Potent asgpr-binding heterobifunctional compounds comprising antibodies for the degradation of targeted proteins

Abstract

This invention provides extracellular protein degraders and compositions that have an asialoglycoprotein receptor (ASGPR) Binding Ligand bound to a specific Extracellular Protein Targeting Ligands 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 COMPRISING ANTIBODIES FOR THE DEGRADATION OF TARGETED PROTEINS 5 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. 10 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 a specific Extracellular Protein 15 Targeting Ligands 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 “19121-040WO1_st26” which was created on April 20 29, 2025, and is 1,646,592 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 25 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 30 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 1

[0002] 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 5 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 10 Trustees of the Leland Stanford Junior University; WO 2021 / 142377 assigned to Lycia Therapeutics; WO 2022 / 192478, WO 2022 / 178425, WO 2021 / 072246, and WO 2021 / 072269, 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)) 15 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 20 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 25 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, galactose- 30 deficient IgG, sFLT-1, 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 2

[0003] are provided. The extracellular protein degraders of the present invention contain an ASGPR Binding Ligand covalently attached by a Linker to a specific Extracellular Protein Targeting Ligand. In certain embodiments the Extracellular Protein Targeting Ligand is an antibody. An antibody-based Extracellular Protein Targeting Ligand can be highly selective for the Target 5 Protein. High selectivity, for example for a pathologic form of a protein, can minimize off-target effects. Antibody-based Extracellular Protein Targeting Ligands may also have long circulating half-lives which may maximize the time between doses. 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, 10 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. 15 While tradition 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 immunoglobulin degraders feature select ASGPR ligands that feature high binding affinity for ASGPR. As a result 20 of this high ASGPR binding affinity, a extracellular protein degrader 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 a previously disclosed degrader. In certain aspects a compound of Formula I, Formula II, or Formula III is provided: 25 (I) 3

[0004] (II) III); or a phar In additional embodiments, the invention includes a compound of the structure of Formula 5 IV: (IV), or a salt thereof; that can be used as . In these Formulas, the ASGPR Binding Ligand is selected from: , 4

[0005] ; C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle, 5 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 10 a bond to LinkerA; and wherein for Formula IV one of R1, R1b, and R5is replaced with a bond to LinkerE; ; in certain embodiment ; 15 R3, R3a, R3b, and R3ca ently selected at each occurrence from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and - NR8R9; 5

[0006] 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, 5 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, 10 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; 15 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, 20 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; R76is selected from alkyl, alkenyl, alkynyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, haloalkoxy, C0-C6alkyl-OR6, C0-C6alkyl-SR6, C0-C6alkyl-NR6R7, C0-C6alkyl-C(O)R3, 25 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- 30 C(O)R3, C0-C6alkyl-S(O)R3, C0-C6alkyl-C(S)R3, C0-C6alkyl-S(O)2R3, -N=S(O)(R3)2, 6

[0007] 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, 5 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; is heteroaryl or phenyl; 10 is selected from d ituted with n substituents independently selected from R75and one R1substituent; , and 6-membered heteroaryl 15 substitu h 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, 20 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; 7

[0008] 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; 5 LinkerDis a chemical group that links each LinkerAto the Extracellular Protein Targeting Ligand; LinkerEis selected from ; R11, R12, R13, R14, R15, R urrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, 10 -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 15 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, 20 -NR8S(O)R3, haloalkyl, aryl, heteroaryl, and heterocycle; and Extracellular Protein Targeting Ligand is a peptide or antibody described herein that binds to an extracellular protein described herein. In certain embodiments, L is selected fro . In certain embodiments, L is selected fro . 8

[0009] 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 , 5 ention include: , 9

[0010] 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 , 5 invention include: , 10

[0011] In certain embodiments the ASGPR Binding Ligand is selected from: . In certain embodiments the ASGPR Binding Ligand is selected from: 5 . selected from 11

[0012] . In certain embodiments the ASGPR Binding Ligand is selected from , 5 nd ce a aspecs a co pou o o ua , o ua , o o ua s povided: IB) 12

[0013] B) IB) or a pha zz is selected from 1, 2, 3, 4, 5, or 6. 5 In certain embodiments, zz is 1. In certain embodiments, zz is 2. In certain embodiments, zz is 4. In certain embodiments, zz is 6. In certain embodiments, zz is 2 and the compound of Formula IB is of the formula 10 o a pa aceu ca y accepa e sa eeo. 13

[0014] In certain embodiments, zz is 2, LinkerBis bound to the fragment crystallizable (Fc) region of an Extracellular Protein Targeting Ligand described herein, and the compound of Formula IB is of the formula 5 In certain embodiments, zz is 4, LinkerBis bound to the Fc region of an Extracellular Protein Targeting Ligand described herein, and the compound of Formula IB10 is of the formula 14

[0015] 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 an antibody for the selected immunoglobulin to a potent ASGPR binder through specific linking 5 groups. In certain embodiments of the present invention, the selected immunoglobulin degrader degrades IgG. In certain aspects an IgG degrading compound of Formula I-A, Formula II-A, or Formula III-A is provided: A) 10 A) A) or a pha wherein: IgG Targeting Ligand is a Ligand that binds to immunoglobulin G, for example in certain 15 embodiments the IgG Targeting Ligand is a galactose deficient IgA which binds to an IgG that causes IgA nephropathy. In certain aspects the IgG Targeting Ligand is an IgA which comprises an IgA hinge region. 15

[0016] 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, 5 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 10 the present invention an IgG degrader of the present invention uses a 1:1 ratio of ASGPR Binding Ligand to Extracellular Protein Targeting Ligand. 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 15 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 IgA nephropathy, Graves’ eye disease, Graves’ ophthalmopathy, Graves’ orbitopathy, thyroid eye disease, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). 20 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 embodiments, a compound of the present invention which degrades IgM is used25 to treat a disorder selected from IgM Monoclonal Gammopathy with Neuropathy (without anti- MAG Ab), Rheumatoid Arthritis, and Multifocal Motor Neuropathy, CIDP with IgM autoAbs, Antibody-Mediated Transplant Rejection. In certain embodiments the extracellular protein degrader of the present invention is provided as an isotopically enriched extracellular protein degrader, for example an 30 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 16

[0017] 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 5 the Extracellular Protein Targeting Ligand portion of the molecule. 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 10 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 15 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 20 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 25 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; 17

[0018] (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 5 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 10 BRIEF DESCRIPTION OF THE FIGURES FIG.1 provides non-limiting examples of formulas of the present invention DETAILED DESCRIPTION OF THE INVENTION 15 Novel extracellular protein degraders and their pharmaceutically acceptable salts and compositions thereof that degrade a Target Extracellular Protein, for example IgG including for example galactose-deficient 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 20 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, 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 25 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 30 improved selectivity, pharmacokinetics, pharmacodynamics, solubility, fewer side effects and / or improved tolerability. 18

[0019] 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. In certain embodiments the Extracellular Protein 5 Targeting Ligand is an antibody which binds an immunoglobulin. For example, in certain embodiments the Extracellular Protein Targeting Ligand is a galactose deficient IgA for example a galactose deficient IgA1. In certain aspects the compound of the present invention is a compound of Formula I (I); 10 or a pharm In certain aspects the compound of the present invention is a compound of Formula I: 19

[0020] or or a pharm In certain aspects the compound of the present invention is a compound of Formula I: 5 20

[0021] or or a pharm In certain aspects the compound of the present invention is a compound of Formula I: 5 21

[0022] or or a pharma In other aspects the compound of the present invention is a compound of Formula II: 5 II); or a phar 22

[0023] In certain embodiments, the compound of the present invention is a compound of Formula II: 5 23

[0024] or ; IJĴ

[0025] or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present invention is a compound of Formula: 25

[0026] or ; or a pharm 26

[0027] In certain embodiments, the compound of the present invention is a compound of Formula: or ; or a phar . 27

[0028] In certain aspects an extracellular protein degrading compound of Formula I-X, Formula II-X, or Formula III-X is provided: X) 5 X) X); or a pha 28

[0029] wherein the ASGPR Binding LigandBis selected from: , , 5 , , 29

[0030] ; , 5 30

[0031] or ASGPR Binding LigandBis selected from: ; 5 kyl, 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, 3, 10 or 4 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; ; 15 , , , , e from hydrogen, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NR8R9; R4ais selected from hydrogen, alkyl, haloalkyl, and halogen; 31

[0032] 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- 5 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; 10 R42is selected from bond, C1-C4alkyl, C1-C4haloalkyl, C2-C4alkenyl, and C2-C4alkynyl; R23Bis selected from bond , , C1-C4alkyl, C1-C4haloalkyl, C2-C4alkenyl, and C2-C4alkynyl; R66, and R67Bare independently selected at each instance from hydrogen, C0-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, heterocycle, heterocycloalkyl, 15 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, 3, or 4 substituents independently selected at each occurrence from R100; R75B, R76B, R77B, R78B, and R79are independently selected at each instance from hydrogen, 20 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, 3, or 4 substituents independently selected at each occurrence from R102; 25 n, m, and p are independently 0, 1, 2, 3, or 4, as allowed by valence; q is 1, 2, or 3; l; 32

[0033] or is phenyl; is aryl, heterocycle, cycloalkyl, or heteroaryl; is aryl, heterocycle, cycloalkyl, bicycle, or heteroaryl; 5 , Y is CH, CR75B, or N; Z is selected from -O-, -NR6-, -S-, -S(O)-, -S(O)2-, and -CR3aR3b-; and 10 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 -SF5wherein the optional substituent is selected such that a stable 15 compound results; and all other variables are as defined herein. 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 20 be alkyl. 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 33

[0034] 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 5 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 Ligand is ASGPR Binding LigandB. In certain embodiments, ASGPR Binding LigandBis ASGPR Binding Ligand. 10 In certain embodiments, ASGPR Binding Ligand is selected fro . bodiments, ASGPR Binding Ligand is selected from and 34

[0035] In certain embodiments, ASGPR Binding Ligand is selected from . ding Ligand is selected from . 5 ing Ligand is selected from . Ligand is selected from . 35

[0036] In certain embodiments, ASGPR Binding Ligand is selected from and om 5 . inding Ligand is selected from . , ing Ligand is selected from nd 36

[0037] . diments, ASGPR Binding Ligand is selected from and 5 In certain embodiments, ASGPR Binding Ligand is selected from . 37

[0038] In certain embodiments, ASGPR Binding Ligand is selected fro . 5 In certain embodiments, ASGPR Binding Ligand . In certain embodiments, ASGPR Bindin selected from . , inding Ligand is selected from . 38

[0039] In certain embodiments, ASGPR Binding Ligand is selected fro . In certain embodiments, ASGPR Binding LigandBis selected from: 5 , , 39

[0040] , , , 5 , 40

[0041] , 5 In certain embodiments ASGPR Binding LigandBis selected from: , 41

[0042] , , , 5 , 42

[0043] , , 5 43

[0044] . 5 . 44

[0045] In certain embodiments, ASGPR Binding LigandBis selected from5 . 45

[0046] 5 46

[0047] . 5 . 47

[0048] In certain embodiments, ASGPR Binding LigandBis selected from 5 . 48

[0049] 

[0050] nd 5 , 50

[0051] , 5 In certain embodiments, the ASGPR Binding LigandBis selected from , . 51

[0052] In certain embodiments, the ASGPR Binding Ligand is selected from nd 5 , , 52

[0053] , In certain embodiments, the ASGPR Binding LigandBis selected from:5 ,, 53

[0054] , 5 and 54

[0055] . odiments, the ASGPR Binding LigandBis selected from: 5 . 55

[0056] In certain embodiments, the ASGPR Binding LigandBis a compound selected from ,,5 Non-limiting examples of ASGPR Binding LigandBinclude: , 56

[0057] , 57

[0058] In certain embodiments, the ASGPR Binding LigandBis selected from , 5 . 58

[0059] In certain embodiments, the ASGPR Binding LigandBis selected from , , , 5 , 59

[0060] , , , , 60

[0061] , , , , 61

[0062] , . Non-limiting examples of ASGPR Binding LigandBinclude: 5 , 62

[0063] . , 5 , , , 63

[0064] 5 nd 64

[0065] In certain embodiments, the ASGPR Binding LigandBis selected from: ,5 . 65 In certain embodiments, the ASGPR Binding LigandBis selected from: 5

[0066] In certain embodiments, the ASGPR Binding LigandBis selected from ,5 67

[0067] and ,5 68

[0068] , 5 , 69

[0069] In certain embodiments, the ASGPR Binding LigandBis selected from ,,5 , 70

[0070] In certain embodiments, the ASGPR Binding LigandBis selected from nd5 ,, 71

[0071] 5 In certain embodiments, ASGPR Binding LigandBis selected from , 72

[0072] ,,,, 73

[0073] nd . 5 dBis selected from: . 74

[0074] In certain embodiments, ASGPR Binding LigandBis selected from: . 5 75

[0075] . 76

[0076] In certain embodiments ASGPR Binding LigandBis a compound selected from: 5 77

[0077] In certain embodiments ASGPR Binding LigandBis a compound selected from: und selected from:5 . , , 78

[0078] , 5 , , 79

[0079] 5

[0080] ,,5, 81

[0081] . In alternative embodiments the ASGPR Binding Ligand is selected from: , 5 R23is selected from ; 82

[0082] is selected from 5 ents 10 independently selected from R75; s cycloalkyl; 83

[0083] is aryl or heteroaryl; rein all other variables are as defined herein. In certain embodiments, the protein degrading compound of the invention is 5 84

[0084] In certain embodiments, the protein degrading compound of the invention is 85

[0085] or a pharmaceutically acceptable salt thereof. 86

[0086] In certain embodiments, the protein degrading compound of the invention is or a 5 pharmaceutically acceptable salt thereof. 87

[0087] In certain embodiments, the protein degrading compound of the invention is 88

[0088] or a pharmaceutically acceptable salt thereof. In certain embodiments, the protein degrading compound of the invention is 5 or a parmaceutca y accepta e sat tereo. 89

[0089] In certain embodiments, . . . 5 In certain embodiments . . 10 In certain embodiments, . 90

[0090] . In certain embodiments, . In certain embodiments, . 5 In certain embodiments, . In certain embodiments, . In certain embodiments, . In certain embodiments, . In certain embodiments, . 91

[0091] In certain embodiments an extracellular protein degrading compound is provided: 5 ; or a pharma In certain embodiments an extracellular protein degrading compound is provided: 10 92

[0092] ; or a pharma 5 In certain embodiments an extracellular protein degrading compound is provided: 93

[0093] ; or a pharma I. COMPOUND TERMINOLOGY 5 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, 10 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 15 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 20 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. 94

[0094] 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 5 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 10 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. 15 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, 20 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. 25 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. 30 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 95

[0095] 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 5 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 10 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 15 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 20 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 25 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. 30 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 96

[0096] 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, 5 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 10 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. 15 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. 20 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 25 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 30 through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in nonlimiting embodiments, CDH2, CD2H, CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, 97

[0097] OCDH2, OCD2H, or OCD3etc.). 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. 5 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 10 (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. “Alkyl” is a branched, straight chain, or cyclic saturated aliphatic hydrocarbon group. In 15 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 20 described as a unique species. For example, the term C1-C6alkyl 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 25 these is described as an independent species. When C0-Cnalkyl 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 30 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 98

[0098] 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 5 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 10 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 more15 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- 20 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 25 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 of30 haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2- fluoroethyl, and penta-fluoroethyl. 99

[0099] “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” 5 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 10 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 (which15 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]; 20 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, 25 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, 30 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 100

[0100] 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 5 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: 10 des . ed and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, S, 15 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 20 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 101

[0101] 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 5 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, 10 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. 15 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. 20 “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. The term “percent (%) identity”, “percent (%) homology”, “percent (%) homologous to” 25 “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. 30 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 102

[0102] 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 5 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 10 “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”, 15 “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 20 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 25 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 30 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. 103

[0103] 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. 5 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. 10 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. 15 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. 20 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,25 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. 30 In certain embodiments “haloalkyl” has one carbon and three halogens. In certain embodiments “haloalkyl” has two carbons. 104

