantibodies to DSG-2 can be used in the treatment of diseases including but not limited to Arrhythmogenic Right Ventricular Cardiomyopathy or post-COVID-19 cardiac syndrome. In certain embodiments, the Extracellular Protein Targeting LigandBis a DSG-2 fusion protein wherein the fusion protein comprises a whole or a portion of a DSG-2 protein and a whole or a portion of an immunoglobulin protein (as described in WO 2022 / 132854A1 and WO2023 / 081674). In certain embodiments, the Extracellular Protein Targeting LigandBis a DSG-2 fusion protein wherein the fusion protein comprises the extracellular region of DSG-2 protein (SEQ ID NO: 889) and a whole or a portion of an immunoglobulin protein. SEQ ID NO: 889 Ala Trp Ile Thr Ala Pro Val Ala Leu Arg Glu Gly Glu Asp Leu Ser Lys Lys Asn Pro Ile Ala Lys Ile His Ser Asp Leu Ala Glu Glu Arg Gly Leu Lys Ile Thr Tyr Lys Tyr Thr Gly Lys Gly Ile Thr Glu Pro Pro Phe Gly Ile Phe Val Phe Asn Lys Asp Thr Gly Glu Leu Asn Val Thr Ser Ile Leu Asp Arg Glu Glu Thr Pro Phe Phe Leu Leu Thr Gly Tyr Ala Leu Asp Ala Arg Gly Asn Asn Val Glu Lys Pro Leu Glu Leu Arg Ile Lys Val Leu Asp Ile Asn Asp Asn Glu Pro Val Phe Thr Gln Asp Val Phe Val Gly Ser Val Glu Glu Leu Ser Ala Ala His Thr Leu Val Met Lys Ile Asn Ala Thr Asp Ala Asp Glu Pro Asn Thr Leu Asn Ser Lys Ile Ser Tyr Arg Ile Val Ser Leu Glu Pro Ala Tyr Pro Pro Val Phe Tyr Leu Asn Lys Asp Thr Gly Glu Ile Tyr Thr Thr Ser Val Thr Leu Asp Arg Glu Glu His Ser Ser Tyr Thr Leu Thr Val Glu Ala Arg Asp Gly Asn Gly Glu Val Thr Asp Lys Pro Val Lys Gln Ala Gln Val Gln Ile Arg Ile Leu Asp Val Asn Asp Asn Ile Pro Val Val Glu Asn Lys Val Leu Glu Gly Met Val Glu Glu Asn Gln Val Asn Val Glu Val Thr Arg Ile Lys Val Phe Asp Ala Asp Glu Ile Gly Ser Asp Asn Trp Leu Ala Asn Phe Thr Phe Ala Ser Gly Asn Glu Gly Gly Tyr Phe His Ile Glu Thr Asp Ala Gln Thr Asn Glu Gly Ile Val Thr Leu Ile Lys Glu Val Asp Tyr Glu Glu Met Lys Asn Leu Asp Phe Ser Val Ile Val Ala Asn Lys Ala Ala Phe His Lys Ser Ile Arg Ser Lys Tyr Lys Pro Thr Pro Ile Pro Ile Lys Val Lys Val Lys Asn Val Lys Glu Gly Ile His Phe Lys Ser Ser Val Ile Ser Ile Tyr Val Ser Glu Ser Met Asp Arg Ser Ser Lys Gly Gln Ile Ile Gly Asn Phe Gln Ala Phe Asp Glu Asp Thr Gly Leu Pro Ala His Ala Arg Tyr Val Lys Leu Glu Asp Arg Asp Asn Trp Ile Ser Val Asp Ser Val Thr Ser Glu Ile Lys Leu Ala Lys Leu Pro Asp Phe Glu Ser Arg Tyr Val Gln Asn Gly Thr Tyr Thr Val Lys Ile Val Ala Ile Ser Glu Asp Tyr Pro Arg Lys Thr Ile Thr Gly Thr Val Leu Ile Asn Val Glu Asp Ile Asn Asp Asn Cys Pro Thr Leu Ile Glu Pro Val Gln Thr Ile Cys His Asp Ala Glu Tyr Val Asn Val Thr Ala Glu Asp Leu Asp Gly His Pro Asn Ser Gly Pro Phe Ser Phe Ser Val Ile Asp Lys Pro Pro Gly Met Ala Glu Lys Trp Lys Ile Ala Arg Gln Glu Ser Thr Ser Val Leu Leu Gln Gln Ser Glu Lys Lys Leu Gly Arg Ser Glu Ile Gln Phe Leu Ile Ser Asp Asn Gln Gly Phe Ser Cys Pro Glu Lys Gln Val Leu Thr Leu Thr Val Cys Glu Cys Leu His Gly Ser Gly Cys Arg Glu Ala Gln His Asp Ser Tyr Val Gly In certain embodiments, the Extracellular Protein Targeting LigandBis a DSG-2 fusion protein wherein the fusion protein comprises the extracellular cadherin domain 1 (EC1), extracellular cadherin domain 2 (EC2), extracellular cadherin domain 3 (EC3), extracellular cadherin domain 4 (EC4), and / or extracellular anchor domain (EA) of DSG-2 protein and a whole or a portion of an immunoglobulin protein. Desmoglein-1 (DSG-1) Autoantibodies In certain embodiments, the Extracellular Protein Targeting LigandBbinds a desmoglein- 1 (DSG-1) autoantibody. In certain embodiments, a Targeted Protein Degrader that degrades autoantibodies to DSG-1 can be used in the treatment of diseases including but not limited to pemphigus vulgaris and pemphigus foliaceus. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-1. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of an extracellular domain of DSG-1. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of the ectodomain of DSG-1. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-1 bound by IgG1 autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-1 bound by IgG4 autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-1 bound by IgG1 and IgG4 autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 890, or a fragment thereof. SEQ ID NO: 890 EWIKFAAACREGEDNSKRNPIAKIHSDCAANQQVTYRISGVGIDQPPYGIFVINQKTGEIN ITSIVDREVTPFFIIYCRALNSMGQDLERPLELRVRVLDINDNPPVFSMATFAGQIEENSN ANTLVMILNATDADEPNNLNSKIAFKIIRQEPSDSPMFIINRNTGEIRTMNNFLDREQYGQ YALAVRGSDRDGGADGMSAECECNIKILDVNDNIPYMEQSSYTIEIQENTLNSNLLEIRVI DLDEEFSANWMAVIFFISGNEGNWFEIEMNERTNVGILKVVKPLDYEAMQSLQLSIGVR NKAEFHHSIMSQYKLKASAISVTVLNVIEGPVFRPGSKTYVVTGNMGSNDKVGDFVAT DLDTGRPSTTVRYVMGNNPADLLAVDSRTGKLTLKNKVTKEQYNMLGGKYQGTILSID DNLQRTCTGTININIQSFGNDDRTNTEPNTKITTNTGRQESTSSTNYDTSTTSTDSSQVYS SEPGNGAKDLLSDNVHFGP In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 891, or a fragment thereof. SEQ ID NO: 891 EFRIQVRDYNTKNGTIKWHSIRRQKR In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 892, or a fragment thereof. SEQ ID NO: 892 EWIKFAAACREGEDNSKRNPIAKIHSDCAANQQVTYRISGVGIDQPPYGIFVINQKTGEIN ITSIVDREVTPFFIIYCRALNSMGQDLERPLELRVRVLDINDNPPVFS In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 893, or a fragment thereof. SEQ ID NO: 893 MATFAGQIEENSNANTLVMILNATDADEPNNLNSKIAFKIIRQEPSDSPMFIINRNTGEIRT MNNFLDREQYGQYALAVRGSDRDGGADGMSAECECNIKILDVNDNIPYME In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 894, or a fragment thereof. SEQ ID NO: 894 RPGSKTYVVTGNMGSNDKVGDFVATDLDTGRPSTTVRYVMGNNPADLLAVDSRTGKL TLKNKVTKEQYNMLGGKYQGTILSIDDNLQRTCTGTININIQSFGNDDRTNTEPN Desmoglein-3 (DSG-3) Autoantibodies In certain embodiments, the Extracellular Protein Targeting LigandBbinds a desmoglein- 3 (DSG-3) autoantibody. In certain embodiments, a Targeted Protein Degrader that degrades autoantibodies to DSG-3 can be used in the treatment of diseases including but not limited to pemphigus vulgaris and pemphigus foliaceus. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-3. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of an extracellular domain of DSG-3. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-3 bound by IgG1 autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-3 bound by IgG4 autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of DSG-3 bound by IgG1 and IgG4 autoantibodies. In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 895, or a fragment thereof. SEQ ID NO: 895 EWVKFAKPCREGEDNSKRNPIAKITSDYQA In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 896, or a fragment thereof. SEQ ID NO: 896 TQKITYRISGVGIDQPPFGIFVVDKNTGDI In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 897, or a fragment thereof. SEQ ID NO: 897 NITAIVDREETPSFLITCRALNAQGLDVEK In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 898, or a fragment thereof. SEQ ID NO: 898 PLILTVKILDTNDNPPVFSQQIFMGEIEEN In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 899, or a fragment thereof. SEQ ID NO: 899 SASNSLVMILNATDADEPNHLNSKIAFKIV In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 900, or a fragment thereof. SEQ ID NO: 900 SOQEAGTPMFLLSRNTGEVRTLTNSLDREQ In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 901, or a fragment thereof. SEQ ID NO: 901 ASSYRLVVSGADKDGEGLSTQCECNIKVKD In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 902, or a fragment thereof. SEQ ID NO: 902 RDSQYSARIEENILSSELLRFQVTDLDEEY In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 903, or a fragment thereof. SEQ ID NO: 903 GNEGNWFEIQTDPRTNEGILKVVKALDYEQ In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 904, or a fragment thereof. SEQ ID NO: 904 SRYRVQSTPVTIQVINVREGIAFRPASKTF In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 905, or a fragment thereof. SEQ ID NO: 905 QKGISSKKLVDYILGTYQAIDEDTNKAASN In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 906, or a fragment thereof. SEQ ID NO: 906 DSKTAEIKFVKNMNRDSTFIVNKTITAEVL In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 907, or a fragment thereof. SEQ ID NO: 907 EWVKFAKPCREGEDNSKRNPIAKITSDYQATQKITYRISGVGIDQPPFGIFVVDKNTGDIN ITAIVDREETPSFLITCRALNAQGLDVEKPLILTVKILDINDNPPVFSQQIFMGEIEENSASN SLVMILNATDADEPNHLNSKIAFKIVSQEPAGTPMFLLSRNTGEVRTLTNSLDREQASSY RLVVSGADKDGEGLSTQCECNIKVKDVNDNFPMFRDSQYSARIEENILSSELLRFQVTDL DEEYTDNWLAVYFFTSGNEGNWFEIQTDPRTNEGILKVVKALDYEQLQSVKLSIAVKNK AEFHQSVISRYRVQSTPVTIQVINVREGIAFRPASKTFTVQKGISSKKLVDYILGTYQAIDE DTNKAASNVKYVMGRNDGGYLMIDSKTAEIKFVKNMNRDSTFIVNKTITAEVLAIDEYT GKTSTGTVYVRVPDFNDNCPTAVLEKDAVCSSSPSVVVSARTLNNRYTGPYTFALEDQP VKLPAVWSITTLNATSALLRAQEQIPPGVYHISLVLTDSQNNRCEMPRSLTLEVCQCDNR GICGTSYPTTSPGTRYGRPHSGR In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 908, or a fragment thereof. SEQ ID NO: 908 ELRIETKGQYDEEEMTMQQAKRRQKR In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 909, or a fragment thereof. SEQ ID NO: 909 EWVKFAKPCREGEDNSKRNPIAKITSDYQATQKITYRISGVGIDQPPFGIFVVDKNTGDIN ITAIVDREETPSFLITCRALNAQGLDVEKPLILTVKILDINDNPPVFS In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 910, or a fragment thereof. SEQ ID NO: 910 QQIFMGEIEENSASNSLVMILNATDADEPNHLNSKIAFKIVSQEPAGTPMFLLSRNTGEVR TLTNSLDREQASSYRLVVSGADKDGEGLSTQCECNIKVKDVNDNFPMFR In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 911, or a fragment thereof. SEQ ID NO: 911 DSQYSARIEENILSSELLRFQVTDLDEEYTDNWLAVYFFTSGNEGNWFEIQTDPRTNEGIL KVVKALDYEQLQSVKLSIAVKNKAEFHQSVISRYRVQSTPVTIQVINVREGIAF In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 912, or a fragment thereof. SEQ ID NO: 912 ASKTFTVQKGISSKKLVDYILGTYQAIDEDTNKAASNVKYVMGRNDGGYLMIDSKTAEI KFVKNMNRDSTFIVNKTITAEVLAIDEYTGKTSTGTVYVRVPDFNDNCPTAVLEK Anti-Muscle Specific Kinase Autoantibodies In certain embodiments, the Extracellular Protein Targeting LigandBbinds a muscle specific kinase (MuSK) autoantibody. In certain embodiments, a Targeted Protein Degrader that degrades autoantibodies to MuSK can be used in the treatment of diseases including but not limited to myasthenia gravis (MG). The clinical features of patients with MuSK antibody-positive MG (MuSK MG) are distinctive. These patients often have severe bulbar dysfunction and respiratory insufficiency that can be difficult to treat effectively with immunosuppressive and immunomodulatory strategies. Atrophy of the facial and tongue muscles is also common. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of MuSK. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of an extracellular domain of MuSK. In certain embodiments, the Extracellular Protein Targeting LigandBis or comprises a fragment of an extracellular domain of MuSK lacking the Frizzled cysteine-rich domain (Lamprini S. et al. Expression of extracellular domains of muscle specific kinase (MuSK) and use as immunoadsorbents for the development of an antigen-specific therapy Journal of Neuroimmunology 276(1–2) 2014, 150-158). In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 913, or a fragment thereof. SEQ ID NO: 913 PVITTPLETVDALVEEVATFMCAVESYPQPEISWTRNKILIKLFDTRYSIRENGQLLTILSV EDSDDGIYCCTANNGVGGAVESCGALQ In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 914, or a fragment thereof. SEQ ID NO: 914 PKITRPPINVKIIEGLKAVLPCTTMGNPKPSVSWIKGDSPLRENSRIAVLESGSLRIHNVQK EDAGQYRCVAKNSLGTAYSKVVK In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 915, or a fragment thereof. SEQ ID NO: 915 ARILRAPESHNVTFGSFVTLHCTATGIPVPTITWIENGNAVSSGSIQESVKDRVIDSRLQLF ITKPGLYTCIATNKHGEKFSTAKAAATIS In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 916, or a fragment thereof. SEQ ID NO: 916 PVITTPLETVDALVEEVATFMCAVESYPQPEISWTRNKILIKLFDTRYSIRENGQLLTILSV EDSDDGIYCCTANNGVGGAVESCGALQPKITRPPINVKIIEGLKAVLPCTTMGNPKPSVS WIKGDSPLRENSRIAVLESGSLRIHNVQKEDAGQYRCVAKNSLGTAYSKVVKARILRAP ESHNVTFGSFVTLHCTATGIPVPTITWIENGNAVSSGSIQESVKDRVIDSRLQLFITKPGLY TCIATNKHGEKFSTAKAAATIS In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 917, or a fragment thereof. SEQ ID NO: 917 LPKAPVITTPLETVDALVEEVATFMCAVESYPQPEISWTRNKILIKLFDTRYSIRENGQL LTILSVEDSDDGIYCCTANNGVGGAVESCGALQVKMKPKITRPPINVKIIEGLKAVLPCT TMGNPKPSVSWIKGDSPLRENSRIAVLESGSLRIHNVQKEDAGQYRCVAKNSLGTAYSK VVKLEVEVFARILRAPESHNVTFGSFVTLHCTATGIPVPTITWIENGNAVSSGSIQESVKD RVIDSRLQLFITKPGLYTCIATNKHGEKFSTAKAAATISIAEWSKPQKDNKGYCAQYRGE VCNAVLAKDALVFLNTSYADPEEAQELLVHTAWNELKVVSPVCRPAAEALLCNHIFQE CSPGVVPTPIPICREYCLAVKELFCAKEWLVMEEKTHRGLYRSEMHLLSVPECSKLPSM HWDPTACARLPHLDYNKENLKTFPPMTSSKPSVDIPNLPSSSSSSFSVSPTYSMT In certain embodiments, the Extracellular Protein Targeting LigandBis a linear or cyclic peptide with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a SEQ ID NO: 918, or a fragment thereof. SEQ ID NO: 918 LPKAPVITTPLETVDALVEEVATFMCAVESYPQPEISWTRNKILIKLFDTRYSIRENGQL LTILSVEDSDDGAYCCTANNGVGGAVESCGALQVKMKPKITRPPINVKIIEGLKAVLPCT TMGNPKPSVSWIKGDSPLRENSRIAVLESGSLRIHNVQKEDAGQYRCVAKNSLGTAYSK VVKLEVEVFARILRAPESHNVTFGSFVTLHCTATGIPVPTITWIENGNAVSSGSIQESVKD RVIDSRLQLFITKPGLYTCIATNKHGEKFSTAKAAATISIAEWSKPQKDNKGYCAQYRGE VCNAVLAKDALVFLNTSYADPEEAQELLVHTAWNELKVVSPVCRPAAEALLCNHIFQE CSPGVVPTPIPICREYCLAVKELFCAKEWLVMEEKTHRGLYRSEMHLLSVPECSKLPSM HWDPTACARLPHLDYNKENLKTFPPMTSSKPSVDIPNLPSSSSSSFSVSPTYSMT IB. EXTRACELLULAR PROTEIN TARGETING LIGANDAImmunoglobulin Degradation In some aspects of the invention, the Extracellular Protein Targeting Ligand targets an immunoglobulin, for example IgG, IgA, IgM, or IgE. The immunoglobulin degrading compounds described herein degrade a target immunoglobulin, for example IgG, IgA, IgM, or IgE, by linking a ligand for the selected immunoglobulin to a potent ASGPR binder through specific linking groups. In certain embodiments of the present invention, the selected immunoglobulin degrader degrades IgG. In certain aspects an immunoglobulin degrading compound of Formula I-A, Formula II-A, or Formula III-A is provided: or a pharmaceutically acceptable salt thereof; wherein: Immunoglobulin Targeting Ligand is a Ligand that binds to an immunoglobulin, for example IgG, IgA, IgM, or IgE. In certain aspects an IgG degrading compound of Formula I-B, Formula II-B, or Formula III-B is provided:

[0113] or a pharmaceutically acceptable salt thereof; wherein: IgG Targeting Ligand is a Ligand that binds to immunoglobulin G. In certain embodiments, the IgG Targeting Ligand binds an antibody to either a foreign antigen or an autologous antigen (i.e. an autoantibody). In certain embodiments, the IgG Targeting Ligand binds an autoantibody. The IgG Targeting Ligand can bind a certain subclass of IgG, including IgG1, IgG2, IgG3, and IgG4, or a combination thereof. For example, a pan-IgG degrading compound could bind all subclasses of IgG. In certain embodiments, the IgG Targeting Ligand binds IgG1 and IgG2. In certain embodiments, the IgG Targeting Ligand binds IgG1, IgG2, and IgG4. In some aspects of the present invention an IgG degrader of the present invention uses a 1:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In other aspects of the present invention an IgG degrader of the present invention uses a 2:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In other aspects of the present invention an IgG degrader of the present invention uses a 3:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. In certain embodiments the IgG Targeting Ligand is a peptide. In certain embodiments, the peptide IgG Targeting Ligand is a cyclic or linear peptide. In certain embodiments, the peptide IgG Targeting Ligand comprises one or more, or is entirely D-amino acids. In certain embodiments, the peptide-based IgG targeting ligand is the peptide Fc-BP2. For example, an IgG Targeting Ligand of structure: . In certain embodiments, the peptide-based IgG Targeting Ligand is the peptide Fc-III-4C. For example, an IgG targeting ligand of structure: . In certain embodiments, the peptide-based IgG Targeting Ligand is the peptide Fc-III. For example, an IgG targeting ligand of structure: In certain embodiments, a compound of the present invention which degrades IgG is used to treat a disorder selected from dilated cardiomyopathy, glaucoma, Postural orthostatic tachycardia syndrome (POTS), post-Covid syndrome, Duchenne’s muscular dystrophy (DMD), bronchial dysplasia, and Chagas’ heart disease. An extracellular protein degrading compound described herein can be used to treat a disorder mediated by an immunoglobulin, for example IgG, including for example an autoimmune disorder, other immune dysfunction, hematology-related disorder, renal disorder, allergic condition, or liver disorder. In certain embodiments, the autoimmune disorder is mediated by an autoantibody that can be degraded by the immunoglobulin degrader described herein. In certain aspects of the invention, a method for treating a disorder mediated by an immunoglobulin is provided that includes administering to a host in need thereof an effective amount of an immunoglobulin degrader described herein, or its pharmaceutically acceptable salt, prodrug, N- oxide, and / or a pharmaceutically acceptable composition thereof optionally in a pharmaceutically acceptable carrier. Immunoglobulins, for example IgG, can cause, modulate, or amplify diseases in vivo, such as abnormal cellular proliferation such as tumors and cancer, autoimmune disorders, inflammation, and aging-related diseases. For example, immunoglobulins bind to cell surface receptors, often initiating aberrant signaling in multiple diseases such as cancer and inflammation. The immunoglobulin degraders described herein or their pharmaceutically acceptable salt and / or pharmaceutically acceptable compositions thereof can be used to treat a disorder which is mediated by an immunoglobulin that binds to the Immunoglobulin Targeting Ligand. The described degraders are capable of targeting immunoglobulins that mediate pathological disorders for lysosomal degradation. The selected immunoglobulin may modulate a disorder in a human via a mechanism of action such as modification of a biological pathway, pathogenic signaling, or modulation of a signal cascade or cellular entry. The immunoglobulin is recruited with an Immunoglobulin Targeting Ligand, which is a ligand for the immunoglobulin. Accordingly, in some embodiments, a method to treat a host with a disorder mediated by an immunoglobulin is provided that includes administering an effective amount of a degrader targeting the immunoglobulin or its pharmaceutically acceptable salt described herein to the host, typically a human, optionally in a pharmaceutically acceptable composition. The immunoglobulin can be either the normal form of the protein or an aberrant form. For example, the immunoglobulin can be a mutant protein, or a protein, for example, where a partial, or full, gain-of-function or loss-of-function is encoded by nucleotide polymorphisms. In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof.