[0104] 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. 5 Non-limiting examples of “haloalkyl” include: , , and . Additional non-limiting examples of “haloalkyl” include: , Additional non-limiting examples of “haloalkyl” includ nd . 10 Additional non-limiting examples of “haloalkyl” includ . Embodiments of “heteroaryl” Non-limiting examples of 5 membered “heteroaryl” groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, 15 thiazole, thiadiazole, and thiatriazole. Additional non-limiting examples of 5 membered “heteroaryl” groups include: , 105

[0105] 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: 5 , ntaining 1 or 2 atoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of “heteroaryl” groups that are bicyclic include indole, benzofuran, 10 isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzooxazole, and benzothiazole. Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . e: 15 . clic include: . In certain embodiments “heteroaryl” is a 10 membered bicyclic aromatic group containing 20 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. 106

[0106] Additional non-limiting examples of “heteroaryl” groups that are bicyclic include: . Embodiments of heterocycle 5 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, 10 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. 15 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, 20 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 25 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 107

[0107] on a heterocyclic ring. For example e” group. Howev is an “aryl” group. Non-limiting examples of “heterocycle also include: . 5 . 10 . mples of “heterocycle” also include: . include: . 15 eterocycle” include: . 108

[0108] Aryl In certain embodiments “aryl” is a 6 carbon aromatic group (phenyl). In certain embodiments “aryl” is a 10 carbon aromatic group (naphthyl). 5 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. F l i “ l” p. 10 up. Embodiments of “arylalkyl” Non-limiting examples of “arylalkyl” include: 15 an aryl group. Non-limiting examples of “arylalkyl” include: 20 . 109

[0109] 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 5 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 10 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 15 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. Accordingly, in some embodiments, a method to treat a host with a disorder mediated by a 20 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 25 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, 30 that has a partial, or full, gain-of-function or loss-of-function. In some embodiments, the degrader targets the aberrant form of the protein and not the normal form of the protein. 110

[0110] In certain embodiments, the Extracellular Protein Targeting Ligand is an monoclonal antibody, antibody fragment (including Fab, Fab', F(ab')2, and Fv fragments), diabody, single domain antibody (including VHH fragments and VNAR fragments), chimeric antibody, humanized antibody, isolated antibody, or single-chain antibody that binds to the Target Extracellular Protein 5 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, 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. 10 The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains (an IgM antibody consists of 5 of the basic heterotetramer unit along with an additional polypeptide called J chain, and therefore contain 10 antigen binding sites, while secreted IgA antibodies can polymerize to form polyvalent assemblages comprising 2-5 of the basic 4-chain units along with J chain). In the case of IgGs, the 15 4-chain unit is generally about 150,000 daltons. Each L chain is linked to a H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the α and γ chains and four CH domains for μ and ε isotypes. 20 Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain (CL) at its other end. The VLis aligned with the VHand the CLis aligned with the first constant domain of the heavy chain (CH1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, 25 see, e.g., Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), 30 immunoglobulins can be assigned to different classes or iso types. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated α, δ, ε, γ, and μ, 111

[0111] respectively. The γ and α classes are further divided into subclasses on the basis of relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The "variable region" or "variable domain" of an antibody refers to the amino -terminal 5 domains of the heavy or light chain of the antibody. The variable domain of the heavy chain may be referred to as "VH." The variable domain of the light chain may be referred to as "VL." These domains are generally the most variable parts of an antibody and contain the antigen-binding sites. The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domain mediates antigen binding and defines 10 specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable domains. Instead, the V regions consist of relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability called "hypervariable regions" that are each 9-12 amino acids long. The variable domains of native heavy and light chains each comprise four FRs, largely 15 adopting a β-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the β-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, 20 National Institutes of Health, Bethesda, MD. (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC). "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, 25 Fab', F(ab')2, and Fv fragments; diabodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. In one embodiment, an antibody fragment comprises an antigen binding site of the intact antibody and thus retains the ability to bind antigen. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize 30 readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1). Each Fab fragment is 112

[0112] monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having divalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having additional few residues 5 at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known. 10 The Fc fragment comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, which region is also the part recognized by Fc receptors (FcR) found on certain types of cells. "Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable 15 region domain in tight, non-covalent association. In a single-chain Fv (scFv) species, one heavy- and one light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a "dimeric" structure analogous to that in a two-chain Fv species. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer 20 antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen. "Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the VHand VLantibody domains connected into a single polypeptide chain. Preferably, the sFv 25 polypeptide further comprises a polypeptide linker between the VHand VLdomains which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp.269-315 (1994); Borrebaeck 1995. The term "diabodies" refers to antibody fragments with two antigen-binding sites, which 30 fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL). The small antibody fragments are prepared 113

[0113] by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites. Diabodies may be bivalent or bispecific. Bispecific diabodies are heterodimers of two "crossover" 5 sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described more fully in, for example, EP 404,097; WO 93 / 11161; Hudson et al, Nat. Med.9: 129-134 (2003); and Hollinger et al, Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al, Nat. Med.9: 129-134 (2003). In certain embodiments, the Extracellular Protein Targeting Ligand is an 10 scFv, Fv, scFab, Fab’, or Fab. In certain embodiments, the Extracellular Protein Targeting Ligand is a single chain molecule. Although the two domains of the binding domain, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by an artificial linker - as described herein - that enables them to be made as a single protein chain in which the VL and VH regions pair to15 form a monovalent molecule; see e.g., Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879- 5883). Binding domains are obtained using conventional techniques known to those with skill in the art, and the binding domains are evaluated for function in the same manner as are full- length antibodies or IgGs. An scFv for example is hence a fusion protein of the variable region of the 20 heavy chain (VH) and of the light chain (VL) of immunoglobulins, usually connected with a short linker peptide. The linker is typically rich in glycine for flexibility, as well as serine or also threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and introduction of the linker. 25 Bispecific single chain molecules are known in the art and are described in WO 99 / 54440, Mack, J. Immunol. (1997), 158, 3965-3970, Mack, PNAS, (1995), 92, 7021-7025, Kufer, Cancer Immunol. Immunother., (1997), 45, 193-197, Loffler, Blood, (2000), 95, 6, 2098- 2103, Bruhl, Immunol., (2001), 166, 2420-2426, Kipriyanov, J. Mol. Biol., (1999), 293, 41-56. Techniques described for producing single chain antibody constructs (see, inter alia, US Patent 4,946,778, 30 Kontermann and Diibel (2010), loc. cit. and Little (2009), loc. cit.) can be adapted to produce single chain antibody constructs specifically recognizing an elected targets. 114

[0114] An example of a peptide linker connecting the two binding domains is a SG4S linker. A multispecific molecule of the present invention may have one, two, three, four, five, or six repeats of the SG4S linker. For example, two SG4S repeats would be binding domain (e.g. scFv)- SGGGGSSGGGGS-binding domain (e.g. scFv) (SGGGGSSGGGGS given by SEQ ID NO: 23). 5 In certain embodiments, the multispecific molecules of the present invention have one SG4S as a linker. In other embodiments, the linker comprises two, three, or four SG4S repeats. In other embodiments, the linker comprises five or six SG4S repeats. In other embodiments, the linker comprises seven or more SG4S repeats, as long as the multispecific molecule is able to be expressed and purified. Other examples of linkers include linkers comprising a sequence selected 10 from the group consisting of (Gly3Ser)3 (SEQ ID NO: 1), (Gly4Ser)3(SEQ ID NO: 2), (Gly3Ser)4(SEQ ID NO: 3), (Gly4Ser)4(SEQ ID NO: 4), (Gly3Ser)5 (SEQ ID NO: 5), (Gly4Ser)5 (SEQ ID NO: 6), (Gly3Ser)6 (SEQ ID NO: 7), (Gly4Ser)6 (SEQ ID NO: 8), GSADDAKKDAAKKDAAKKDDAKKDDAGS (SEQ ID NO: 9), GSADDAKKDAAKKDAAKKDDAKKDDAKKDAGS (SEQ ID NO: 10), (Gly3Gln)215 (SEQ ID NO: 11), (Gly4Gln)2 (SEQ ID NO: 12), (Gly3Gln)3 (SEQ ID NO: 13), (Gly4Gln)3 (SEQ ID NO: 14), (Gly3Gln)4 (SEQ ID NO: 15), (Gly4Gln)4 (SEQ ID NO: 16), (Gly3Gln)5 (SEQ ID NO: 17), (Gly4Gln)5(SEQ ID NO: 18), (Gly3Gln)6(SEQ ID NO: 19), (Gly4Gln)6(SEQ ID NO: 20), (Gly3Ser)2(SEQ ID NO: 21), (Gly4Ser)2(SEQ ID NO: 22), (Gly)5(SEQ ID NO: 30), KESGSVSSEQLAQFRSLD (SEQ ID NO: 31), and EGKSSGSGSESKST (SEQ ID NO: 32). 20 SEQ ID NO: 1GGGSGGGSGGGS (Gly3Ser)3 115

[0115] SEQ ID NO: 14GGGGQGGGGQGGGGQ(Gly4Gln)3SEQ ID NO: 15GGGQGGGQGGGQGGGQ (Gly3Gln)4)2)3)4 )5)6)7 The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in 5 minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. 10 The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies useful in the present invention may be prepared by the hybridoma methodology first described by Kohler et al., Nature, 256:495 (1975), or may be made using recombinant DNA methods in bacterial, eukaryotic animal or plant cells (see, e.g., U.S. Patent No. 4,816,567). The "monoclonal antibodies" may also be isolated from 116

[0116] phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. MoI. Biol, 222:581-597 (1991), for example. The monoclonal antibodies herein include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies 5 derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Patent No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric10 antibodies of interest herein include "primatized" antibodies comprising variable domain antigen- binding sequences derived from a non-human primate (e.g. Old World Monkey, Ape etc), and human constant region sequences. "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized 15 antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. 20 Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally 25 also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also the following review articles and references cited therein: Vaswani and Hamilton. Allergy, Asthma and Immunol, 1: 105-115 (1998); Harris, Biochem. Soc. Transactions, 23:1035- 30 1038 (1995); Hurle and Gross, Curr. Op. Biotech., 5:428-433 (1994). 117

[0117] A "human antibody" is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human and / or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human 5 antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al, J. MoI Biol, 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al, J. Immunol, 147(l):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. 10 Pharmacol, 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. See, for example, Li et al, Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology. 15 An "isolated antibody" is one which has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as 20 determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural 25 environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step. The term "hypervariable region", "HVR", or "HV", when used herein refers to the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six hypervariable regions; three in the VH (H1, H2, 30 H3), and three in the VL (L1, L2, L3). A number of hypervariable region delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based 118

[0118] on sequence variability and are the most commonly used (Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (Chothia and Lesk, Mol. Biol.196:901-917 (1987)). 5 "Framework" or "FR" residues are those variable domain residues other than the hypervariable region residues herein defined. Extracellular Protein Targeting Ligands according to the present invention are envisioned to have a format that does not result in self-binding. For example, an Extracellular Protein Targeting Ligand engineered to bind IgG should be devoid of an Fc region. In certain 10 embodiments, Extracellular Protein Targeting Ligands according to the present invention preferably demonstrate monovalent binding to immunoglobulin, as immunoglobulin cross-linking can activate the immune system resulting in side effects such as anaphylaxis. In certain embodiments, compounds of the present invention bind and deplete immunoglobulin. Depletion of immunoglobulin is thought to be beneficial in the treatment of 15 patients having antibody-mediated autoimmune disease (also referred to as autoantibody-induced disease). As used herein, a “patient” refers to a human. Autoantibody-induced disease result from the body’s immune system not being able to discriminate between self and non-self antigens, resulting in the immune system attacking normal parts on the body potentially resulting in damage and / or disease. For example, the immune system may begin producing antibodies that attack the 20 body’s own tissues. Examples of treatments for autoimmune disease include antiinflammatory drugs, corticosteroids, pain-killing medication, immunosuppressant drugs, physical therapy, surgery, high dose immunosuppression, and disease-specific treatments. Extracellular Protein Targeting Ligand Mutants 25 In certain embodiments, an amino acid of an Extracellular Protein Targeting Ligand described herein is variable (denoted by an “X” in the SEQ ID NO). Variable amino acids (“X”), can be any natural or non-natural amino acid, including both D- and L- amino acids. In certain embodiments, the “X” amino acid is an amino acid selected from the group consisting of G, A, V, L, I, T, S, M, C, P, F, Y, W, H, K, R, D, E, N, and Q. In certain embodiments, the “X” amino acid 30 is an amino acid selected from the group consisting of Aad, bAad, bAla, Abu, 4Abu, Acp, Ahe, 119

[0119] Aib, bAib, Apm, Dbu, Des, Dpm, Dpr, EtGly, EtAsn, Hyl, aHyl, 3Hyp, 4Hyp, Ide, alle, MeGly, MeIle, MeLys, MeVal, Nva, Nle, and Orn. In certain embodiments, an amino acid of an Extracellular Protein Targeting Ligand described herein is substituted with histidine, as further described below. Histidine is a basic amino 5 acid and can be protonated in acidic compartments of the body or cells, for example the endolysosome. In certain embodiments, the Extracellular Protein Targeting Ligand carrying a histidine substitution 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 10 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, an Extracellular Protein Targeting Ligand described herein has a 15 binding affinity for the target molecule that is calcium dependent and / or pH dependent In certain embodiments, an 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 20 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, an Extracellular Protein Targeting Ligand described herein has a higher koffrate for the target molecule intraendosomally 25 than extracellularly. In certain embodiments, an Extracellular Protein Targeting Ligand described herein binds FcRn intraendosomally. In certain embodiments, an Extracellular Protein Targeting Ligand described herein facilitates externalization from the cell via FcRn. In certain embodiments, an Extracellular Protein Targeting Ligand described herein has 30 one or more mutations that impart pH-dependent binding affinity for the target molecule. In certain embodiments, an Extracellular Protein Targeting Ligand described herein has been mutated with 120

[0120] one or more histidine substitutions. In certain embodiments, an amino acid residue selected from aspartic acid (D), leucine (L), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), tryptophan (W), and tyrosine (Y) is replaced by histidine in an Extracellular Protein Targeting Ligand described herein. In certain embodiments, an Extracellular Protein Targeting Ligand 5 described herein wherein the one or more histidine substitutions are located in the binding or CDR region of the antibody, antibody fragment, or Target Protein binding moiety. In certain embodiments a D, L, N, P, Q, R, S, W, or Y amino acid in an Extracellular Protein Targeting Ligand herein is replaced by histidine, for example a D, L, N, P, Q, R, S, W, or Y amino acid in a CDR1, CDR2, or CDR3 region of an antibody described herein. Cysteine(s) may be further 10 introduced to improve stability (see e.g. Reiter et al., Biochemistry 1994, 33, 5451-5459) and are not expected to alter catabolic properties of the molecule. The conversion of an scFab molecule to a bispecific scFv molecule is not expected to alter the catabolic properties of the molecule. In certain aspects a D, L, N, P, Q, R, S, W, or Y amino acid in a sequence listing described herein is replaced by histidine, for example a D, L, N, P, Q, R, S, W, or Y amino acid in a CDR1, 15 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 an S amino acid is 20 replaced by histidine. In certain embodiments a W amino acid is replaced by histidine. In certain embodiments a Y amino acid is replaced by histidine. In certain embodiments, the Extracellular Protein Targeting Ligand can be omalizumab, or a fragment or mutant thereof, with one or more amino acids replaced with histidine. The sequences of wild-type omalizumab is publicly known. For instance, the DrugBank Accession No. for 25 omalizumab is DB00043. In certain embodiments, the Extracellular Protein Targeting Ligand comprises a light chain with a sequence of SEQ ID NO: 33. In certain embodiments, the Extracellular Protein Targeting Ligand comprises a heavy chain with a sequence of SEQ ID NO: 34. In certain embodiments, the Extracellular Protein Targeting Ligand comprises a light chain of SEQ ID NO: 33 with one or more amino acids replaced with histidine and a heavy chain of SEQ 30 ID NO: 34 with one or more amino acids replaced with histidine. 121

[0121] In certain embodiments, the Extracellular Protein Targeting Ligand can be ligelizumab, or a fragment or mutant thereof, with one or more amino acids replaced with histidine. The sequences of wild-type ligelizumab are publicly known. For instance, the KEGG Entry ID for ligelizumab is D11761. In certain embodiments, the Extracellular Protein Targeting Ligand comprises a light 5 chain with a sequence of SEQ ID NO: 35. In certain embodiments, the Extracellular Protein Targeting Ligand comprises a heavy chain with a sequence of SEQ ID NO: 36. In certain embodiments, the Extracellular Protein Targeting Ligand comprises a light chain of SEQ ID NO: 35 with one or more amino acids replaced with histidine and a heavy chain of SEQ ID NO: 36 with one or more amino acids replaced with histidine. Identifier Sequence SEQ ID NO: 33 EVQLVESGGGLVQPGGSLRLSCAVSGYSITSGYSWNWIRQAPGKGLEWVASITYD V K A N S E P Y P S W Y I V S 10 5H (LC), Y57H (LC), L443C (HC), M252Y (HC), S254T (HC), and T256E (HC). In some embodiments, omalizumab includes the following mutations: S35H (LC), Y57H (LC), L443C (HC), M252Y (HC), S254T (HC), and T256E (HC). In some embodiments, ligelizumab includes one or more of the following mutations: 15 W33H (HC), Y50H (LC), N100bH (HC), W94H (LC), L443C (HC), M252Y (HC), S254T (HC), and T256E (HC). In some embodiments, ligelizumab includes the following mutations: W33H 122

[0122] (HC), Y50H (LC), N100bH (HC), W94H (LC), L443C (HC), M252Y (HC), S254T (HC), and T256E (HC). For example, the table below describes specific amino acids that can be replaced with histidine. Omalizumab DIQLTQSPSSLSASVGDRVTITCRASQSVDYDGDHYMNWYQQKPGK S35H-LC APKLLIYAASYLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQS SEQ ID NO: 37 HEDPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF D K S F D T S T V K L V I T K V I T K V 5 By way of a non-limited example, an antibody useful within the disclosure can bind to a circulating protein. As will be understood by one skilled in the art, any antibody that may recognize and specifically bind to a circulating protein is useful in the present disclosure. The disclosure should not be construed to be limited to any one type of antibody, either known or heretofore 10 unknown, provided that the antibody can specifically bind to a circulating protein, and prevent or minimize biological activity of the circulating protein. The antibody of interest can be incorporated within the compounds of the disclosure using any methods known in the art and / or any techniques described or illustrated herein. For example, the antibody can be attached to a Linker through a carboxylic acid group on the antibody's surface, 123

[0123] using for example amide or ester formation chemistry. For example, the antibody can be attached to a Linker through an amine group on the antibody's surface, using for example amide formation chemistry. For example, the antibody can be attached to a Linker through a thiol group on the antibody's surface, using for example nucleophilic substitution chemistry. In that case, the surface 5 cysteine residue can exist in the wild-type form of the Ab and / or can be introduced by mutation, using for example site-directed mutagenesis. The Linker useful within the disclosure can be any linker known in the art, as long as the presence of the linker does not significantly disturb the Ab's ability to bind to the circulating protein. Methods of making and using such antibodies are well known in the art. For example, the 10 generation of polyclonal antibodies may be accomplished by inoculating the desired animal with the antigen and isolating antibodies which specifically bind the antigen therefrom. Monoclonal antibodies directed against full length or peptide fragments of a protein or peptide may be prepared using any well-known monoclonal antibody preparation procedures, such as those described, for example, in Harlow et al. (1989, Antibodies, A Laboratory Manual, Cold Spring Harbor, New 15 York) and in Tuszynski et al. (1988, Blood 72:109-115). Quantities of the desired peptide may also be synthesized using chemical synthesis technology. Alternatively, DNA encoding the desired peptide may be cloned and expressed from an appropriate promoter sequence in cells suitable for the generation of large quantities of peptide. Monoclonal antibodies directed against the peptide are generated from mice immunized with the peptide using standard procedures as referenced 20 herein. However, the disclosure should not be construed as being limited solely to methods and compositions including these antibodies, but should be construed to include other antibodies, as that term is defined elsewhere herein. In some instances, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as rodents (e.g., mice), primates (e.g., humans), and so forth. Descriptions 25 of techniques for preparing such monoclonal antibodies are well known and are described, for example, in Harlow et al., ANTIBODIES: A LABORATORY MANUAL, COLD SPRING HARBOR LABORATORY, Cold Spring Harbor, N.Y. (1988); Harlow et al., USING ANTIBODIES: A LABORATORY MANUAL, (Cold Spring Harbor Press, New York, 1998); Breitling et al., RECOMBINANT ANTIBODIES (Wiley-Spektrum, 1999); and Kohler et al., 1997 30 Nature 256: 495-497; and U.S. Patent Nos.5,693,762; 5,693,761; 5,585,089; and 6,180,370. 124

[0124] Nucleic acid encoding an antibody obtained using the procedures described herein may be cloned and sequenced using technology that is available in the art, and is described, for example, in Wright et al. (Critical Rev. Immunol.1992, 12:125-168) and the references cited therein. Further, the antibody useful within the disclosure may be "humanized" using the technology described in 5 Wright et al. (supra) and in the references cited therein, and in Gu et al. (Thrombosis and Hematocyst 1997, 77:755-759). Alternatively, antibodies may be generated using phage display technology. To generate a phage antibody library, a cDNA library is first obtained from mRNA that is isolated from cells, e.g., the hybridoma, which express the desired protein to be expressed on the phage surface, e.g., 10 the desired antibody. cDNA copies of the mRNA are produced using reverse transcriptase. cDNA which specifies immunoglobulin fragments are obtained by PCR and the resulting DNA is cloned into a suitable bacteriophage vector to generate a bacteriophage DNA library comprising DNA specifying immunoglobulin genes. The procedures for making a bacteriophage library comprising heterologous DNA are well known in the art and are described, for example, in Sambrook et al. 15 (1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York). Bacteriophages that encode the desired antibody may be engineered such that the protein is displayed on the surface thereof in such a manner that it is available for binding to its corresponding binding protein, e.g., the antigen against which the antibody is directed. Thus, when bacteriophage that express a specific antibody are incubated in the presence of a cell that expresses 20 the corresponding antigen, the bacteriophage will bind to the cell. Bacteriophage that do not express the antibody will not bind to the cell. Such panning techniques are well known in the art and are described for example, in Wright et al. (Critical Rev. Immunol.1992, 12:125-168). Processes such as those described herein have been developed for the production of human antibodies using M13 bacteriophage display (Burton et al., 1994, Adv. Immunol. 57:191-280). 25 Essentially, a cDNA library is generated from mRNA obtained from a population of antibody- producing cells. The mRNA encodes rearranged immunoglobulin genes and thus, the cDNA encodes the same. Amplified cDNA is cloned into M13 expression vectors creating a library of phage which express human Fab fragments on their surface. Phage that display the antibody of interest are selected by antigen binding and are propagated in bacteria to produce soluble human 30 Fab immunoglobulin. Thus, in contrast to conventional monoclonal antibody synthesis, this 125

[0125] procedure immortalizes DNA encoding human immunoglobulin rather than cells which express human immunoglobulin. The procedures just presented describe the generation of phage that encode the Fab portion of an antibody molecule. However, the disclosure should not be construed to be limited solely to 5 the generation of phage encoding Fab antibodies. Rather, phage that encode single chain antibodies (scFv / phage antibody libraries) are also included in the disclosure. Fab molecules comprise the entire Ig light chain, that is, they comprise both the variable and constant region of the light chain, but include only the variable region and first constant region domain (CH1) of the heavy chain. Single chain antibody molecules comprise a single chain of protein comprising the Ig Fv fragment. 10 An Ig Fv fragment includes only the variable regions of the heavy and light chains of the antibody, having no constant region contained therein. Phage libraries comprising scFv DNA may be generated following the procedures described in Marks et al. (1991, J Mol Biol 222:581-597). Panning of phage so generated for the isolation of a desired antibody is conducted in a manner similar to that described for phage libraries comprising Fab DNA. 15 The disclosure should also be construed to include synthetic phage display libraries in which the heavy and light chain variable regions may be synthesized such that they include nearly all possible specificities (Barbas, 1995, Nature Medicine 1:837-839; de Kruif et al., 1995, J Mol Biol 248:97-105). The disclosure encompasses polyclonal, monoclonal, synthetic antibodies, and the like. 20 One skilled in the art would understand, based upon the disclosure provided herein, that an important feature of the antibody useful within the disclosure is that the antibody specifically bind with a circulating protein. For example, in certain embodiments, a peptide Extracellular Protein Targeting Ligand shows an overall degree of sequence homology or identity with a reference polypeptide that is at 25 least about 60-70%, and is often greater than about 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more and / or includes at least one region (e.g., a conserved region that may in certain embodiments be or comprise a characteristic sequence element) that shows very high sequence identity, often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such a conserved region usually encompasses at least 3-4 and often up to 20 or more amino acids; in certain 30 embodiments, a conserved region encompasses at least one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids. In certain embodiments, a relevant peptide 126

[0126] Extracellular Protein Targeting Ligand may comprise or consist of a fragment of a parent polypeptide. In certain embodiments, a useful peptide Extracellular Protein Targeting Ligand may comprise or consist of a plurality of fragments, each of which is found in the same parent polypeptide in a different spatial arrangement relative to one another than is found in the peptide 5 Extracellular Protein Targeting Ligand (e.g., fragments that are directly linked in the parent may be spatially separated in the peptide Extracellular Protein Targeting Ligand or vice versa, and / or fragments may be present in a different order in the peptide Extracellular Protein Targeting Ligand than in the parent), so that the peptide Extracellular Protein Targeting Ligand is a derivative of its parent polypeptide. 10 A compound described herein may be prepared by several routes employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group of an Extracellular Protein Targeting Ligand with a linker reagent to form, for example: 15 via a covalent bond, follow nd; and (2) reaction of a nucleophilic group of an ASGPR Binding Ligand with a linker reagent, to form, for example: , via a covalent bond, f of an Extracellular Protein Targeting Ligand. 20 Nucleophilic groups on Extracellular Protein Targeting Ligands, e.g. antibodies, include, but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated. Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active 25 esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups. Certain antibodies have reducible interchain disulfides, i.e. cysteine bridges. Antibodies may be made reactive for conjugation with linker reagents by treatment with a reducing agent such as DTT 127

[0127] (dithiothreitol) or tricarbonylethylphosphine (TCEP), such that the antibody is fully or partially reduced. Each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. Additional nucleophilic groups can be introduced into antibodies through modification of lysine residues, e.g., by reacting lysine residues with 2-iminothiolane (Traut's reagent), resulting in 5 conversion of an amine into a thiol. Reactive thiol groups may be introduced into an antibody by introducing one, two, three, four, or more cysteine residues (e.g., by preparing variant antibodies comprising one or more non-native cysteine amino acid residues). Compounds of the invention may also be produced by reaction between an electrophilic group on an Extracellular Protein Targeting Ligand, e.g. an antibody, such as an aldehyde or ketone 10 carbonyl group, with a nucleophilic group on a Linker. Useful nucleophilic groups on a Linker include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. In one embodiment, an antibody is modified to introduce electrophilic moieties that are capable of reacting with nucleophilic substituents on the Linker. In another embodiment, the sugars of glycosylated antibodies may be oxidized, e.g. with periodate 15 oxidizing reagents, to form aldehyde or ketone groups which may react with the amine group of a Linker. The resulting imine Schiff base groups may form a stable linkage, or may be reduced, e.g. by borohydride reagents to form stable amine linkages. In one embodiment, reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium meta- periodate may yield carbonyl (aldehyde and ketone) groups in the antibody that can react with 20 appropriate groups on the drug (Hermanson, Bioconjugate Techniques). In another embodiment, antibodies containing N-terminal serine or threonine residues can react with sodium meta- periodate, resulting in production of an aldehyde in place of the first amino acid (Geoghegan & Stroh, (1992) Bioconjugate Chem.3:138-146; US 5362852). Such an aldehyde can be reacted with a drug moiety or linker nucleophile. 25 Nucleophilic groups on an ASGPR Binding Ligand or Linker include, but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on linker moieties and linker reagents including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as 30 haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups. 128

[0128] Cross-linking reagents which can be used to prepare an compound described herein include but are not limited to: BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate) which are 5 commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A; see pages 467-498, 2003-2004 Applications Handbook and Catalog. Extracellular protein degrading compounds of the invention may also be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC), 10 iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis- (p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6- diisocyanate), bis- active fluorine compounds (such as l,5-difluoro-2,4-dinitrobenzene), N-succinimidyl-3-(2-15 pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1- carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis- diazonium derivatives (such as bis-(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such20 as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as l,5-difluoro-2,4- dinitrobenzene). The extracellular protein degrading compounds of the invention may also be prepared with linker reagents: BMPEO, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-25 SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate), and including bis- maleimide reagents: DTME, BMB, BMDB, BMH, BMOE, 1,8-bis- maleimidodiethyleneglycol (BM(PEO)2), and 1,11-bis-maleimidotriethyleneglycol (BM(PEO)3), which are commercially available from Pierce Biotechnology, Inc., ThermoScientific, Rockford, IL, and other reagent suppliers. Bis-maleimide reagents allow the attachment of the thiol group of a cysteine engineered 30 antibody to a thiol-containing drug moiety, label, or linker intermediate, in a sequential or concurrent fashion. Other functional groups besides maleimide, which are reactive with a thiol 129

[0129] group of a cysteine engineered antibody, drug moiety, label, or linker intermediate include iodoacetamide, bromoacetamide, vinyl pyridine, disulfide, pyridyl disulfide, isocyanate, and isothiocyanate. The loading (ASGPR Ligand / antibody ratio) of a compound described herein may be 5 controlled in different ways, e.g., by: (i) limiting the molar excess of ASGPR Binding Ligand- linker intermediate relative to antibody, (ii) limiting the conjugation reaction time or temperature, and (iii) partial or limiting reductive conditions for cysteine thiol modification. It is to be understood that where more than one nucleophilic group reacts with an ASGPR Binding Ligand-linker intermediate, then the resulting product is a mixture of compounds with a 10 distribution of one or more drug moieties attached to an antibody. The average number of ASGPR ligands per antibody may be calculated from the mixture by a dual ELISA antibody assay, which is specific for antibody and specific for the drug. Individual molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g. hydrophobic interaction chromatography (see, e.g., McDonagh et al (2006) Prot. Engr. Design & Selection 19(7):299-307; 15 Hamblett et al (2004) Clin. Cancer Res.10:7063-7070; Hamblett, KJ., et al. "Effect of drug loading on the pharmacology, pharmacokinetics, and toxicity of an anti-CD30 antibody-drug conjugate," Abstract No.624, American Association for Cancer Research, 2004 Annual Meeting, March 27- 31, 2004, Proceedings of the AACR, Volume 45, March 2004; Alley, S.C., et al. "Controlling the location of drug attachment in antibody-drug conjugates," Abstract No.627, American Association 20 for Cancer Research, 2004 Annual Meeting, March 27-31, 2004, Proceedings of the AACR, Volume 45, March 2004). In certain embodiments, a compound with a single loading value may be isolated from the conjugation mixture by electrophoresis or chromatography. Conjugation of the ASGPR Binding Ligand 25 In some embodiments, the ASGPR Binding Ligand is connected to antibody moieties through certain types groups and / or amino acid residues. For example, in some embodiments, the ASGPR Binding Ligand is connected to lysine residues optionally through linker moieties. In some embodiments, the ASGPR Binding Ligand is connected to cysteine residues optionally through linker moieties. In some embodiments, the ASGPR Binding Ligand is connected to unnatural 30 amino acid residues optionally through linker moieties. In some embodiments, the present disclosure provides technologies for selectively linking the ASGPR Binding Ligand to certain 130

[0130] particular amino acid residues optionally through linker moieties. In some embodiments, an amino acid of the peptide or antibody is selectively connected to the ASGPR Binding Ligand through a Linker. For example, in some embodiments, the ASGPR Binding Ligand is connected to K246 and K248 of an IgG1 heavy chain and amino acid residues corresponding thereto through the 5 Linker. For example, in some embodiments, the ASGPR Binding Ligand is connected to K251 and K253 of an IgG2 heavy chain and amino acid residues corresponding thereto the Linker. For example, in some embodiments, the ASGPR Binding Ligand is connected to K239 and K241 of an IgG4 heavy chain and amino acid residues corresponding thereto through the Linker. In some embodiments, the ASGPR Binding Ligand is connected to a particular amino acid residue or site 10 through the Linker. In some embodiments, each the ASGPR Binding Ligand is independently connected to a particular amino acid residue or site through the Linker. In certain embodiments an ASGPR Binding Ligand or ASGPR Binding LigandBis conjugated to an Extracellular Protein Targeting Ligand that is a peptide (for example an antibody or fragment thereof) by using a bioconjugate technique. According to this technique, a small 15 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 20 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 25 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 30 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 131