[0114] In certain embodiments, the compound of the present invention is a compound of Formula: or a pharmaceutically acceptable salt thereof. Targeting specific immunoglobulins is accomplished by the present invention through the use of specific Immunoglobulin Targeting Ligand. The target immunoglobulins of the current invention may include, but are not limited to, immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE). These immunoglobulins mediate a range of diseases that can be treated with an effective amount of the disclosed ASGPR-binding Immunoglobulin Degraders described herein. In certain embodiments, the Immunoglobulin Targeting Ligand comprises an antibody that binds to an immunoglobulin. In certain embodiments, the Immunoglobulin Targeting Ligand antibody binds to the Fc region of the target antibody. In certain embodiments, Extracellular Protein Targeting LigandAbinds to an immunoglobulin. In certain embodiments, Extracellular Protein Targeting LigandAbinds to an autoantibody. In certain embodiments, the Immunoglobulin Targeting Ligand comprises an antibody binding moiety described in WO 2019 / 023501, incorporated by reference herein. In some embodiments, Extracellular Protein Targeting LigandAis an affinity substance described in AU 2018259856 or WO 2018199337, the affinity substance of each of which is incorporated herein by reference. In some embodiments, an Extracellular Protein Targeting LigandAis or comprises an adapter protein agent, e.g., as described in Hui, et al., Bioconjugate Chem.2015, 26, 1456−1460, doi: 10.1021 / acs.bioconjchem.5b00275. In some embodiments, when utilized in accordance with the present disclosure, adapter proteins do not require reactive residues (e.g., BPA) to achieve one or more or all advantages. In some embodiments, Extracellular Protein Targeting LigandAis or comprises a triazine moiety, e.g., one described in US 2009 / 0286693. In some embodiments, an Extracellular Protein Targeting LigandAis of such a structure that its corresponding compound is a compound described in US 2009 / 0286693, the compounds of which are independently incorporated herein by reference. In some embodiments, Extracellular Protein Targeting LigandAis a compound described in US 2009 / 0286693, the compounds of which are independently incorporated herein by reference. In some embodiments, such a compound can bind to an antibody. In some embodiments, such a compound can bind to Fc region of an antibody. In some embodiments, an Extracellular Protein Targeting LigandAis or comprises a triazine moiety, e.g., one described in Teng, et al., A strategy for the generation of biomimetic ligands for affinity chromatography. Combinatorial synthesis and biological evaluation of an IgG binding ligand, J. Mol. Recognit. 1999;12:67-75 ("Teng"). In some embodiments, Extracellular Protein Targeting LigandAis of such a structure that its corresponding compound is a compound described in Teng, the compounds of which are independently incorporated herein by reference. In some embodiments, Extracellular Protein Targeting LigandAis a compound described in Teng, the compounds of which are independently incorporated herein by reference. In some embodiments, such a compound can bind to an antibody. In some embodiments, such a compound can bind to Fc region of an antibody. In some embodiments, an Extracellular Protein Targeting LigandAis a triazine moiety, e.g., one described in Uttamchandani, et al., Microarrays of Tagged Combinatorial Triazine Libraries in the Discovery of Small-Molecule Ligands of Human IgG, J Comb Chem. 2004 Nov- Dec;6(6):862-8 ("Uttamchandani"). In some embodiments, Extracellular Protein Targeting LigandAis of such a structure that its corresponding compound is a compound described in Uttamchandani, the compounds of which are independently incorporated herein by reference. In some embodiments, Extracellular Protein Targeting LigandA, ABT is of such a structure that H- ABT is a compound described in Uttamchandani, the compounds of which are independently incorporated herein by reference. In some embodiments, such a compound can bind to an antibody. In some embodiments, such a compound can bind to Fc region of an antibody. In some embodiments, Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein A. In some embodiments, Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein G. In some embodiments, Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein L. In some embodiments, Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein Z. In some embodiments, Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein LG. In some embodiments, Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein LA. In some embodiments, an Extracellular Protein Targeting LigandAbinds to one or more binding sites of protein AG. In some embodiments, an Extracellular Protein Targeting LigandAis described in Choe, W., Durgannavar, T. A., & Chung, S. J. (2016). Fc-binding ligands of immunoglobulin G: An overview of high affinity proteins and peptides. Materials, 9(12). https: / / doi.org / 10.3390 / ma9120994. In some embodiments, Extracellular Protein Targeting LigandAcan bind to a nucleotide- binding site. In some embodiments, Extracellular Protein Targeting LigandAis a small molecule moiety that can bind to a nucleotide-binding site. In some embodiments, a small molecule is tryptamine. In some embodiments, Extracellular Protein Targeting LigandAis tryptamine. Certain useful technologies were described in Mustafaoglu, et al., Antibody Purification via Affinity Membrane Chromatography Method Utilizing Nucleotide Binding Site Targeting with A Small Molecule, Analyst.2016 November 28; 141(24): 6571-6582. Many technologies are available for identifying and / or assessing and / or characterizing antibody binding moieties and / or their utilization in provided technologies, e.g., those described in WO / 2019 / 023501, the technologies of which are incorporated herein by reference. In some embodiments, Extracellular Protein Targeting LigandAis a moiety (e.g., small molecule moiety, peptide moiety, nucleic acid moiety, etc.) that can selectively bind to IgG, and when used in provided technologies can provide and / or stimulate uptake and / or degradation. In some embodiments, peptide display technologies (e.g., phase display, non-cellular display, etc.) can be utilized to identify Extracellular Protein Targeting Ligands. In some embodiments, Extracellular Protein Targeting LigandAis a moiety (e.g., small molecule moiety, peptide moiety, nucleic acid moiety, etc.) that can bind to IgG and optionally can compete with known antibody binders, e.g., protein A, protein G, protein L, etc. As appreciated by those skilled in the art, antibodies of various properties and activities (e.g., antibodies recognizing different antigens, having optional modifications, etc.) may be targeted by Extracellular Protein Targeting Ligands described in the present disclosure. In some embodiments, such Extracellular Protein Targeting Ligands include antibodies administered to a subject, e.g., for therapeutic purposes. In some embodiments, Extracellular Protein Targeting Ligands described herein may bind antibodies toward different antigens and are useful for conjugating moieties of interest with various antibodies. In some embodiments, Extracellular Protein Targeting LigandAis or comprises a meditope agent moiety. In some embodiments, a meditope agent is described in, e.g., US 2019 / 0111149. In some embodiments, Extracellular Protein Targeting LigandAcan bind to human IgG. In some embodiments, Extracellular Protein Targeting LigandAcan bind to rabbit IgG. In some embodiments, Extracellular Protein Targeting LigandAbinds to IgGl. In some embodiments, Extracellular Protein Targeting LigandAbinds to lgG2. In some embodiments, Extracellular Protein Targeting LigandAbinds to lgG3. In some embodiments, Extracellular Protein Targeting LigandAbinds to lgG4. In some embodiments, Extracellular Protein Targeting LigandAbinds to IgGl, lgG2 and / or lgG4. In some embodiments, Extracellular Protein Targeting LigandAbinds to IgGl, lgG2 and lgG4. In certain embodiments, the Extracellular Protein Targeting LigandAis selected from:

[0115]

[0116] . In certain embodiments, the Extracellular Protein Targeting LigandAis selected from:

[0117] . Immunoglobulin G Immunoglobulin G (IgG) mediates a range of autoimmune, infectious and metabolic diseases, including systemic fibroinflammatory disease. In addition, overexpression of IgG4 is associated with IgG4-related diseases, which generally include multiple organs, and disorders include type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, storiform fibrosis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond’s disease), aortitis and periaortitis, proximal biliary strictures, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, tumefactive lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren’s syndrome, psoriatic arthritis, systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture disease, encephalitis, thrombotic thrombocytopenic purpura, immune thrombocytopenia, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non-REM parasomnia, and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysis bullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, and paraneoplastic pemphigus, among others. Specific degradation of IgG can be accomplished through the use of an IgG-specific Immunoglobulin Targeting Ligand In certain embodiments, the Immunoglobulin Targeting Ligand binds to the Fc region of IgG. In certain embodiments the IgG-specific Immunoglobulin Targeting Ligand is an Fc-binding peptide. In certain embodiments, the IgG-specific Immunoglobulin Targeting Ligand is Fc-BP2. In certain embodiments, the IgG-specific Immunoglobulin Targeting Ligand is Fc-III. In certain embodiments, the Extracellular Protein Targeting LigandAis an antibody that binds IgG. In certain alternative embodiments any compound drawn herein with stereochemistry drawn in the Targeting Ligand is also described herein without stereochemistry. For example, in certain embodiments:

[0118] . The Protein Data Bank website provides the crystal structure of IgG searchable by 1H3X (Krapp, S., et al., J. Mol. Biol., 2003, 325: 979); and 5V43 (Lee, C.H., et al., Nat. Immunol., 2017, 18: 889-898); as well as the crystal structure of IgG bound to various compounds searchable by 5YC5 (Kiyoshi M., et al., Sci. Rep., 2018, 8: 3955-3955); 5XJE (Sakae Y., et al., Sci. Rep.,2017, 7: 13780-13780); 5GSQ (Chen, C. L., et al., ACS Chem. Biol., 2017, 12: 1335-1345); and 1HZH (Saphire E. O., et al., Science, 2001, 293: 1155-1159). Additionally, Kiyoshi, M., et al., provides insight into the structural basis for binding of human IgG1 to its high-affinity human receptor FcγRI. (Kiyosi M., et al., Nat Commun., 2015, 6, 6866). Representative IgG Targeting Ligand are provided in Fig.1. Additional representative IgG Targeting Ligand include: wherein XR is O, S, NH, or N-C1-C3 alkyl; and XM is O, S, NH, or N-C1-C3 alkyl. In other embodiments the IgG Targeting Ligand is selected from: . In some embodiments, the IgG Targeting Ligand is a group according to the chemical structure: wherein RN02is a dinitrophenyl group optionally linked through CH2, S(O), S(O)2, -S(O)2O, - OS(O)2, or OS(O)2O. In certain embodiments the IgG Targeting Ligand is selected from: wherein X100is selected from O, CH2, NH, N-C1-C3 alkyl, NC(O)C1-C3 alkyl, S(O), S(O)2, - S(O)2O, - OS(O)2, or OS(O)2O. In some embodiments, the IgG Targeting Ligand is a 3-indoleacetic acid group according to the chemical structure: . In some embodiments, the IgG Targeting LigandAis a peptide. Nonlimiting examples of IgG Targeting LigandApeptides include: SEQ ID NO:919 PAM (RTY)4K2KG (Fassina, et al, J. Mol. Recognit.1996, 9, 564-569) ; D-PAM, wherein the amino acids of the PAM sequence are all D-amino acids (Verdoliva, et al, J. Immunol. Methods, 2002, 271, 77-88) SEQ ID NO:920 (RTY)4K2KG D-PAM-Φ, wherein the amino acids of the PAM sequence are all D-amino acids with further modifications wherein the four N-terminal arginines are acetylated with phenylacetic acid (Dinon, et al J. Mol. Recognit.2011, 24, 1087-1094) SEQ ID NO:921 (RTY)4K2KG SEQ ID NO:922 TWKTSRISIF (Krook, et al, J. Immunol. Methods 1998, 221, 151-157) SEQ ID NO:923 FGRLVSSIRY (Krook, et al, J. Immunol. Methods 1998, 221, 151-157) SEQ ID NO:924 Fc-III (DCAWHLGELVWCT-NH2) (DeLano et al, Science 2000, 287, 1279- 1283) ; SEQ ID NO:925 FCBP-Ser DSAWHLGELWST (see WO2014010813) SEQ ID NO:926 DCHKRSFWADNCT (see WO2014010813) SEQ ID NO:927 DCRTQFRPNQTCT (see WO2014010813) SEQ ID NO:928 DCQLCDFWRTRCT (see WO2014010813) SEQ ID NO:929 DCFEDFNEQRTCT (see WO2014010813) SEQ ID NO:930 DCLAKFLKGKDCT (see WO2014010813) SEQ ID NO:931 DCWHRRTHKTFCT (see WO2014010813) SEQ ID NO:932 DCRTIQTRSCT (see WO2014010813) SEQ ID NO:933 DCIKLAQLHSVCT (see WO2014010813) SEQ ID NO:934 DCWRHRNATEWCT (see WO2014010813) SEQ ID NO:935 DCQNWIKDVHKCT (see WO2014010813) SEQ ID NO:936 DCAWHLGELVWCT (see WO2014010813) SEQ ID NO:937 DCAFHLGELVWCT (see WO2014010813) SEQ ID NO:938 DCAYHLGELVWCT (see WO2014010813) SEQ ID NO:939 FcBP- 1 PAWHLGELVWP (Kang, et al, J. Chromatogr. A 2016, 1466, 105-112) ; SEQ ID NO:940 FcBP-2 PDCAWHLGELVWCTP (Dias, et al, J. Am. Chem. Soc. 2006, 128, 2726-2732) ; SEQ ID NO:941 Fc-lll-4c CDCAWHLGELVWCTC (Gong, et al, Bioconjug. Chem. 2016, 27, 1569-1573) ; SEQ ID NO: 942 APAR (Camperi, et al, Biotechnol. Lett.2003, 25, 1545-1548) SEQ ID NO:943 FcRM (CFHH)2KG (Fc Receptor Mimetic, Verdoliva, et al., ChemBioChem 2005, 6, 1242-1253) ; SEQ ID NO: 944 HWRGWV (Yang, et al., J Peptide Res.2006, 66, 110-137) SEQ ID NO: 945 HYFKFD (Yang, et al, J. Chromatogr. A 2009, 1216, 910-918) SEQ ID NO: 946 HFRRHL (Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104) SEQ ID NO: 947 HWCitGWV (Menegatti, et al, J. Chromatogr. A 2016, 1445, 93-104) SEQ ID NO:948 HWmetCitGWmetV (US10,266,566) SEQ ID NO:949 D2AAG (Small Synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158- 167) SEQ ID NO:950 DAAG (Small Synthetic peptide ligand, Lund, et al, J. Chromatogr. A 2012, 1225, 158- 167); SEQ ID NO: 951 cyclo[(Nα-Ac) S(A)-RWHYFK-Lact-E] (Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237); SEQ ID NO: 952 cyclo[(Nα-Ac)-Dap(A)-RWHYFK-Lact-E] (Menegatti, et al, Anal. Chem. 2013, 85, 9229-9237); SEQ ID NO: 953 cyclo[Link M-WFRHYK] (Menegatti, et al, Biotechnol. Bioeng.2013, 110, 857-870); SEQ ID NO: 954 NKFRGKYK (Sugita, et al, Biochem. Eng. J.2013, 79, 33-40); SEQ ID NO: 955 NARKFYKG (Sugita, et al, Biochem. Eng. J.2013, 79, 33-40); SEQ ID NO: 956 FYWHCLDE (Zhao, et al, Biochem. Eng. J.2014, 88, 1-11); SEQ ID NO: 957 FYCHWALE (Zhao, et al, J Chromatogr. A 2014, 1355, 107-114); SEQ ID NO: 958 FYCHTIDE (Zhao, et al., Z Chromatogr. A 2014, 1359, 100-111); SEQ ID NO:959 Dual 1 / 3 (FYWHCLDE-FYCHTIDE) (Zhao, et al, J. Chromatogr. A 2014, 1369, 64-72); SEQ ID NO: 960 RRGW (Tsai, et al, Anal. Chem.2014, 86, 2931-2938); SEQ ID NO: 961 KHRFNKD (Yoo and Choi, BioChip J.2015, 10, 88-94); SEQ ID NO: 962 CPSTHWK (Sun et al. Polymers 2018, 10, 778); SEQ ID NO: 963 NVQYFAV (Sun et al. Polymers 2018, 10, 778); SEQ ID NO: 964 ASHTQKS (Sun et al. Polymers 2018, 10, 778); SEQ ID NO: 965 QPQMSHM (Sun et al. Polymers 2018, 10, 778); SEQ ID NO: 966 TNIESLK (Sun et al. Polymers 2018, 10, 778); SEQ ID NO: 967 NCHKCWN (Sun et al. Polymers 2018, 10, 778); SEQ ID NO: 968 SHLSKNF (Sun et al. Polymers 2018, 10, 778). SEQ ID NO: 969 EPIHRSTLTALL (Ehrlich, et al, J. Biochem. Biophys. Method 2001, 49, 443— 454) In certain embodiments, these IgG degrading compounds have a small molecule or nonpeptidic IgG Targeting Ligand. Non-limiting examples of small molecule IgG Targeting Ligand include: . The selective targeting of IgG can be particularly beneficial when the present invention is used in the treatment of a disease known to be caused primarily by IgG, such as thyroid eye disease, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, warm autoimmune hemolytic anemia, and type-1 autoimmune pancreatitis. In certain embodiments a compound of the present invention which degrades IgG is used to treat a disorder selected from...