[0131] number: 93; and Yang Feng et al. “Conjugates of Small Molecule Drugs with Antibodies and Other Proteins”. Biomedicines (2014), 2(1): 1–13. 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 5 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. 10 In certain embodiments, a native and / or engineered lysine residue on the antibody may be conjugated to the Linker, for example to the LinkerBthrough a pentafluorophenoxy ester (shown below). 15 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 20 the N-terminus of an amino acid sequence described herein, for example through the reaction of 132

[0132] 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, 5 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 10 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 15 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 20 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- 133

[0133] limiting examples of alkynes for use in the click reaction include , . racellular Protein Targeting Ligand through a triazole. In certain embodiments the Linker is attached to the N-terminus of an amino 5 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. 10 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. 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 15 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. In certain embodiments, fewer than the theoretical maximum of ASGPR Ligands are 20 conjugated to an antibody during a conjugation reaction. An antibody may contain, for example, lysine residues that do not react with the ASGPR Binding Ligand-linker intermediate. Generally, antibodies do not contain many free and reactive cysteine thiol groups which may be linked to an ASGPR Binding Ligand-linker intermediate; indeed most cysteine thiol residues in antibodies 134

[0134] exist as disulfide bridges. In certain embodiments, an antibody may be reduced with a reducing agent such as dithiothreitol (DTT) or tricarbonylethylphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups. In certain embodiments, an antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups such as lysine 5 or cysteine. In one aspect, the Extracellular Protein Targeting Ligand is a cysteine engineered antibody, wherein one or more amino acids of a parent antibody are replaced with a free cysteine amino acid as disclosed in WO2006 / 034488; US 2007 / 0092940 (herein incorporated by reference in its entirety). Any form of antibody Extracellular Protein Targeting Ligand may be so engineered, i.e. 10 mutated. For example, a parent Fab antibody fragment may be engineered to form a cysteine engineered Fab, referred to as "ThioFab." Similarly, a parent monoclonal antibody may be engineered to form a "ThioMab." It should be noted that a single site mutation yields a single engineered cysteine residue in a ThioFab, while a single site mutation yields two engineered cysteine residues in a ThioMab, due to the dimeric nature of the IgG antibody. The cysteine 15 engineered Extracellular Protein Targeting Ligands include monoclonal antibodies, humanized or chimeric monoclonal antibodies, and antigen-binding fragments of antibodies, fusion polypeptides and analogs thereof. A cysteine engineered antibody may alternatively comprise an antibody comprising a cysteine at a position disclosed herein in the antibody or Fab, resulting from the sequence design and / or selection of the antibody, without necessarily altering a parent antibody, 20 such as by phage display antibody design and selection or through de novo design of light chain and / or heavy chain framework sequences and constant regions. A cysteine engineered antibody comprises one or more free cysteine amino acids having a thiol reactivity value in the ranges of 0.6 to 1.0; 0.7 to 1.0 or 0.8 to 1.0. A free cysteine amino acid is a cysteine residue which has been engineered into the parent antibody and is not part of a disulfide bridge. Cysteine engineered 25 antibodies are useful for attachment of an ASGPR Binding Ligand at the site of the engineered cysteine through, for example, a maleimide or haloacetyl. The nucleophilic reactivity of the thiol functionality of a Cys residue to a maleimide group is about 1000 times higher compared to any other amino acid functionality in a protein, such as amino group of lysine residues or the N- terminal amino group. Thiol specific functionality in iodoacetyl and maleimide reagents may react 30 with amine groups, but higher pH (>9.0) and longer reaction times are required (Garman, 1997, Non-Radioactive Labelling: A Practical Approach, Academic Press, London). 135

[0135] In certain embodiments, the cysteine engineered antibody may be conjugated to the Linker, for example to the LinkerBthrough a maleimide (shown below). 5 y have an engineered cysteine at any one of the following positions, where the position is numbered according to Kabat et al. in the light chain (see Kabat et al (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD) and according to EU numbering in the heavy chain (including the Fc region) (see Kabat et 10 al. (1991), supra). In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine at LC-V205C. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine at HC-Al 18C (EU number: Ala 118; Kabat number 114). In certain embodiments, a cysteine engineered Extracellular 15 Protein Targeting Ligand comprises an engineered cysteine at Fc-S400C (EU number: Ser 400; Kabat number 396). In other embodiments, the engineered cysteine of the heavy chain (including the Fc region) is at any one of the following positions (according to Kabat numbering with EU numbering in parenthesis): 5, 23, 84, 112, 114 (118 EU numbering), 116 (120 EU numbering), 278 (282 EU 20 numbering), 371 (375 EU numbering) or 396 (400 EU numbering). 136

[0136] In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises a cysteine introduced at a position selected from: V5C, A23C, A84C, S112C, A114C (A118C EU Numbering), T116C (T120C EU numbering), V278C (V282C EU numbering), S371C (S375C EU numbering) or S396C (S400C EU numbering). 5 In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises a cysteine introduced at a position selected from: Q5C, K23C, S84C, S112C, A114C (A118C EU Numbering), T116C (T120C EU numbering), V278C (V282C EU numbering), S371C (S375C EU numbering) or S396C (S400C EU numbering). In other embodiments, the engineered cysteine of the light chain is at any one of the following positions (according to Kabat numbering): 10 15, 110, 114, 121, 127, 168, 205. In certain embodiments, the cysteine mutation in the heavy chain is selected from the group of cysteine mutations comprising HC-T114C, HC-A140C, HC-L174C, HC-L179C, HC-T187C, HC-T209C, HC-V262C, HC-G371C, HC-Y373C, HC-E382C, HC-S424C, HC-N434C, and HC- Q438C according to EU numbering. 15 In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of E152C according to EU numbering, or E150C according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of K274C according to EU numbering, or K287C 20 according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of K290C according to EU numbering, or K307C according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand 25 comprises an engineered cysteine mutation of K326C according to EU numbering, or K345C according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of K320C according to EU numbering, or K320C according to Kabat numbering. 137

[0137] In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of K340C according to EU numbering, or K340C according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand 5 comprises an engineered cysteine mutation of S375C according to EU numbering, or K398C according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of N361C according to EU numbering, or N361C according to Kabat numbering. 10 In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of K414C according to EU numbering, or K445C according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of V422C according to EU numbering, or V453C 15 according to Kabat numbering. In certain embodiments, a cysteine engineered Extracellular Protein Targeting Ligand comprises an engineered cysteine mutation of E152C and S375C according to EU numbering, or E150C and S398C according to Kabat numbering. The Extracellular Protein Targeting Ligands of the disclosure include engineered 20 antibodies and antibody fragments where 1, 2, 3, 4, 5, or 6 or more amino acids chosen from positions: 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442 of the antibody heavy chain wherein the numbering system of the constant region is that of the EU index as set forth in Kabat et al. (1991, NIH Publication 91- 3242, National Technical Information Service, Springfield, VA, hereinafter "Kabat") of a parent, native, or wild type 25 antibody are substituted with another amino acid (including natural and synthetic amino acids). It should be noted that a single substitution, for example of a cysteine residue, normally results in the display of two corresponding residues in the resultant antibody due to the homodimeric nature of IgG molecules. The resultant Extracellular Protein Targeting Ligands of the disclosure may display at least 1, 2, 3, 4, 5, or 6 or more reactive groups for the purpose of conjugation to a Linker, 30 for example a LinkerA. In an embodiment, one or more of the substitutions is with a cysteine 138

[0138] residue, and the resulting Extracellular Protein Targeting Ligands may display at least 1, 2, 3, 4, 5, or 6 or more thiol groups for the purpose of conjugation to a Linker. In some embodiments, the Extracellular Protein Targeting Ligands comprise at least one substitution at positions selected from: 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 5 384, 398, 400, 440, 422, and 442 of the heavy chain of an antibody, wherein the numbering system of the constant region is that of the EU index as set forth in Kabat et al. (supra). In other embodiments, the Extracellular Protein Targeting Ligands comprise at least two substitutions selected from the positions 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442 of the heavy chain of an antibody wherein the numbering system of the 10 constant region is that of the EU index as set forth in Kabat. In other embodiments, the Extracellular Protein Targeting Ligands of the disclosure comprise at least three substitutions selected from the positions 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442 of the heavy chain of an antibody wherein the numbering system of the constant region is that of the EU index as set forth in Kabat. In other embodiments, the 15 Extracellular Protein Targeting Ligands of the disclosure comprise at least four substitutions selected from the positions 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442 of the heavy chain of an antibody wherein the numbering system of the constant region is that of the EU index as set forth in Kabat. In other embodiments, the Extracellular Protein Targeting Ligands of the disclosure comprise at least five substitutions 20 selected from the positions 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442 of the heavy chain of an antibody wherein the numbering system of the constant region is that of the EU index as set forth in Kabat. In other embodiments, the Extracellular Protein Targeting Ligands of the disclosure comprise at least six substitutions selected from the positions 282, 289, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 25 400, 440, 422, and 442 of the heavy chain of an antibody wherein the numbering system of the constant region is that of the EU index as set forth in Kabat. In one embodiment, an Extracellular Protein Targeting Ligand described herein comprises one or more of the following pairs of substitutions: a) 289 and 440; 30 b) 330 and 440; c) 339 and 440; 139

[0139] d) 359 and 440; e) 289 and 359; f) 330 and 359; g) 339 and 359; 5 h) 289 and 339; i) 330 and 339; j) 289 and 330; and k) 339 and 442. In another embodiment, the engineered antibodies comprise one or more of the following 10 groups of substitutions: a) 289, 339, and 442; b) 289, 330, and 339; c) 330, 339, and 442; and d) 289, 330, and 442. 15 In certain embodiments, the engineered antibodies of the disclosure comprise a substitution of at least one naturally occurring amino acid chosen from: Val282, Thr289, Asp312, Ser324, Ala330, Thr335, Ser337, Ala339, Glu356, Thr359, Asn361, Ser383, Asn384, Leu398, Ser400, Ser440, Val422, and Ser442 of the heavy chain of an antibody wherein the numbering system of the constant region is that of the EU index as set forth in Kabat. 20 In certain embodiments, the Extracellular Protein Targeting Ligand comprises a cysteine insertion mutation selected from: (a) an insertion of a cysteine residue between positions 39 and 40 in the VL domain; (b) an insertion of a cysteine residue between positions 40 and 41 in the VL domain; (c) an insertion of a cysteine residue between positions 126 and 127 in the CL domain; (d) an insertion of a cysteine residue between positions 148 and 149 in the CL domain; (e) an 25 insertion of a cysteine residue between positions 149 and 150 in the CL domain; (f) an insertion of a cysteine residue between positions 9 and 10 in the VH domain; (g) an insertion of a cysteine residue between positions 169 and 170 in the CHI domain; (h) an insertion of a cysteine residue between positions 237 and 238 in the CH2 domain; (i) an insertion of a cysteine residue between positions 295 and 296 in the CH2 domain, and (j) an insertion of a cysteine residue between 30 positions 299 and 300 in the CH2 domain, wherein the numbering of amino acids in the VL, CL, 140

[0140] VH and CHI domains is Rabat numbering and the numbering of amino acids in the CH2 domain is EU numbering, Antibody cysteine thiol groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on linker reagents and drug-linker intermediates including: (i) 5 active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides, such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups; and (iv) disulfides, including pyridyl disulfides, via sulfide exchange. Nucleophilic groups on a drug moiety include, but are not limited to amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide groups capable of reacting to form 10 covalent bonds with electrophilic groups on the Linker. Cysteine engineered antibodies may be made reactive for conjugation with Linker reagents by treatment with a reducing agent such as DTT (Cleland's reagent, dithiothreitol) or TCEP (tris(2- carboxyethyl)phosphine hydrochloride; Getz et al (1999) Anal. Biochem. VoI 273:73-80; Soltec Ventures, Beverly, MA), followed by reoxidation to reform interchain and intrachain disulfide 15 bonds. For example, full length, cysteine engineered monoclonal antibodies (ThioMabs) expressed in CHO cells are reduced with about a 50-fold molar excess of TCEP for 3 hrs at 37°C to reduce disulfide bonds in cysteine adducts which may form between the newly introduced cysteine residues and the cysteine present in the culture media. The reduced ThioMab is diluted and loaded onto HiTrap S column in 10 mM sodium acetate, pH 5, and eluted with PBS containing 0.3M 20 sodium chloride. Disulfide bonds are reestablished between cysteine residues present in the parent Mab with dilute (200 nM) aqueous copper sulfate (CuSO4) at room temperature, overnight. Alternatively, dehydroascorbic acid (DHAA) is an effective oxidant to reestablish the intrachain disulfide groups of the cysteine engineered antibody after reductive cleavage of the cysteine adducts. Other oxidants, i.e. oxidizing agents, and oxidizing conditions, which are known in the 25 art may be used. Ambient air oxidation is also effective. This mild, partial reoxidation step forms intrachain disulfides efficiently with high fidelity and preserves the thiol groups of the newly introduced cysteine residues. In some embodiments, the Fc domains form a heterodimer as a result of knobs-in-holes (KIH) mutations. In some embodiments, the KIH mutations comprise Y349T and T394F, 30 according to EU numbering scheme. In some embodiments, the first Fc domain comprises the Y349T mutation and the second Fc domain comprises the T394F mutation. In some embodiments, 141

[0141] the KIH mutations comprise T366W, S354C, T366S, L368A, Y407V, and Y349C, according to the EU numbering scheme. In some embodiments, the first Fc domain comprises the T366W, and S354C mutations and the second Fc domain comprises the T366S, L368A, Y407V, and Y349C mutations, according to the EU numbering scheme. 5 Other amino acids besides cysteine, including natural and / or non-natural amino acids, may be used in the substitution to allow for conjugation of various agents. Such other amino acids include lysine (described in Benhar et al., (1994) Bioconjug. Chem. 55, 321-326), tyrosine (described in Byers & Baldwin, (1988) Immunology.65, 329-335), histidine (described in Waibel et al. (1999) Nature Biotechnol. 17: 897-901), selenocysteine, selenomethionine, and / or non- 10 natural amino acids. Thus, where one or more substitutions are described herein, one of ordinary skill in the art may optionally employ one or more of these natural and / or non-natural amino acids instead of or in addition to cysteine. In certain embodiments, an antibody or antibody fragment targeting ligand described herein may comprise any combination of amino acids in the substitution, such as substituting with cysteine and lysine to produce a variant antibody or antibody fragment 15 with cysteines substituted at some positions and lysines at others. In some embodiments, the first and / or second Fc domain comprises one or more mutated amino acid residues that increase half-life. In some embodiments, the first and / or second Fc domain comprises one of the following mutated amino acid residues: M252Y, S254T, and T256E, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain 20 comprises a combination of the following mutated amino acid residues: M252Y, S254T, and T256E, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises one of the following mutated amino acid residues: M428L and N434S, according to the EU numbering scheme. In some embodiments, the first and / or second Fc domain comprises a combination of the following mutated amino acid residues: M428L and N434S, 25 according to the EU numbering scheme. Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues falls within the scope of this invention. Other modifications include hydroxylation of proline and lysine, phosphorylation of 30 hydroxyl groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, 142

[0142] W. H. Freeman & Co., San Francisco, 1983, pp.79-86), acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group. Another type of covalent modification of the molecules included within the scope of this invention comprises altering the glycosylation pattern of the protein. As is known in the art, 5 glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of particular glycosylation amino acid residues, discussed below), or the host cell or organism in which the protein is produced. Particular expression systems are discussed below. Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tri- 10 peptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tri-peptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most 15 commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. In the context of an antibody, the present invention contemplates antibodies that may have clipping of the C-terminal lysine or cysteine residue of the HC. In the context of an antibody or binding domain of the present invention, the N- terminal glutamine and / or the N-terminal glutamic acid may be converted to pyroglutamic acid. 20 Embodiments of Extracellular Protein Targeting Ligand A1. In certain embodiments, the Extracellular Protein Targeting Ligand is selected from a human antibody, humanized antibody, or chimeric antibody. A2. The Extracellular Protein Targeting Ligand of Embodiment A1, wherein the antibody is an 25 IgG antibody. A3. The Extracellular Protein Targeting Ligand of Embodiment A1 or A2, wherein the Extracellular Protein Targeting Ligand comprises an Fc region. A4. The Extracellular Protein Targeting Ligand of Embodiment A3, wherein the Fc region comprises one or more mutations that impart increased binding affinity for FcRn as 30 compared to a reference Fc region lacking the one or more mutations. 143

[0143] A5. The Extracellular Protein Targeting Ligand of Embodiment A4, wherein the Fc region comprises one or more mutations selected from amino acid substitutions methionine (Met) to tyrosine (Tyr), serine (Ser) to threonine (Tyr), and threonine (Thr) to glutamic acid (Glu). A6. The Extracellular Protein Targeting Ligand of any one of the preceding Embodiments, 5 wherein the Extracellular Protein Targeting Ligand has a binding affinity for the target molecule that is calcium dependent and / or pH dependent. A7. The Extracellular Protein Targeting Ligand of Embodiment A6, wherein the Extracellular Protein Targeting Ligand has higher binding affinity for the cell surface target molecule or extracellular target molecule at neutral pH than at low pH. 10 A8. The Extracellular Protein Targeting Ligand of any one of the preceding Embodiments, wherein the Linker can be attached via a site-specific mutation. A9. The Extracellular Protein Targeting Ligand of Embodiment A8, wherein the site-specific mutation comprises a cysteine (Cys). A10. The Extracellular Protein Targeting Ligand of Embodiment A8 or A9, wherein the 15 site-specific mutation is selected from an alanine (Ala) to cysteine (Cys) substitution, a lysine (Lys) to cysteine (Cys) substitution, a serine (Ser) to cysteine (Cys) substitution, a valine (Val) to cysteine (Cys) substitution, and a leucine (Leu) to cysteine (Cys) substitution. A11. The Extracellular Protein Targeting Ligand of any one of Embodiments A8-A10, 20 wherein the site-specific mutation is a leucine (Leu) to cysteine (Cys) substitution. A12. The Extracellular Protein Targeting Ligand of any one of the preceding Embodiments, wherein the Extracellular Protein Targeting Ligand specifically binds a cell surface target molecule associated with a disease or condition of interest. 25 II. EXTRACELLULAR PROTEIN TARGETING LIGAND Immunoglobulin 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 30 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 144

[0144] 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: 5 A) A) A) or a pha wherein: 10 Immunoglobulin Targeting Ligand is a Ligand that binds to an immunoglobulin, for example IgG, IgA, IgM, or IgE. IgA Nephropathy In certain embodiments, the Extracellular Protein Targeting Ligand is an IgA antibody. In 15 certain embodiments, the IgA Extracellular Protein Targeting Ligand has specific glycosylation patterns in the hinge region. Human IgA is represented by two structurally and functionally distinct subclasses, IgAl and IgA2. Notably, IgAl, but not IgA2, possesses a 19-amino-acid hinge region 145

[0145] (HR) with 9 potential O-glycosylation sites; 3 to 6 core 1 O-glycans are attached per HR. In certain embodiments, the IgA Extracellular Protein Targeting Ligand is IgA1. Primary IgA nephropathy (IgAN), the most common type of primary glomerulonephritis worldwide, is an immune-complex-mediated disease characterized by the presence of glomerular 5 IgA-containing immunodeposits. These deposits may be derived from IgAl -containing circulating immune complexes (CIC), often present at increased levels in patients with IgAN. IgAl -containing CIC in patients with IgAN are characterized by Gal-deficient HR O-linked glycans of IgAl (Gd- IgAl). These Gal-deficient O-glycans with terminal or sialylated GalNAc are recognized by anti- glycan antibodies, resulting in production of nephritogenic immune complexes that may deposit 10 in the glomeruli, activate mesangial cells, and induce tissue injury. Patients with IgA nephropathy (IgAN) have elevated circulating levels of IgAl with some O-glycans consisting of galactose (Gal)-deficient N-acetylgalactosamine (GalNAc) with or without N-acetylneuraminic acid (NeuAc). In certain embodiments, the Extracellular Protein Targeting Ligand is IgA1 with sialyl glycosylation. In certain embodiments, the Extracellular 15 Protein Targeting Ligand is IgA1 with α2,6-sialylated O-glycans (NeuAc attached to GalNAc). IgAN patients have an increased activity of a2,6-sialyltransferase. In certain embodiments, the Extracellular Protein Targeting Ligand is an IgA1 comprising one or more sialylated GalNAc residues. In certain embodiments O-linked glycans in a sequence described in this section are based 20 on a core structure with N- acetylgalactosamine (GalNAc) units in the O-linkage with serine or threonine. Typically these O-linked glycans are in a hinge region of IgAl. Therefore, a full-length IgAl polypeptide comprising the hinge region of IgAl or a fragment of the full length IgAl polypeptides comprising the hinge region can be used as an Extracellular Protein Targeting Ligand. 25 In certain embodiments the Extracellular Protein Targeting Ligand comprises an IgAl polypeptide or fragments thereof wherein the hinge region comprises the amino acid sequence SEQ ID NO: 42 VPSTPPTPSP which is Gal-deficient, for example, a SEQ ID NO: 42 containing one GalNAc moiety. In certain embodiments the Extracellular Protein Targeting Ligand comprises an IgAl polypeptide or 30 fragments thereof wherein the hinge region comprises the amino acid sequence SEQ ID NO: 43 STPPTPSPSTPPTPSP 146

[0146] which is Gal-deficient, for example, a SEQ ID NO: 43 containing one GalNAc moiety. In other embodiments the hinge region of the IgA1 polypeptide for use as an Extracellular Protein Targeting Ligand comprises 2, 3, 4, 5, 6, 7, 8, or 9 GalNAc moieties. In certain embodiments, the Extracellular Protein Targeting Ligand comprises or is the 5 following polypeptide wherein the peptide is Gal-deficient: SEQ ID NO: 44 VPSTPPTPSPSTPPTPSPSCCHPR SEQ ID NO: 45 CHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHR, or SEQ ID NO: 46 HYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHR. In certain embodiments, the Extracellular Protein Targeting Ligand comprises or is one of 10 the following polypeptides: SEQ ID NO: 47 VPS(GalNAc)TPPTPSPSTPPTPSPS; SEQ ID NO: 48 VPST(GalNAc)PPTPSPSTPPTPSPS; SEQ ID NO: 49 VPSTPPT(GalNAc)PSPSTPPTPSPS; SEQ ID NO: 50 VPSTPPTPS(GalNAc)PSTPPTPSPS; 15 SEQ ID NO: 51 VPSTPPTPSPS(GalNAc)TPPTPSPS; SEQ ID NO: 52 VPSTPPTPSPST(GalNAc)PPTPSPS; SEQ ID NO: 53 VPSTPPTPSPSTPPT(GalNAc)PSPS; SEQ ID NO: 54 VPSTPPTPSPSTPPTPS(GalNAc)PS; or SEQ ID NO: 55 VPSTPPTPSPSTPPTPSPS(GalNAc); 20 In certain embodiments, the Extracellular Protein Targeting Ligand comprises or is the following polypeptide wherein the peptide is Gal-deficient: SEQ ID NO: 56 CHVKHYTNPS; SEQ ID NO: 57 VTVPCPVPST; SEQ ID NO: 58 STPPTPSPST; 25 SEQ ID NO: 59 TPPTPSPSCC; or SEQ ID NO: 42 VPSTPPTPSP. In certain embodiments, the Extracellular Protein Targeting Ligand comprises or is one of the following polypeptides: SEQ ID NO: 60 CHVKHYT(GalNAc)NPS; 30SEQ ID NO: 61 CHVKHYTNPS(GalNAc);SEQ ID NO: 62 VT(GalNAc)VPCPVPST; SEQ ID NO: 63 VTVPCPVPS(GalNAc)T; SEQ ID NO: 64 VTVPCPVPST(GalNAc); SEQ ID NO: 65 S(GalNAc)TPPTPSPST; 35 SEQ ID NO: 66 ST(GalNAc)PPTPSPST; 147

[0147] SEQ ID NO: 67 STPPT(GalNAc)PSPST; SEQ ID NO: 68 STPPTPS(GalNAc)PST; SEQ ID NO: 69 STPPTPSPS(GalNAc)T; SEQ ID NO: 70 STPPTPSPST(GalNAc); 5 SEQ ID NO: 71 T(GalNAc)PPTPSPSCC; SEQ ID NO: 72 TPPT(GalNAc)PSPSCC; SEQ ID NO: 73 TPPTPS(GalNAc)PSCC; SEQ ID NO: 74 TPPTPSPS(GalNAc)CC SEQ ID NO: 75 VPS(GalNAc)TPPTPSP 10SEQ ID NO: 76 VPST(GalNAc)PPTPSPSEQ ID NO: 77 VPSTPPT(GalNAc)PSP; or SEQ ID NO: 78 VPSTPPTPS(GalNAc)P. In certain embodiments, the Extracellular Protein Targeting Ligand comprises or is one of 15 the following polypeptides: SEQ ID NO: 79 CHVKHYT(GalNAc)NPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHR SEQ ID NO: 80 CHVKHYTNPS(GalNAc)QDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHR SEQ ID NO: 81 CHVKHYTNPSQDVT(GalNAc)VPCPVPSTPPTPSPSTPPTPSPSCCHPRLSLHR SEQ ID NO: 82 CHVKHYTNPSQDVTVPCPVPS(GalNAc)TPPTPSPSTPPTPSPSCCHPRLSLHR 20 SEQ ID NO: 83 CHVKHYTNPSQDVTVPCPVPST(GalNAc)PPTPSPSTPPTPSPSCCHPRLSLHR SEQ ID NO: 84 CHVKHYTNPSQDVTVPCPVPSTPPT(GalNAc)PSPSTPPTPSPSCCHPRLSLHR SEQ ID NO: 85 CHVKHYTNPSQDVTVPCPVPSTPPTPS(GalNAc)PSTPPTPSPSCCHPRLSLHR SEQ ID NO: 86 CHVKHYTNPSQDVTVPCPVPSTPPTPSPS(GalNAc)TPPTPSPSCCHPRLSLHR SEQ ID NO: 87 CHVKHYTNPSQDVTVPCPVPSTPPTPSPST(GalNAc)PPTPSPSCCHPRLSLHR 25SEQ ID NO: 88 CHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPT(GalNAc)PSPSCCHPRLSLHRSEQ ID NO: 89 CHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPS(GalNAc)PSCCHPRLSLHR SEQ ID NO: 90 CHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPS(GalNAc)CCHPRLSLHR, or SEQ ID NO: 91 CHVKHYTNPSQDVTVPCPVPSTPPTPSPSTPPTPSPSCCHPRLS(GalNAc)LHR. In certain embodiments the Extracellular Protein Targeting Ligand is galactose-deficient 30 IgA1 myeloma protein (Mce) (see Moldonveanu et al., Kidney Int. 71:134-8 (2007)). In other embodiments the Extracellular Protein Targeting Ligand is galactose-deficient IgA1 myeloma protein (Ale) (see Suzuki et al., J. Clin. Investe.118:629-39 (2008)). In certain aspects the Extracellular Protein Targeting Ligand comprises an IgAl polypeptide sequence described herein is a single chain antibody, a high affinity Fv antibody 35 fragment, or a Fab antibody fragment that is specific for the hinge-region O-linked glycans of 148

[0148] IgA1. In other embodiments the Extracellular Protein Targeting Ligand is a polypeptide described herein that has not been functionalized as an antibody. For example, SEQ ID NO: 47 connected to the terminal valine (-VPS(GalNAc)TPPTPSPSTPPTPSPS) or SEQ ID NO: 47 connected to the terminal serine (VPS(GalNAc)TPPTPSPSTPPTPSPS-). In other aspects the Extracellular Protein 5 Targeting Ligand is a different polypeptide described herein that is connected to the terminal valine or the terminal serine. In certain embodiments the Extracellular Protein Targeting Ligand is a protein that is has at least 80%, 85%, 90%, 95%, or 98% sequence identity to a sequence described herein. For example, in certain embodiments the Extracellular Protein Targeting Ligand is an amino acid that has at least 95% sequence identity to SEQ ID NO: 47. 10 In certain embodiments, the Extracellular Protein Targeting Ligand for degrading galactose-deficient IgA is or comprises the hinge region of IgAl. Optionally, the Extracellular Protein Targeting Ligand can, for example, comprise a glycopeptide with a single GalNAc residue. The Extracellular Protein Targeting Ligand is recognized by the IgG specific for galactose- deficient IgAl. 15 In certain embodiments, the Extracellular Protein Targeting Ligand for degrading galactose-deficient IgA is KM55, as described in Yasutake, J. et al. “Novel lectin-independent approach to detect galactose-deficient IgA1 in IgA nephropathy” 2015, Nephrol Dial Transplant 30, 1315-1321. 20 1. A compound of Formula (I), Formula (II), or Formula (III) I) II) 149

[0149] II); otein Targeting Ligand has at least 95% sequence identity to (1) a galactose-deficient IgA1, (2) a galactose- deficient fragment of IgA1, (3) a galactose-deficient polypeptide corresponding to the 5 hinge region of IgA1 or (4) a galactose-deficient fragment of a polypeptide corresponding to the hinge region of IgA1. 2. The compound of embodiment 1, wherein the compound is of Formula: (I); 10 3. The compound of embodiment 1, wherein the compound is of Formula: II); 150

[0150] 4. The compound of embodiment 1, wherein the compound is of Formula: II); 5. The compound of any one of embodiments 1-4, wherein the Extracellular Protein Targeting 5 Ligand has at least 95% sequence identity to a galactose-deficient IgA1. 6. The compound of any one of embodiments 1-4, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient fragment of IgA1. 7. The compound of any one of embodiments 1-4, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient polypeptide 10 corresponding to the hinge region of IgA1. 8. The compound of any one of embodiments 1-4, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient fragment of a polypeptide corresponding to the hinge region of IgA1. 9. The compound of any one of embodiments 1-8, wherein the Extracellular Protein Targeting 15 Ligand is or comprises an amino acid that has at least 95% sequence identity to a polypeptide selected from any one of SEQ ID NO: 42 to SEQ ID NO: 91. 10. The compound of any one of embodiments 1-8, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 96% sequence identity to a polypeptide selected from any one of SEQ ID NO: 42 to SEQ ID NO: 91. 20 11. The compound of any one of embodiments 1-8, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 97% sequence identity to a polypeptide selected from any one of SEQ ID NO: 42 to SEQ ID NO: 91. 151

[0151] 12. The compound of any one of embodiments 1-8, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 98% sequence identity to a polypeptide selected from any one of SEQ ID NO: 42 to SEQ ID NO: 91. 13. The compound of any one of embodiments 1-8, wherein the Extracellular Protein Targeting 5 Ligand is or comprises an amino acid that has at least 99% sequence identity to a polypeptide selected from any one of SEQ ID NO: 42 to SEQ ID NO: 91. 14. The compound of any one of embodiments 1-8, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that is a polypeptide selected from any one of SEQ ID NO: 42 to SEQ ID NO: 91. 10 15. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises one GalNAc. 16. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises two GalNAcs. 17. The compound of any one of embodiments 1-14, wherein the Extracellular Protein 15 Targeting Ligand comprises three GalNAcs. 18. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises four GalNAcs. 19. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises five GalNAcs. 20 20. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises six GalNAcs. 21. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises seven GalNAcs. 22. The compound of any one of embodiments 1-14, wherein the Extracellular Protein 25 Targeting Ligand comprises eight GalNAcs. 23. The compound of any one of embodiments 1-14, wherein the Extracellular Protein Targeting Ligand comprises nine GalNAcs. 24. The compound of any one of embodiments 15-23, wherein the GalNAcs are O-linked through serines. 30 25. The compound of any one of embodiments 15-23, wherein the GalNAcs are O-linked through threonines. 152