Claims

1. CLAIMS We claim:

1. An extracellular protein degrading compound of Formula I, Formula II, or Formula III is provided: or a pharmaceutically acceptable salt thereof; wherein the ASGPR Binding Ligand is selected from: , R1, R1b, and R5are independently selected from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, and C0-C6alkylN3, each of which except hydrogen, F, Cl, and Br is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R99; wherein one of R1, R1b, and R5is replaced with a bond to LinkerA;R3and R3care independently selected at each occurrence from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R6and R7are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl- NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is selected from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R42is selected from bond, C1-C4alkyl, C1-C4haloalkyl, C2-C4alkenyl, and C2-C4alkynyl; R66is independently selected at each instance from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, and C0-C6alkylN3, each of which except hydrogen, F, Cl, Br and I is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R100;R67is C(O)R3or heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R100; R75is independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkylN3, heteroaryl, and aryl, each of which except F, Cl, Br and I is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; R77is selected from hydrogen, C2-C6alkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkylN3, heteroaryl, and aryl, each of which except F, Cl, Br, and I is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; R78is selected from hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl- C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkylN3, heteroaryl, and aryl, each of which except F, Cl, Br, and I is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; n and m are independently 0, 1, 2, 3, or 4, as allowed by valence;heteroaryl or phenyl;ii) 6-membered heterocycle substituted with one R1substituent and further optionally substituted with n substituents independently selected from R75;-membered heteroaryl optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R103; R99, R100, R102, and R103are independently selected at each instance from alkyl (including C1-C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, -NR8R9, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR3, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, -C(O)OR3, -C(O)R3, and -SF5; LinkerAis a bond or a moiety that covalently links LinkerB, LinkerC, or LinkerDto the ASGPR Binding Ligand; LinkerBis a bond or a moiety that covalently links LinkerAto an Extracellular Protein Targeting Ligand; LinkerCis a bond or a moiety that covalently links each LinkerAto the Extracellular Protein Targeting Ligand; LinkerDis a bond or a moiety that covalently links each LinkerAto the Extracellular Protein Targeting Ligand; and Extracellular Protein Targeting Ligand is a Ligand that binds to an extracellular protein.

2. The compound of claim 1, wherein Extracellular Protein Targeting Ligand is selected from Extracellular Protein Targeting LigandA.

3. The compound of claim 1, wherein Extracellular Protein Targeting Ligand is selected from Extracellular Protein Targeting LigandB.

4. The compound of any one of claims 1-3, wherein ASGPR Binding Ligand is selected from:

5. The compound of any one of claims 1-4, wherein ASGPR Binding Ligand is.

6. The compound of any one of claims 1-5, wherein ASGPR Binding Ligand is.

7. The compound of any one of claims 1-4, wherein.

8. An extracellular protein degrading compound of Formula I-X, Formula II-X, or Formula III- X is provided:or a pharmaceutically acceptable salt thereof;wherein the ASGPR Binding LigandB is selected,or ASGPR Binding LigandBis selected from:R1, R1b, and R5are independently selected from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, and C0-C6alkylN3, each of which except hydrogen, F, Cl, and Br is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R99; R1cis selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, -C(O)R3, -S(O)R3, -C(S)R3, and -S(O)2R3; wherein one of R1, R1b, R1c, and R5is replaced with a bond to LinkerA; Lis selected fromR3, R3a, R3b, R3c, and R3dare independently selected at each occurrence from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R4ais selected from hydrogen, alkyl, haloalkyl, and halogen;R4bis selected from hydrogen, alkyl, haloalkyl, halogen, C0-C6alkyl-OR6, C0-C6alkyl-SR6, and C0-C6alkyl-NR6R7; R6and R7are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl- NR8R9, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R8and R9are independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle; R10is selected from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, C(O)R3, S(O)R3, C(S)R3, and S(O)2R3; R42is selected from bond, C1-C4alkyl, C1-C4haloalkyl, C2-C4alkenyl, and C2-C4alkynyl;, , C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 alkynyl; R65, R66, and R67Bare independently selected at each instance from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, and C0-C6alkyl-N3, each of which except for F, Cl, Br, and I is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R100; R75B, R76B, R77B, and R78Bare independently selected at each instance from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl- OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl- C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, C0-C6alkyl-CN, C0-C6alkyl-N3, heteroaryl, and aryl, each of which except for F, Cl, Br, and I is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102; n, m, and p are independently 0, 1, 2, 3, or 4, as allowed by valence;is aryl, heterocycle, cycloalkyl, or heteroaryl, optionally substituted with R75B, R76B, R77B, and R78B;is aryl, heterocycle, cycloalkyl, bicycle, or heteroaryl;aryl or heteroaryl;bicycle or spirocycle; X is CH, CR75B, or N; Y is CH, CR75B, or N; Z is selected from -O-, -NR6-, -S-, -S(O)-, -S(O)2-, and -CR3aR3b-; and R99, R100, and R102are independently selected at each instance from alkyl (including C1- C4alkyl), alkenyl (including C2-C4alkenyl), alkynyl (including C2-C4alkynyl), haloalkyl (including C1-C4haloalkyl), -OR6, F, Cl, Br, I, -NR6R7, -NR8R9, heterocycle, heteroaryl, aryl, cyano, nitro, hydroxyl, azide, amide, -SR3, -S(O)(NR6)R3, -NR8C(O)R3, -C(O)NR6R7, -C(O)OR3, -C(O)R3, and -SF5.

9. The compound of claim 8, wherein.

10. The compound of claim 8, wherein11. The compound of any one of claims 1-10, wherein L is selected from, ,12. The compound of any one of claims 1-10, wherein L is selected from , , and.

13. The compound of claim 8, wherein ASGPR LigandBisor.

14. The compound of any one of claims 8-12, whereinis selected from15. The compound of any one of claims 8-12, whereinis selected from16. The compound of any one of claims 8-12, whereinis selected from17. The compound of any one of claims 8-12, whereinis selected from19. The compound of any one of claims 8-18, wherein R75Bis selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, F, Cl, Br, I, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0- C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-CN, C0-C6alkylN3, each of which is optionally substituted with 1, 2, or 3 substituents independently selected at each occurrence from R102.

20. The compound of any one of claims 8-18, wherein R75Bis selected from F, Cl, Br, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-CN, C0- C6alkylN3, each of which is optionally substituted with 1 or 2 substituents independently selected at each occurrence from R102.