[0152] 26. The compound of any one of embodiments 15-23, wherein the GalNAcs are O-linked through serines and threonines. 27. The compound of any one of embodiments 1-26, wherein the Extracellular Protein Targeting Ligand is attached to the Linker through the C-terminus. 5 28. The compound of any one of embodiments 1-26, wherein the Extracellular Protein Targeting Ligand is attached to the Linker through the N-terminus. In certain embodiments, anti-gd-IgAl is an IgG anti-gd-IgAl. In certain embodiments, anti-gd-IgAl is an IgM anti-gd-IgAl. 10 In certain embodiments, anti-gd-IgAl is an IgE anti-gd-IgAl. In certain embodiments, anti-gd-IgAl is an IgD anti-gd-IgAl. In certain embodiments, IgA deposits occur by accumulation of IgAl immune complexes (e.g., gd-IgAl immune complexes and / or IgAl immune complexes having a normal O- glycosylation). In certain embodiments, IgA deposits occur by accumulation of gd-IgAl immune 15 complexes. In certain embodiments, IgA deposits occur by accumulation of IgAl immune complexes. In certain embodiments, IgA deposits occur by accumulation of anti-gd-IgAl immune complexes, e.g., along with the gd-IgAl antigen (Selvskandan, H. et al. Frontiers in Immunology, 2020). In certain embodiments, an immune complex comprising IgAl, gd-IgAl, and / or anti-gd- IgAl comprises an antigen recognized by the antibody, one or more components of a complement 20 system, one or more additional immunoglobulins, or combinations thereof. In certain embodiments, disease associated with increased and / or aberrant IgA is IgA nephropathy (IgAN). In certain embodiments, the disclosure provides a method for treating IgAN by delivering to a patient in need of such treatment a compound of the present invention or a composition comprising the same, e.g., as disclosed herein. For example, the compound that bind 25 to IgAl, gd-IgAl, and / or anti-gd-IgA1, or composition comprising the same can be used. In certain embodiments, the Extracellular Protein Targeting Ligand comprises 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 30 epitope comprises one or more additional amino acid residues, e.g., on the 5' end and / or the 3' end of the epitope. 153

[0153] 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 5 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- 10 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 15 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 20 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 Ligand disclosed herein comprises one or more peptides that specifically bind to one or more idiotopes of an anti-gd-IgAl 25 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 30 Serine mutation occurs in a YCAR amino acid sequence or a YCAK amino acid sequence of a 154

[0154] 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 Ligand disclosed herein comprises one or more peptides that specifically bind to a CDR3 IgH region of an anti-gd-IgAl 5 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 Ligand disclosed 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 10 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. Immunoglobulin G (IgG) 15 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 20 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 25 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, 30 and membranous nephropathy, multiple sclerosis, hyperthyroid Grave’s disease, epidermolysis 155

[0155] bullosa acquisita, pemphigoid gestationis, anti-p200 pemphigoid, and paraneoplastic pemphigus, among others. In certain embodiments, the Extracellular Protein Targeting Ligand that binds to an anti- gd-IgAl autoantibody binds to an IgG protein, or a fragment or a variant thereof. In certain 5 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. In certain aspects an IgG degrading compound of Formula I-B, Formula II-B, or Formula III-B is provided: 10 B) B) -B) B) 156

[0156] B) -B) or a ph wherein: 5 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, 10 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 certain embodiments, a compound of the present invention which degrades IgG is used to treat a disorder selected from dilated cardiomyopathy, glaucoma, Postural orthostatic 15 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 157

[0157] 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 5 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 10 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 15 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 20 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. 25 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. Targeting specific immunoglobulins is accomplished by the present invention through the use of specific Immunoglobulin Targeting Ligand. The target immunoglobulins of the current 30 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 158

[0158] treated with an effective amount of the disclosed ASGPR-binding Immunoglobulin Degraders described herein. 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 5 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 Immunoglobulin Targeting Ligand comprises an antibody that 10 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 Ligand binds to an immunoglobulin. In certain embodiments, Extracellular Protein Targeting Ligand binds to an autoantibody. 15 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 Ligand is an affinity substance described in AU 2018259856 or WO 2018199337, the affinity substance of each of which is incorporated herein by reference. 20 In certain embodiments, Extracellular Protein Targeting Ligand is an scFv that specifically binds immunoglobulin. An scFv Extracellular Protein Targeting Ligand of the present invention may be a single-chain polypeptide that comprises a first scFv-linker-second scFv. An scFv, or single-chain variable fragment, is made of the variable domains of an antibody heavy chain and light chain that may be linked together by a short peptide linker. For example, (G4S)3linker may 25 be used, at any number of repeats, such as one to four. The orientation from the N-terminus to the C-terminus of each scFv may be VL-linker-VH or VH-linker-VL. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety that exhibits decreased affinity for IgG at lower pH. For example, after uptake via ASGPR, the endosome begins to acidify. Decreased IgG 30 binding in an acidic environment may facilitate recycling of the IgG degrading compound to the cell surface and into the plasma. 159

[0159] In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising any one of SEQ ID NO: 92 to SEQ ID NO: 97. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a sequence with at least 85% 5 homology with any one of SEQ ID NO: 92 to SEQ ID NO: 97. In certain embodiments, the IgG- binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising any one of SEQ ID NO: 92 to SEQ ID NO: 97 in a cyclic (i.e. stapled) or glycosylated form. SEQ ID NO: 92 DTYIH HCDR1 SEQ ID NO: 93 2 3 1 2 3 10 In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR1 sequence of SEQ ID NO: 92. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR2 sequence of SEQ ID NO: 93. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an 15 antibody, antibody fragment, or IgG-binding moiety comprising a HCDR3 sequence of SEQ ID NO: 94. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR1 sequence of SEQ ID NO: 95. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR2 sequence of SEQ ID 20 NO: 96. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR3 sequence of SEQ ID NO: 97. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR1 sequence with at least25 about 85%, 90, or 95% sequence homology to SEQ ID NO: 92. In certain embodiments, the IgG- binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding 160

[0160] moiety comprising a HCDR2 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 93. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR3 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 94. In certain 5 embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR1 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 95. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR2 sequence with at least about 85%, 90, or 95% sequence homology to SEQ 10 ID NO: 96. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR3 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 97. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a variable light domain region 15 comprising the HCDR1 sequence SEQ ID NO: 92, the HCDR2 sequence SEQ ID NO: 93, and the HCDR3 sequence SEQ ID NO: 94. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety that is at least about 85%, 90%, or 95% homologous to a variable light domain region comprising the HCDR1 sequence SEQ ID NO: 92, the HCDR2 sequence SEQ ID NO: 93, and the HCDR3 sequence SEQ ID NO: 20 94. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a variable light domain region comprising the LCDR1 sequence SEQ ID NO: 95, the LCDR2 sequence SEQ ID NO: 96, and the LCDR3 sequence SEQ ID NO: 97. In certain embodiments, the IgG-binding Extracellular Protein 25 Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety that is at least about 85%, 90%, or 95% homologous to a variable heavy domain region comprising the LCDR1 sequence SEQ ID NO: 95, the LCDR2 sequence SEQ ID NO: 96, and the LCDR3 sequence SEQ ID NO: 97. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an 30 antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 98, (ii) a variable light domain region 161

[0161] comprising the amino acid sequence of SEQ ID NO: 99, or (iii) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 98 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 99. ELQLQQSGAE LVRPGASVKL SCTTSGFNVK DTYIHWVRQR PEQGLEWIGR IDPANGNTKY DPKFQDRATI TTDTSSITAY LQLSSLTSED TAVYYCARNY SEQ ID NO: 98 GSNYDPMDYW GQGTSLTVSS Y G 5 , g g g g g an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 98, (ii) a variable light domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 99, or (iii) a variable heavy 10 domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 98 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 99. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising (i) the amino acid sequence of 15 SEQ ID NO: 100, (ii) the amino acid sequence of SEQ ID NO: 101, or (iii) the amino acid sequence of SEQ ID NO: 100 and the amino acid sequence of SEQ ID NO: 101, optionally linked with a peptide linker. In certain embodiments, the peptide linker is selected from SEQ ID NO: 1 to SEQ ID NO: 32. ELQLQQSGAE LVRPGASVKL SCTTSGFNVK DTYIHWVRQR PEQGLEWIGR IDPANGNTKY DPKFQDRATI TTDTSSITAY LQLSSLTSED TAVYYCARNY K V TI V P S Y G KI T 162

[0162] In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising (i) an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 100, (ii) an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 101, or 5 (iii) an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 100 and an amino acid sequence of SEQ ID NO: 101, optionally linked with a peptide linker. In certain embodiments, the peptide linker is selected from SEQ ID NO: 1 to SEQ ID NO: 32. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an 10 antibody, antibody fragment, or IgG-binding moiety comprising the amino acid sequence of SEQ ID NO: 102, SEQ ID NO: 103, or a fragment thereof. EQLEESGGDL VKPGASLTLT CTASGFSFTS DYYMCWVRQA PGKGLEWIAC IGAGDIHTTY YANWAKGRFT ISKTSSTTVT T V G L K L S T N G P N IS DI W P C FI G T In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising the amino acid sequence of SEQ ID NO: 15 104, SEQ ID NO: 103, or a fragment thereof. EQLEESGGDL VKPGASLTLT CTASGFSFTS DYYMCWVRQA PGKGLEWIAC DT C G FP 163

[0163] PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT S G A IS P T Y A Q T ce a e o e s, e g - g ace u a oe a ge g ga s a a ody, antibody fragment, or IgG-binding moiety comprising the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 103, or a fragment thereof. EQLEESGGDL VKPGASLTLT CTASGFSFTS DYYHCWVRQA PGKGLEWIAC IGAGDIHTTY YANWAKGRFT ISKTSSTTVT LQMTTLTAAD TATYFCARDT C G P E R T S G A IS P T Y A Q T 5 In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising one, two, three, four, five, or six of SEQ ID NO: 106 to SEQ ID NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a 10 sequence with at least 85% homology with one, two, three, four, five, or six of SEQ ID NO: 106 to SEQ ID NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting 164

[0164] Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising one, two, three, four, five, or six of SEQ ID NO: 106 to SEQ ID NO: 111 in a cyclic (i.e. stapled) or glycosylated form. SEQ ID NO: 106 SDYYMC SEQ ID NO: 107 CIGAGDIHTT YYANWAKG llular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR1 sequence of SEQ ID 5 NO: 106. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR2 sequence of SEQ ID NO: 107. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR3 sequence of SEQ ID NO: 108. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an 10 antibody, antibody fragment, or IgG-binding moiety comprising a LCDR1 sequence of SEQ ID NO: 109. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR2 sequence of SEQ ID NO: 110. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR3 sequence of SEQ ID 15 NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR1 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 106. In certain embodiments, the IgG- binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding 20 moiety comprising a HCDR2 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 107. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR3 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 108. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody 25 fragment, or IgG-binding moiety comprising a LCDR1 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 109. In certain embodiments, the IgG-binding 165

[0165] Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR2 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 110. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a LCDR3 sequence with at 5 least about 85%, 90, or 95% sequence homology to SEQ ID NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 112, (ii) a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113, or (iii) a variable heavy domain region 10 comprising the amino acid sequence of SEQ ID NO: 112 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113. EQLEESGGDL VKPGASLTLT CTASGFSFTS DYYMCWVRQA PGKGLEWIAC IGAGDIHTTY YANWAKGRFT ISKTSSTTVT LQMTTLTAAD TATYFCARDT SEQ ID NO: 112 Y A s an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence 15 of SEQ ID NO: 112, (ii) a variable light domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 113, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 112 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113. 20 In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising one, two, three, four, five, or six of SEQ ID NO: 106, SEQ ID NO: 114, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a sequence with at 25 least 85% homology with one, two, three, four, five, or six of SEQ ID NO: 106, SEQ ID NO: 114, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody 166

[0166] fragment, or IgG-binding moiety comprising one, two, three, four, five, or six of SEQ ID NO: 106, SEQ ID NO: 114, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111 in a cyclic (i.e. stapled) or glycosylated form. SEQ ID NO: 106 SDYYMC SEQ ID NO: 114 CHGAGDIHTT YYANWAKG ellular Protein Targeting Ligand is an 5 antibody, antibody fragment, or IgG-binding moiety comprising a HCDR2 sequence of SEQ ID NO: 114. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR2 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 114. 10 In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 115, (ii) a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113, or (iii) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 115 and a variable light domain region 15 comprising the amino acid sequence of SEQ ID NO: 113. EQLEESGGDL VKPGASLTLT CTASGFSFTS DYYMCWVRQA PGKGLEWIAC HGAGDIHTTY YANWAKGRFT ISKTSSTTVT LQMTTLTAAD TATYFCARDT Y A is an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 115, (ii) a variable light domain region comprising an amino acid sequence with 20 at least about 80% homology to the amino acid sequence of SEQ ID NO: 113, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the 167

[0167] amino acid sequence of SEQ ID NO: 115 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising one, two, three, four, five, or six 5 of SEQ ID NO: 116, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a sequence with at least 85% homology with one, two, three, four, five, or six of SEQ ID NO: 116, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111. In certain 10 embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising one, two, three, four, five, or six of SEQ ID NO: 116, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, and SEQ ID NO: 111 in a cyclic (i.e. stapled) or glycosylated form. SEQ ID NO: 116 SDYYHC SEQ ID NO: 107 racellular Protein Targeting Ligand is an 15 antibody, antibody fragment, or IgG-binding moiety comprising a HCDR1 sequence of SEQ ID NO: 116. In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising a HCDR1 sequence with at least about 85%, 90, or 95% sequence homology to SEQ ID NO: 116. 20 In certain embodiments, the IgG-binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 117, (ii) a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113, or (iii) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 117 and a variable light domain region 25 comprising the amino acid sequence of SEQ ID NO: 113. 168

[0168] EQLEESGGDL VKPGASLTLT CTASGFSFTS DYYHCWVRQA PGKGLEWIAC IGAGDIHTTY YANWAKGRFT ISKTSSTTVT LQMTTLTAAD TATYFCARDT SEQ ID NO: 117 YNIGGYTGDF DLWGPGTLVT VSS Y A an antibody, antibody fragment, or IgG-binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 117, (ii) a variable light domain region comprising an amino acid sequence with 5 at least about 80% homology to the amino acid sequence of SEQ ID NO: 113, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80% homology to the amino acid sequence of SEQ ID NO: 117 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 113. 10 Immunoglobulin G4 IgG4 Binding Fragment described herein is a humanized binding fragment or nanobody that binds IgG4. Non-limiting illustrative examples of humanized IgG4 Binding Fragments include but are not limited to a humanized binding fragment or nanobody comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID 15 NO: 120, SEQ ID NO: 121, and SEQ ID NO: 122, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In certain embodiments the IgG4 Binding Fragment is selected from an amino acid sequence selected from the group consisting of SEQ ID NO: 118 to SEQ ID NO: 122 or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at 20 least 98%, or at least 99% identical thereto. QVQLVESGGGLVQPGGSLRLSCSASGSIFSISAMGWYRQAPGKERELVAVITTDGSTN SEQ ID NO: 118 YADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCGASPRALKWYWGQGTLVT N N N T 169

[0169] EVQLLESGGGLVQPGGSLRLSCAASGSIFSISAMGWYRQAPGKERELVAVITTDGSTN SEQ ID NO: 122 YADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCGASPRALKWYWGQGTLVT VSSW In certain embodiments, Extracellular Protein Targeting Ligand binds to IgG4. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is a Fab, F(ab')2, Fv, Fd, 5 or a single chain Fv fragment (scFv). In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises a heavy chain variable region that binds IgG4. In certain embodiments, the IgG4- binding Extracellular Protein Targeting Ligand comprises a light chain variable region that binds IgG4. 10 In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is a heavy chain variable region. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is a light chain variable region. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises a humanized binding fragment or nanobody naturally devoid of light chains. In certain 15 embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is a single domain antibody. Binding fragments or single domain antibodies naturally devoid of light chains may be obtained, for example, by immunizing camelids (e.g., camels, dromedaries, llamas, alpacas) (Hamers-Casterman et al. Nature.363:446-8(1993); US 6,765,087 B1) or sharks (Greenberg et al. Nature.374:168-73(1995); US 8,865,431 B2). Alternatively, binding fragments or single domain 20 antibodies naturally devoid of light chains may be obtained through a variety of screening, phage display, and / or engineering approaches (Pardon et al. Nat Protoc. 9(3):674-93(2014)). In some embodiment, the single domain antibody comprises a variable domain (VHH) polypeptide. VHH polypeptides are commonly referred to as nanobodies®by those skilled in the art [Note: NANOBODY®, NANOBODIES®, and NANOCLONE®are protected by trademarks or subject to 25 applications registered to Ablynx N.V., an affiliate of Sanofi]. VHH polypeptides are small (~15 kDa) relative to other conventional antibodies (e.g., ~150 kDa monoclonal IgG antibody). VHH polypeptides have excellent thermal and / or chemical stability and solubility profiles. Furthermore, VHH polypeptides are easily expressed in bacterial expression systems (e.g., Saccharomyces 170