21. The compound of any one of claims 8-18, wherein R75Bis selected from F, Cl, Br, C0- C6alkyl-OR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, C0-C6alkyl-CN, C0-C6alkylN3, each of which is optionally substituted with 1 or 2 substituents independently selected at each occurrence from R102.

22. The compound of any one of claims 8-18, wherein R75Bis selected from F, Cl, Br, C0- C6alkyl-OR6, C0-C6alkyl-C(O)R3, and C0-C6alkyl-CN each of which is optionally substituted with 1 or 2 substituents independently selected at each occurrence from R102.

23. The compound of any one of claims 1-22, whereinis a 6-membered heteroaryl.

24. The compound of any one of claims 1-22, whereinis selected from26. The compound of any one of claims 1-22, whereinis a 5-membered heteroaryl.

27. The compound of any one of claims 1-22, wherein is a bicyclic heteroaryl.

28. The compound of any one of claims 1-22, wherein.

29. The compound of any one of claims 1-27, wherein m is 1 or 2.

30. The compound of any one of claims 1-29, wherein R10is hydrogen.

31. The compound of any one of claims 1-30, wherein R6is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

32. The compound of any one of claims 1-30, wherein R6is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

33. The compound of any one of claims 1-30, wherein R6is independently selected at each occurrence from hydrogen, alkyl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

34. The compound of any one of claims 1-30, wherein R6is independently selected at each occurrence from hydrogen and alkyl.

35. The compound of any one of claims 1-34, wherein R7is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

36. The compound of any one of claims 1-34, wherein R7is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

37. The compound of any one of claims 1-34, wherein R7is independently selected at each occurrence from hydrogen, alkyl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

38. The compound of any one of claims 1-34, wherein R7is independently selected at each occurrence from hydrogen and alkyl.

39. The compound of any one of claims 1-38, wherein R8is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, and heterocycle.

40. The compound of any one of claims 1-38, wherein R8is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, and heterocycle.

41. The compound of any one of claims 1-38, wherein R8is independently selected at each occurrence from hydrogen and alkyl.

42. The compound of any one of claims 1-41, wherein R9is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, and heterocycle.

43. The compound of any one of claims 1-41, wherein R9is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, and heterocycle.

44. The compound of any one of claims 1-41, wherein R9is independently selected at each occurrence from hydrogen and alkyl.

45. The compound of any one of claims 1-44, wherein R1is replaced with a bond to LinkerA.

46. The compound of any one of claims 1-44, wherein R1bis replaced with a bond to LinkerA.

47. The compound of any one of claims 1-44, wherein R5is replaced with a bond to LinkerA.

48. The compound of any one of claims 1-47, wherein LinkerAis bond and LinkerBiswherein: R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, and -[C(O)-CH2-O]n-, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, or 4; and R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle.

49. The compound of any one of claims 1-47, wherein LinkerBis bond and LinkerAiswherein:R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, -P(O)(R3)O-, -P(O)(R3)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, -CH2CH2-[O-(CH2)2]n-O-, -CH2CH2-[O-(CH2)2]n-NR6-, -CH2CH2-[O-(CH2)2]n-, -[-(CH2)2-O-]n-, -[O-(CH2)2]n-, -[O-CH(CH3)C(O)]n-, -[C(O)-CH(CH3)-O]n-, -[O-CH2C(O)]n-, and -[C(O)-CH2-O]n-, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; n is independently selected at each instance from 0, 1, 2, 3, or 4; and R21is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR6R7, -NR8SO2R3, -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle.

50. The compound of any one of claims 48-49, wherein.

51. The compound of any one of claims 48-49, wherein.

52. The compound of any one of claims 48-49, wherein53. The compound of any one of claims 48-49, wherein.

54. The compound of any one of claims 48-49, wherein.

55. The compound of any one of claims 48-54, wherein R11, R12, R13, R18, R19, and R20are independently selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6-, -NR6C(O)-, 7-O-, -S-, -NR6-, -C(R21R21)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, and -CH2CH2-[O-(CH2)2]n-O-.

56. The compound of any one of claims 48-54, wherein R11is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-.

57. The compound of any one of claims 48-54, wherein R20is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-.

58. The compound of any one of claims 48-57, whereinis 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

59. The compound of claim 48 or 49, wherein.

60. The compound of any one of claims 48-59, wherein one of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

61. The compound of any one of claims 48-59, wherein two of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

62. The compound of any one of claims 48-59, wherein three of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

63. The compound of any one of claims 48-59, wherein four of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

64. The compound of any one of claims 48-59, wherein five of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

65. The compound of any one of claims 1-64, wherein LinkerCis selected from:. wherein: R22is selected from the group consisting of alkyl, -C(O)N-, -NC(O)-, -N-, -C(R21)-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21.

66. The compound of claim 65, wherein R22is selected from -C(O)N-, -NC(O)-, -N-, and -C(R21)- .

67. The compound of any one of claims 65-66, wherein69. The compound of any one of claims 1-64, wherein LinkerDis selected from:; wherein: R32is independently at each occurrence selected from the group consisting of alkyl, N+X-, -C-, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R21; and X- is an anionic group, for example Br- or Cl-;..

72. The compound of any one of claims 1 or 3-71, wherein the Extracellular Protein Targeting LigandBbinds to an immunoglobulin.

73. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgG.

74. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgG1.

75. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgG2.

76. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgG3.

77. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgG4.

78. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgG1, IgG2, and IgG4.

79. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgA.

80. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgA1.

81. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to IgE.

82. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to an autoantibody.

83. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to an autoantibody that binds to IgA.

84. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to an autoantibody that binds to the beta-1 adrenergic receptor.

85. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to an autoantibody that binds to TSHR.

86. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds to an autoantibody that binds to desmoglein-2.

87. The compound of any one of claims 1 or 3-72, wherein the Extracellular Protein Targeting LigandBbinds anti-citrullinated protein autoantibodies (ACPA).

88. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to an immunoglobulin.

89. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to IgG.

90. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to IgM.

91. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to IgE.

92. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to IgA.

93. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to an autoantibody.

94. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to an autoantibody that binds to IgA.

95. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to an autoantibody that binds to beta-1 adrenergic receptor.

96. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to an interleukin.

97. The compound of any one of claims 1-7 or 23-71, wherein the Extracellular Protein Targeting LigandAbinds to IL-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-17, IL-21, or IL-22.

98. A pharmaceutical composition comprising a compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

99. The pharmaceutical composition of claim 98, for oral administration.

100. The pharmaceutical composition of claim 98, for subcutaneous administration.

101. The pharmaceutical composition of claim 98, for intramuscular administration.

102. The pharmaceutical composition of claim 98, for intravenous administration.

103. A method of treating a disease mediated by an extracellular protein comprising administering an effective amount of a compound of any one of claims 1-97 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 98-102, to a patient in need thereof.

104. The method of treatment of claim 103, wherein the disease is an autoimmune disease.

105. The method of treatment of claim 103, wherein the disease is a hyperproliferative disease.

106. The method of treatment of claim 103, wherein the extracellular protein is IgG and the disease is selected from antiphospholipid Ab syndrome, Behcet syndrome, Hashimoto thyroiditis, MGUS, necrobiotic xanthogranuloma, rheumatoid arthritis, cancer, for example multiple myeloma or peripheral multiple myeloma, paraproteinemia, chronic urticaria, scleroderma, scleromyxedema, thrombocytopenia for example heparin-induced thrombocytopenia, cryoglobulinema, granulomatosis with polyanglititis, for example ANCA associated vasculitis, idiopathic thrombocytopenic purpura, thrombocytopenia, IgG4-RD, paroxysmal nocturnal hemoglobinuria (PNH), warm autoimmune hemolytic anemia, rhabdomyolysis, lupus nephritis, acute disseminated encephalomyelitis, Guillaine-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, Miller Fisher syndrome, neuromyelitis optica spectrum disorder, opsoclonus-myoclonus syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), peripheral neuropathy, transverse myelitis, fibrosis, IPF / fibrosis, and transplantation rejection.