[0170] cerevisiae), wherein a coding sequence may be inserted to express a single VHH polypeptide sequence. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand specifically and selectively binds to a human IgG4. In certain embodiments, the IgG4-binding 5 Extracellular Protein Targeting Ligand comprises four framework region (FR) amino acid sequences, referred to by skilled artisans as framework region 1 or “FR1”, framework region 2 or “FR2”, framework region 3 or “FR3”, and framework region 4 or “FR4”, interspersed with three complementary determining region (CDR) amino acid sequences, referred by skilled artisans as complementary determining region 1 or “CDR1”, complementary determining region 2 or 10 “CDR2”, and complementary determining region 3 or “CDR3”. The framework regions and complementary determining regions are operably linked, in an N-terminal to C-terminal orientation, in the order of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. In some embodiments, the framework regions and complementary determining regions are selected from amino acid sequences disclosed by U.S. Patent No. US 9,850,315 B2, U.S. Patent Application No. US 15 2019 / 0177434 A1, PCT Application No. WO2019009346A1, Chinese Patent No. CN112646040B, Vincke et al. JBC.284(5):3273-84(2009), Corper et al. Nat Struct Biol.4(5):374- 81(1997). In some embodiments, the FR1 is selected from an amino acid sequence of SEQ ID NO: 123 to SEQ ID NO: 160, as defined by Table 1, or an amino acid sequence at least 80%, at least 20 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In certain embodiments, the FR1 has 1, 2, 3, 4, 5, or 6 amino acid changes as defined in Table 13. In some embodiments, the FR2 is selected from an amino acid sequence of SEQ ID NO: 161 to SEQ ID NO: 192, as defined by Table 2, or an amino acid sequence at least 80%, at least 25 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In certain embodiments, the FR2 has 1, 2, or 3 amino acid changes as defined in Table 14. In some embodiments, the FR3 is selected from an amino acid sequence of SEQ ID NO: 193 to SEQ ID NO: 253, as defined by Table 3, or an amino acid sequence at least 80%, at least 30 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical 171

[0171] thereto. In certain embodiments, the FR3 has 1, 2, 3, 4, 5, 6, or 7 amino acid changes as defined in Table 15. In some embodiments, the FR4 is selected from an amino acid sequence of SEQ ID NO: 254 to SEQ ID NO: 268, as defined by Table 4, or an amino acid sequence at least 80%, at least 5 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In certain embodiments, the FR4 has 1, 2, or 3 amino acid changes as defined in Table 16. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid changes as defined in Tables 11-16. In certain 10 embodiments, the IgG4-binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid changes as defined in Table 11. In certain embodiments, the IgG4- binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid changes as defined in Table 12. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid 15 changes as defined in Table 13. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid changes as defined in Table 14. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 amino acid changes as defined in Table 15. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand has 1, 2, 3, 4, 5, 6, 7, 8, 9, 20 10, or more than 10 amino acid changes as defined in Table 16. In some embodiments, the CDR1 is selected from an amino acid sequence of SEQ ID NO: 269 to SEQ ID NO: 326, as defined by Table 5, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. 25 In some embodiments, the CDR2 is selected from an amino acid sequence of SEQ ID NO: 327 to SEQ ID NO: 402, as defined by Table 6, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In some embodiments, the CDR3 is selected from an amino acid sequence of SEQ ID NO: 30 403 to SEQ ID NO: 463, as defined by Table 7, or an amino acid sequence at least 80%, at least 172

[0172] 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In certain embodiments, any of the FR1, FR2, FR3, FR4, CDR1, CDR2, or CDR3 regions have one or more amino acid changes as defined in Tables 9-14. In some embodiments, the IgG4- 5 binding Extracellular Protein Targeting Ligand is an amino acid sequence of SEQ ID NO: 118 to SEQ ID NO: 122 or SEQ ID NO: 674 to SEQ ID NO: 725, as defined by Table 10, or an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical thereto. In certain embodiments, any of the FR1, FR2, FR3, FR4, CDR1, CDR2, or CDR3 regions have one or more amino acid substitutions as defined in 10 Tables 9-14. Table 1. FR1 sequences Sequence SEQ ID NO: 123 QVQLQESGGGLVQAGGSLRLSCAVSG 173

[0173] SEQ ID NO: 145 QVQLQDSGGGLVQAGGSLRLSCEAS SEQ ID NO: 146 QVQLVESGGGLVQPGGSLRLSCSAS X Table 2. FR2 sequences Sequence E ID 11 FR TP EREF A 174

[0174] SEQ ID NO: 178 WYREAPGKQRELVA SEQ ID NO: 179 WFRQAPGKQREWVA Table 3. FR3 sequences Sequence SE ID NO 193 GRFTISRDSGKNTVYL MNNLKPEDTAVYYCAG 175

[0175] SEQ ID NO: 211 RFTVSRDNAKNTVYLQMNSLKPEDTASYYCAA SEQ ID NO: 212 RFTISRDNAKNTVYLQMNSLQPEDTAVYFCAA 176

[0176] SEQ ID NO: 247 RFTISRDSSKNTVYLQMNSLRAEDTAVYLCAG SEQ ID NO: 248 RFTISRDSAKNTVYLQMNSLRAEDTAVYLCAG . q Sequence SEQ ID NO: 254 WGQGTQVTVSS Table 5. CDR1 sequences Sequence 177

[0177] SEQ ID NO: 276 KASQDINSYLI SEQ ID NO: 277 NTLSRYAMG 178

[0178] SEQ ID NO: 312 GRTFRSGLMG SEQ ID NO: 313 GRTSWIYGMA Table 6. CDR2 sequences Sequence SE ID NO 327 TISSGSSYTYYLDSVK 179

[0179] SEQ ID NO: 345 PIRWNNGNTYYADSVE SEQ ID NO: 346 AIRWNNAATYYADSVE 180

[0180] SEQ ID NO: 381 AKPWSANAEYADSVKG SEQ ID NO: 382 AISWSGGTTYYTGSVKG Table 7. CDR3 sequences Sequence 181

[0181] SEQ ID NO: 414 DKVLYSRGGYYSVANDL SEQ ID NO: 415 DRVLYYTDRYDTANDV 182

[0182] SEQ ID NO: 450 RRDYVLYNHEYDS SEQ ID NO: 451 SRAPPHRCYGMDH In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein CDR1 is selected from an amino acid sequence of SEQ ID NO: 269 to SEQ ID NO: 326, 5 or an amino acid sequence at least 95% identical thereto, wherein CDR2 is selected from an amino acid sequence of SEQ ID NO: 327 to SEQ ID NO: 402, or an amino acid sequence at least 95% identical thereto, and wherein CDR3 is selected from an amino acid sequence SEQ ID NO: 403 to SEQ ID NO: 463, or an amino acid sequence at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises, in an N- 10 terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein CDR1 is selected from an amino acid sequence of SEQ ID NO: 269 to SEQ ID NO: 326, or an amino acid sequence with 1, 2, or 3 substitutions thereto, wherein CDR2 is selected from an amino acid sequence of SEQ ID NO: 327 to SEQ ID NO: 402, or an amino acid sequence with 1, 2, or 3 substitutions thereto, and wherein CDR3 is selected from an amino acid sequence of SEQ ID NO: 15 403 to SEQ ID NO: 463, or an amino acid sequence with 1, 2, or 3 substitutions thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 324, or an amino acid sequence at least 95% identical thereto, wherein CDR2 comprises the amino acid sequence of SEQ ID NO: 183

[0183] 400, or an amino acid sequence at least 95% identical thereto, and wherein CDR3 comprises the amino acid sequence of SEQ ID NO: 461, or an amino acid sequence at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, 5 wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 324, or an amino acid sequence with 1, 2, or 3 substitutions thereto, wherein CDR2 comprises the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with 1, 2, or 3 substitutions thereto, and wherein CDR3 comprises the amino acid sequence of SEQ ID NO: 461, or an amino acid sequence with 1, 2, or 3 substitutions thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting10 Ligand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3- CDR3-FR4, wherein CDR1 comprises the amino acid sequence of SEQ ID NO: 324, wherein CDR2 comprises the acid sequence of SEQ ID NO: 400, and wherein CDR3 comprises the amino acid sequence of SEQ ID NO: 461. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is an amino acid sequence of SEQ ID NO: 118 to SEQ ID NO: 122 or 15 SEQ ID NO: 674 to SEQ ID NO: 725, , or an amino acid sequence at least 95% identical thereto, as listed in Table 10. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein FR1 is selected from an amino acid sequence of SEQ ID NO: 123 to SEQ ID NO: 160, 20 wherein FR2 is selected from an amino acid sequence of SEQ ID NO: 161 to SEQ ID NO: 192, wherein FR3 is selected from an amino acid sequence of SEQ ID NO: 193 to SEQ ID NO: 253, wherein FR4 is selected from an amino acid sequence of SEQ ID NO: 254 to SEQ ID NO: 268, wherein CDR1 is selected from an amino acid sequence of SEQ ID NO: 269 to SEQ ID NO: 326, wherein CDR2 is selected from an amino acid sequence of SEQ ID NO: 327 to SEQ ID NO: 402, 25 and wherein CDR3 is selected from an amino acid sequence of SEQ ID NO: 403 to SEQ ID NO: 463. The total number of amino acid residues of the IgG4-binding Extracellular Protein Targeting Ligand can be between the range of 100-150, for example between the range of 110- 140, and / or between the range of 113-137. Amino acid residues of the IgG4-binding Extracellular 30 Protein Targeting Ligand may be numbered according to the numbering standards described in Kabat et al. (Kabat et al. Sequences of proteins of immunological interest. US Department of 184

[0184] Health and Human Services, Public Health Service, National Institutes of Health.91(1991)). The Kabat numbering dictates FR1 comprises amino residues 1-25, CDR1 comprises amino acid residues 26-35, FR2 comprises amino acid residues 36-49, CDR2 comprises amino acid residues 50-65, FR3 comprises amino acid residues 66-94, CDR3 comprises amino acid residues 95-102, 5 and FR4 comprises amino acid residues 103-113. The total number of amino acid residues of a IgG4-binding Extracellular Protein Targeting Ligand may vary and is not limited. The total number of any region, for example, FR1, FR2, FR3, FR4, CDR1, CDR2, and CDR3 regions of the IgG4-binding Extracellular Protein Targeting Ligand may also vary and is not limited and may not correspond to the Kabat numbering. A person skilled in the art, however, is able to align 10 framework and complementary determining regions to polypeptide sequences of interest in accordance with Kabat numbering to number the amino acid residues of any IgG4-binding Extracellular Protein Targeting Ligand. The amino acid residues that are present at each Kabat numbering position of FR1, FR2, FR3, and FR4 are indicated in Tables 13-16. The amino acid sequences that are present at each Kabat numbering position of FR1, FR2, FR3, and FR4 are 15 selected from an amino acid sequence of SEQ ID NO: 123 to SEQ ID NO: 268. The amino acid sequences that are present at each Kabat numbering position of CDR1, CDR2, and CDR3 are selected from an amino acid sequence of SEQ ID NO: 269 to SEQ ID NO: 463. For example, the IgG4-binding Extracellular Protein Targeting Ligand may comprise, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4; wherein FR1 20 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 146, SEQ ID NO: 147, and SEQ ID NO: 148; wherein FR2 comprises an amino acid sequence of SEQ ID NO: 184; wherein FR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 239 and SEQ ID NO: 240; wherein FR4 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 265 and SEQ ID NO: 266; wherein CDR1 comprises 25 an amino acid sequence of SEQ ID NO: 324; wherein CDR2 comprises an amino acid sequence of SEQ ID NO: 400; and, wherein CDR3 comprises an amino acid sequence of SEQ ID NO: 461. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4; wherein FR1 comprises: 30SEQ ID NO: 149 XVQLXXXXGXXXXXGXSXXXXCXXX;wherein position 1 of FR1 (Kabat Position 1) is selected from the group consisting of E and Q; 185

[0185] wherein position 5 of FR1 (Kabat Position 5) is selected from the group consisting of L, Q, and V; wherein position 6 of FR1 (Kabat Position 6) is selected from the group consisting of D and E; wherein position 7 of FR1 (Kabat Position 7) is selected from the group consisting of S and T; wherein position 8 of FR1 (Kabat Position 8) is selected from the group consisting of G and R; 5 wherein position 10 of FR1 (Kabat Position 10) is selected from the group consisting of G and V; wherein position 11 of FR1 (Kabat Position 11) is selected from the group consisting of F, L, M, N, P, S, T, V, W, and Y; wherein position 12 of FR1 (Kabat Position 12) is selected from the group consisting of I and V; wherein position 13 of FR1 (Kabat Position 13) is selected from the group consisting of K, Q, and 10 R; wherein position 14 of FR1 (Kabat Position 14) is selected from the group consisting of A, P, and T; wherein position 16 of FR1 (Kabat Position 16) is selected from the group consisting of D, E, G, and R; 15 wherein position 18 of FR1 (Kabat Position 18) is selected from the group consisting of L and V; wherein position 19 of FR1 (Kabat Position 19) is selected from the group consisting of K and R; wherein position 20 of FR1 (Kabat Position 20) is selected from the group consisting of I and L; wherein position 21 of FR1 (Kabat Position 21) is selected from the group consisting of A and S; wherein position 23 of FR1 (Kabat Position 23) is selected from the group consisting of A, E, R, 20 S, T, and V; wherein position 24 of FR1 (Kabat Position 24) is selected from the group consisting of A, D, and V; wherein position 25 of FR1 (Kabat Position 25) is selected from the group consisting of L and S; wherein FR2 comprises: 25 SEQ ID NO: 185 WXRXXXGXXXXXVX wherein position 2 of FR2 (Kabat Position 37) is selected from the group consisting of A, F, H, I, L, P, S, V, and Y; wherein position 4 of FR2 (Kabat Position 39) is selected from the group consisting of E, Q, and R; 30 wherein position 5 of FR2 (Kabat Position 40) is selected from the group consisting of A, G, L, P, T, and V; 186

[0186] wherein position 6 of FR2 (Kabat Position 41) is selected from the group consisting of L, P, S, and T; wherein position 8 of FR2 (Kabat Position 43) is selected from the group consisting of A, K N, Q, and T; 5 wherein position 9 of FR2 (Kabat Position 44) is selected from the group consisting of A, D, E, F, G, K, L, M, N, P, Q, R, S, V, W, and Y; wherein position 10 of FR2 (Kabat Position 45) is selected from the group consisting of C, D, E, G, H, I, K, L, P, Q, R, S, V, W, and Y; wherein position 11 of FR2 (Kabat Position 46) is selected from the group consisting of E, Q, T, 10 and V; wherein position 12 of FR2 (Kabat Position 47) is selected from the group consisting of A, D, E, F, G, H, I, K, L, M, Q, R, S, T, V, W, and Y; wherein position 14 of FR2 (Kabat Position 49) is selected from the group consisting of A, G, and S; 15 wherein FR3 comprises: SEQ ID NO: 241 RXXXXXXXXXXXXXLXXXXXXXXDXXXYXCXX; wherein position 2 of FR3 (Kabat Position 67) is selected from the group consisting of F and V; wherein position 3 of FR3 (Kabat Position 68) is selected from the group consisting of I and T; wherein position 4 of FR3 (Kabat Position 69) is selected from the group consisting of I and V; 20 wherein position 5 of FR3 (Kabat Position 70) is selected from the group consisting of F, S, and Y; wherein position 6 of FR3 (Kabat Position 71) is selected from the group consisting of G, K, M, N, and R; wherein position 7 of FR3 (Kabat Position 72) is selected from the group consisting of D and E; 25 wherein position 8 of FR3 (Kabat Position 73) is selected from the group consisting of D, G, K, N, S, and Y; wherein position 9 of FR3 (Kabat Position 74) is selected from the group consisting of A, G, P, S, T, and V; wherein position 10 of FR3 (Kabat Position 75) is selected from the group consisting of E, G, H, 30 K, N, and Q; 187