107. The method of treatment of claim 103, wherein the extracellular protein is IgG and the disease is selected from IgA nephropathy (also known as Berger’s disease), celiac disease, Crohn’s disease, Henoch-Schönlein purpura (HSP) (also known as IgA vasculitis), IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic liver cirrhosis, acquired immunodeficiency syndrome, IgA multiple myeloma, α-chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, and primary glomerulonephritis.

108. The method of treatment of claim 103, wherein the extracellular protein is IgG4 and the disease is selected from type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, storiform fibrosis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond’s disease), aortitis and periaortitis, proximal biliary strictures, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, tumefactive lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren’s syndrome, psoriatic arthritis, systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture disease, encephalitis, thrombotic thrombocytopenic purpura, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non- REM parasomnia, and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysis bullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, and paraneoplastic pemphigus.

109. The method of treatment of claim 103, wherein the extracellular protein is an immunoglobulin and the disease is selected from systemic fibroinflammatory disease, type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, storiform fibrosis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond’s disease), aortitis and periaortitis, proximal biliary strictures, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, tumefactive lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren’s syndrome, psoriatic arthritis, systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture disease, encephalitis, thrombotic thrombocytopenic purpura, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non-REM parasomnia, and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysisbullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, paraneoplastic pemphigus, IgA nephropathy (also known as Berger’s disease), celiac disease, Crohn’s disease, Henoch- Schönlein purpura (HSP) (also known as IgA vasculitis), IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic liver cirrhosis, acquired immunodeficiency syndrome, IgA multiple myeloma, α- chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, primary glomerulonephritis, atopic asthma, allergic rhinitis, atopic dermatitis, cutaneous contact hypersensitivity, IgE-mediated food allergy, IgE-mediated animal allergies, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, eosinophilic gastrointestinal disease, bullous pemphigoid, chemotherapy induced hypersensitivity reaction, seasonal allergic rhinitis, interstitial cystitis, eosinophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic obstructive pulmonary disease, gastroenteritis, hyper-IgE syndrome (Job's Syndrome), IgE monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), pemphigus vulgaris, mucus membrane pemphigoid, chronic urticaria, autoimmune uveitis, rheumatoid arthritis, autoimmune pancreatitis, and allergic rhinoconjunctivitis.

110. The method of treatment of claim 103, wherein the disorder is dilated cardiomyopathy.

111. The method of treatment of claim 103, wherein the disorder is arthritis.

112. Use of a compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 98-102, to treat a disease mediated by an extracellular protein.

113. Use of a compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 98-102, in the manufacture of a medicament to treat a disease mediated by an extracellular protein.

114. The use of claim 112 or 113, wherein the disease is an autoimmune disease.

115. The use of claim 112 or 113, wherein the disease is a hyperproliferative disease.

116. The use of claim 112 or 113, wherein the extracellular protein is IgG and the disease is selected from antiphospholipid Ab syndrome, Behcet syndrome, Hashimoto thyroiditis, MGUS, necrobiotic xanthogranuloma, rheumatoid arthritis, cancer, for example multiple myeloma or peripheral multiple myeloma, paraproteinemia, chronic urticaria, scleroderma,scleromyxedema, thrombocytopenia for example heparin-induced thrombocytopenia, cryoglobulinema, granulomatosis with polyanglititis, for example ANCA associated vasculitis, idiopathic thrombocytopenic purpura, thrombocytopenia, IgG4-RD, paroxysmal nocturnal hemoglobinuria (PNH), warm autoimmune hemolytic anemia, rhabdomyolysis, lupus nephritis, acute disseminated encephalomyelitis, Guillaine-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, Miller Fisher syndrome, neuromyelitis optica spectrum disorder, opsoclonus-myoclonus syndrome, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS), peripheral neuropathy, transverse myelitis, fibrosis, IPF / fibrosis, and transplantation rejection.

117. The use of claim 112 or 113, wherein the extracellular protein is IgG and the disease is selected from IgA nephropathy (also known as Berger’s disease), celiac disease, Crohn’s disease, Henoch-Schönlein purpura (HSP) (also known as IgA vasculitis), IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic liver cirrhosis, acquired immunodeficiency syndrome, IgA multiple myeloma, α-chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, and primary glomerulonephritis.

118. The use of claim 112 or 113, wherein the extracellular protein is IgG4 and the disease is selected from type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, storiform fibrosis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond’s disease), aortitis and periaortitis, proximal biliary strictures, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, tumefactive lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren’s syndrome, psoriatic arthritis, systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture disease, encephalitis, thrombotic thrombocytopenic purpura, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non-REM parasomnia, and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysisbullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, and paraneoplastic pemphigus.

119. The use of claim 112 or 113, wherein the extracellular protein is an immunoglobulin and the disease is selected from systemic fibroinflammatory disease, type 1 autoimmune pancreatitis, interstitial nephritis, Riedel's thyroiditis, storiform fibrosis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis, retroperitoneal fibrosis (Ormond’s disease), aortitis and periaortitis, proximal biliary strictures, idiopathic hypocomplementemic tubulointerstitial nephritis, multifocal fibrosclerosis, pachymeningitis, pancreatic enlargement, tumefactive lesions, pericarditis, rheumatoid arthritis (RA), inflammatory bowel disease, multiple sclerosis, myasthenia gravis, ankylosing spondylitis, primary Sjögren’s syndrome, psoriatic arthritis, systemic lupus erythematosus (SLE), sclerosing cholangitis, IgG monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), melanoma, bullous pemphigoid, Goodpasture disease, encephalitis, thrombotic thrombocytopenic purpura, chronic inflammatory polyneuropathy, limbic encephalitis, neuromyotonia, Morvan syndrome, pemphigus foliaceus, pemphigus vulgaris, REM and non-REM parasomnia, and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysis bullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, paraneoplastic pemphigus, IgA nephropathy (also known as Berger’s disease), celiac disease, Crohn’s disease, Henoch- Schönlein purpura (HSP) (also known as IgA vasculitis), IgA pemphigus, dermatitis herpetiformis, inflammatory bowel disease (IBD), Sjögren's syndrome, ankylosing spondylitis, alcoholic liver cirrhosis, acquired immunodeficiency syndrome, IgA multiple myeloma, α- chain disease, IgA monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, primary glomerulonephritis, atopic asthma, allergic rhinitis, atopic dermatitis, cutaneous contact hypersensitivity, IgE-mediated food allergy, IgE-mediated animal allergies, allergic conjunctivitis, allergic urticaria, anaphylactic shock, nasal polyposis, keratoconjunctivitis, mastocytosis, eosinophilic gastrointestinal disease, bullous pemphigoid, chemotherapy induced hypersensitivity reaction, seasonal allergic rhinitis, interstitial cystitis, eosinophilic esophagitis, angioedema, acute interstitial nephritis, atopic eczema, eosinophilic bronchitis, chronic obstructive pulmonary disease, gastroenteritis, hyper-IgE syndrome (Job's Syndrome),IgE monoclonal gammopathy, monoclonal gammopathy of undetermined significance (MGUS), pemphigus vulgaris, mucus membrane pemphigoid, chronic urticaria, autoimmune uveitis, rheumatoid arthritis, autoimmune pancreatitis, and allergic rhinoconjunctivitis.

120. The use of claim 112 or 113, wherein the disorder is dilated cardiomyopathy.

121. The use of claim 112 or 113, wherein the disorder is arthritis.

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