[0187] wherein position 11 of FR3 (Kabat Position 76) is selected from the group consisting of D, K, N, S, T, and Y; wherein position 12 of FR3 (Kabat Position 77) is selected from the group consisting of A, I, L, M, S, and T; 5 wherein position 13 of FR3 (Kabat Position 78) is selected from the group consisting of A, E, G, I, L, M, T, and V; wherein position 14 of FR3 (Kabat Position 79) is selected from the group consisting of D, F, H, N, S, and Y; wherein position 16 of FR3 (Kabat Position 81) is selected from the group consisting of E, L, Q, 10 and V; wherein position 17 of FR3 (Kabat Position 82) is selected from the group consisting of I, L, M, and V; wherein position 18 of FR3 (Kabat Position 82a) is selected from the group consisting of D, G, H, N, S, and T; 15 wherein position 19 of FR3 (Kabat Position 82b) is selected from the group consisting of N and S; wherein position 20 of FR3 (Kabat Position 82c) is selected from the group consisting of I and L; wherein position 21 of FR3 (Kabat Position 83) is selected from the group consisting of A, D, E, G, I, K, L, M, N, Q, R, S, and T; wherein position 22 of FR3 (Kabat Position 84) is selected from the group consisting of A, D, F, 20 G, H, L, N, P, R, S, T, V, and Y; wherein position 23 of FR3 (Kabat Position 85) is selected from the group consisting of D, E, and G; wherein position 25 of FR3 (Kabat Position 87) is selected from the group consisting of M and T; wherein position 26 of FR3 (Kabat Position 88) is selected from the group consisting of A, D, and 25 G; wherein position 27 of FR3 (Kabat Position 89) is selected from the group consisting of I, L, M, R, S, and V; wherein position 29 of FR3 (Kabat Position 91) is selected from the group consisting of F, H, L, S, and Y; 30 wherein position 31 of FR3 (Kabat Position 93) is selected from the group consisting of A, F, G, H, K, N, S, T, V, and Y; 188

[0188] wherein position 32 of FR3 (Kabat Position 94) is selected from the group consisting of A, G, I, K, R, and T; wherein FR4 comprises: SEQ ID NO: 267 XXXGXXXXVSS; 5 wherein position 1 of FR4 (Kabat Position 103) is selected from the group consisting of F, G, K, L, N, P, Q, R, S, V, W, and Y; wherein position 2 of FR4 (Kabat Position 104) is selected from the group consisting of A, D, G, R, S, and T; wherein position 3 of FR4 (Kabat Position 105) is selected from the group consisting of K, P, Q, 10 and R; wherein position 5 of FR4 (Kabat Position 107) is selected from the group consisting of S and T; wherein position 6 of FR4 (Kabat Position 108) is selected from the group consisting of E, H, L, N, P, Q, R, and T; wherein position 7 of FR4 (Kabat Position 109) is selected from the group consisting of I and V; 15 and, wherein position 8 of FR4 (Kabat Position 110) is selected from the group consisting of A, N, and T. In general, one or more of the amino acids fulfilling the above criteria is substituted. In some embodiments, all or most of the amino acids fulfilling the above criteria are substituted. 20 In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand of the invention binds to humanized IgG4 with a desired binding affinity. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand of the invention selectively binds to human IgG4 over other human immunoglobulin (Ig) subtypes including but not limited to IgA, IgD, IgE, IgG, and IgM, as well as IgG subclasses including IgG1, IgG2, and IgG3. In certain embodiments, 25 the IgG4-binding Extracellular Protein Targeting Ligand that can selectively bind to, has affinity for, and / or has specificity to IgG4, may be raised “against” or directed “against” the target molecule. Sequence optimization and production of humanized IgG4 Binding Fragment In another aspect, a nucleic acid construct comprising a nucleic acid sequence encodes for 30 the IgG4-binding Extracellular Protein Targeting Ligand as defined herein above. In certain embodiments, a nucleic acid construct encoding the IgG4-binding Extracellular Protein Targeting 189

[0189] Ligand is operably linked to a promoter and optionally regulatory sequences selected from enhancers, polyadenylation signals, terminators, signal sequences, or a combination thereof. Use of recombinant techniques to introduce nucleic acid constructs into host cells are particularly useful for the purposes of small- to large-scale expression of a protein, for example, the IgG4- 5 binding Extracellular Protein Targeting Ligand. In certain embodiments, the host cell is a host cell for production of one or more IgG4-binding Extracellular Protein Targeting Ligand s of the invention. The host cell may be any host cell suitable for expressing small to large amounts of the IgG4-binding Extracellular Protein Targeting Ligand of the invention, including but not limited to a prokaryotic host cell, a mammalian host cell, a plant host cell, a fungal host cell, a yeast host 10 cell, or an insect host cell. In certain embodiments, the prokaryotic host cell comprises E. coli. In certain embodiments, the mammalian host cell is selected from CHO cells, HeLa cells, COS cells, HEK293 cells, or PER.C6 cells. In certain embodiments, the insect host cell is Sf9 cells or Sf+ cells. In certain embodiments, the yeast host cell is selected from S. cerevisiae cells, P. pastoris cells, H. polymorpha cells, or K. lactis cells. In certain embodiments, the nucleic acid sequences 15 encoding the IgG4-binding Extracellular Protein Targeting Ligand are codon-optimized to enhance expression yield in a host cell. Codon optimization of nucleic acid sequences is well known in the art (Mauro. BioDrugs. 32:69-81(2018)). In certain embodiments, the nucleic acid sequences encoding the IgG4-binding Extracellular Protein Targeting Ligand are codon-optimized to encode for a humanized IgG4 Binding Fragment to reduce the immunogenicity of the 20 humanized IgG4 Binding Fragment in a human. Humanization of Binding Fragments In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is a humanized IgG4 Binding Fragment described herein. The humanization of an IgG4 Binding Fragment of a non-human species substantially reduces immunogenicity in humans but retains the 25 affinity and expression yield of the IgG4 Binding Fragment of a non-human species. The process of humanizing a Binding Fragment is known to a person skilled in the art, for example by following the basis as described below and the prior art describing humanization referred to herein. The Binding Fragment of a non-human origin is not to be strictly limited to a non-human species but may also include de novo synthetically designed Binding Fragment polypeptide sequences. The 30 substitution of non-human CDRs interspersed between human framework regions is most likely to result in retention of the correct spatial orientation of the CDRs if the human framework regions 190

[0190] adopt the same or similar conformation to the non-human framework regions from which the CDRs originated. In certain embodiments, nucleic acid sequences encoding the CDRs of an IgG4 Binding Fragment may be grafted into a nucleic acid sequence encoding a universal Binding Fragment 5 scaffold with humanized FRs. In certain embodiments, nucleic acid sequences encoding the CDRs of an IgG4 Binding Fragment may be grafted into the h-NbBcII10FGLA universal Binding Fragment scaffold with humanized FRs (Vincke et al. JBC.284(5):3273-84(2009)). In certain embodiments, nucleic acid sequences encoding the CDRs of an IgG4 Binding Fragment may be grafted into a nucleic acid sequence encoding a Binding Fragment scaffold humanized using in silico methods 10 (Sang et al. Structure. 30(3):P418-P429.E2(2022)). In certain embodiments, a humanized IgG4 Binding Fragment may be designed de novo by a by methods including, but not limited to, in silico structure-based engineering. In certain embodiments, nucleic acid sequences encoding the CDRs of a humanized IgG4 Binding Fragment may be grafted into a nucleic acid sequence encoding a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment 15 comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein the humanized IgG4 Binding Fragment has one or more amino acid changes to correspond with an amino acid of a corresponding position(s) of a human VH3 Binding Fragment and is sufficiently humanized to avoid a significant immune response in the patient treated. In certain embodiments, humanized IgG4 Binding Fragment comprises, in an N-terminal to C-terminal 20 orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein the humanized IgG4 Binding Fragment has one or more amino acid substitutions according to Tables 11-16. In certain embodiments, the one or more amino acid substitutions comprise between 1-24 total amino acid substitutions, for example 2 or more substitutions, 3 or more substitutions, 4 or more substitutions, 5 or more substitutions, 6 or more substitutions, 7 or more substitutions, 8 or 25 more substitutions, 9 or more substitutions, 10 or more substitutions, 11 or more substitutions, 12 or more substitutions, 13 or more substitutions, 14 or more substitutions, 15 or more substitutions, 16 or more substitutions, 17 or more substitutions, 18 or more substitutions, 19 or more substitutions, 20 or more substitutions, 21 or more substitutions, 22 or more substitutions, 23 or more substitutions, or 24 substitutions with an amino acid of a corresponding position(s) of a 30 human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has one or more amino acid substitutions with an amino acid of a corresponding position(s) of a 191

[0191] human VH3 Binding Fragment selected from Kabat positions 1, 5, 28, 30, 37, 44, 45, 47, 74, 75, 76, 83, 84, 93, 94, 103, 104, 108, 111, or a combination thereof (see Tables 11-12). In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Glutamate or Glutamine corresponding to Kabat position 1 of a human VH3 Binding Fragment. In 5 certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Leucine or Valine corresponding to Kabat position 5 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Threonine corresponding to Kabat position 28 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Serine 10 corresponding to Kabat position 30 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Valine or Phenylalanine corresponding to Kabat position 37 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Glycine corresponding to Kabat position 44 of a human VH3 Binding Fragment. In certain embodiments, 15 the humanized IgG4 Binding Fragment has an amino acid substitution with Leucine corresponding to Kabat position 45 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Alanine or Tryptophan corresponding to Kabat position 47 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Alanine or Serine corresponding to 20 Kabat position 74 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Lysine corresponding to Kabat position 75 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Asparagine or Serine corresponding to Kabat position 76 of a human VH3 Binding Fragment. In certain embodiments, the humanized 25 IgG4 Binding Fragment has an amino acid substitution with Arginine corresponding to Kabat position 83 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Alanine corresponding to Kabat position 84 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Alanine, Lysine, or Threonine corresponding to 30 Kabat position 93 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Lysine, Arginine, or Threonine 192

[0192] corresponding to Kabat position 94 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Tryptophan corresponding to Kabat position 103 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Glycine corresponding 5 to Kabat position 104 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Leucine corresponding to Kabat position 108 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Valine corresponding to Kabat position 111 of a human VH3 Binding Fragment. In certain embodiments, the humanized IgG4 Binding 10 Fragment has one or more amino acid substitutions with an amino acid of a corresponding position(s) of a human VH3 Binding Fragment comprising Kabat positions 44 and 45. In certain embodiments, the humanized IgG4 Binding Fragment has an amino acid substitution with Glycine corresponding to Kabat position 44 and an amino acid substitution with Leucine corresponding to Kabat position 45 of a human VH3 Binding Fragment. In certain embodiments, the VH3 Binding 15 Fragment is selected from DP-29 (SEQ ID NO: 671), DP-47 (SEQ ID NO: 672), DP-51 (SEQ ID NO: 673), or a combination thereof. In certain embodiments, the humanized IgG4 Binding Fragment has at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 105%, at least 110%, at least 115%, or at least 120% the affinity for and / or specificity for IgG4 of the IgG4 Binding Fragment of a non-human species. 20 In certain embodiments, humanized IgG4 Binding Fragment comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein the humanized IgG4 Binding Fragment has one or more amino acid changes according to the formula below: Ser substituted with an amino acid selected from Ser, Thr, Gly, or Asn; Arg substituted with an amino acid selected from Arg, His, Gln, Lys, or Glu; 25 Leu substituted with an amino acid selected from Leu, Ile, Phe, Tyr, Met, or Val; Pro substituted with an amino acid selected from Pro, Gly, Ala, or Thr; Thr substituted with an amino acid selected from Thr, Pro, Ser, Ala, Gly, His, or Gln; Ala substituted with an amino acid selected from Ala, Gly, Thr, or Pro; Val substituted with an amino acid selected from Val, Met, Tyr, Phe, Ile, or Leu; 30 Gly substituted with an amino acid selected from Gly, Ala, Thr, Pro, or Ser; Ile substituted with an amino acid selected from Ile, Met, Tyr, Phe, Val, or Leu; 193

[0193] Phe substituted with an amino acid selected from Phe, Trp, Met, Tyr, Ile, Val, or Leu; Tyr substituted with an amino acid selected from Tyr, Trp, Met, Phe, Ile, Val, or Leu; His substituted with an amino acid selected from His, Glu, Lys, Gln, Thr, or Arg; Gln substituted with an amino acid selected from Gln, Glu, Lys, Asn, His, Thr, or Arg; 5 Asn substituted with an amino acid selected from Asn, Glu, Asp, Gln, or Ser; Lys substituted with an amino acid selected from Lys, Glu, Gln, His, or Arg; Asp substituted with an amino acid selected from Asp, Glu, or Asn; Glu substituted with an amino acid selected from Glu, Asp, Lys, Asn, Gln, His, or Arg; Met substituted with an amino acid selected from Met, Phe, Ile, Val, Leu, or Tyr. 10 In general, one or more of the amino acids fulfilling the above criteria is substituted. In some embodiments, all or most of the amino acids fulfilling the above criteria are substituted. In certain embodiments, the humanized IgG4 Binding Fragment comprises a Binding Fragment of non-human origin. In certain embodiments, the humanized IgG4 Binding Fragment comprises an amino acid sequence selected from SEQ ID NO: 464 to SEQ ID NO: 670 (Table 8), 15 or an amino acid at least 90% identical thereto. Table 8. Non-limiting examples of non-human IgG4 Binding Fragment sequences Sequence L E L A LRL A TL RYAM FR TP EREF AAIR S R S R S R S R S 194

[0194] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGNEREFVAAIR WNNGATYYADSVEGRFTISRDNGKNTVYLQMNNLQPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R S R S R S R S R S 195

[0195] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNNGATYYAESVEGRFTISRDNGKNTVYLQMNNLQPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R R S R S R S R S 196

[0196] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGNEREFVAAIR WNNGATYYADSVEGRFTISRDTGKNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R S R S R S R S R S 197

[0197] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNNGATYYADSVKGRFTISRDNGKNTVYLQMNNLQPEDTAVYYCAGRFLGYAS R R S R S R S R S R S R S R S R S R S R S 198

[0198] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNNGATYYAESVEGRFTISRDNGKNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R R S R S R S R S 199

[0199] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNNGATYYADSVKGRFTISRDTGKNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R S R S R S R R S R S R S R S R S R S R S 200

[0200] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGNEREFVAAIR WNNGATYYADSVKGRFTISRDNGRNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R R S R S R S R S R S R R S R R S R S 201

[0201] QVQLQDSGGGLVQAGGSLRLSCAVSGNTLSRYATGWFRQAPGNEREFVAAIR WNNGNTYYADSVEGRFTIARDSARDTVYLQMNNLQPEDTAVYYCAARFLPYAS R S R S R S S R S R S R S R S R S R S 202

[0202] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNNAATYYAESVEGRFTISRDTGKNTVYLQMNNLQPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R S R S R R S R S 203

[0203] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNEGATYYADAVEGRFTISRDNAKNTVYLQMNNLQPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R S R S R S R S R S 204

[0204] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGNEREFVAAIR WNNAATYYADAVEGRFTISRDNAKNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R S R S R S R S R S R R S R S R S R S R S 205

[0205] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNNGATYYADSVEGRFTISRDNAKNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R S R S R S R S R S R S R S R S R S R S R S 206

[0206] QVQLQESGGGLVQAGGSLRLSCAVSGNTLSRYAMGWFRQTPGKEREFVAAIR WNEGATYYADSVEGRFTISRDSGKNTVYLQMNNLKPEDTAVYYCAGRFLGYAS R S R S R R S R S R S R S R S Y R 207

[0207] QVQLQDSGGGLVQPGGSLRLSCAASENARSINVMGWYRQLPGTQRELVATIAE DGSTNYADSVKGRFTISRDKTKNTIYLQMNSLKPEDTAVYYCNADRVLYYGDLG T G S T T E S T S N F D N W 208

[0208] QVQLQESGGGLVQAGGSLRLSCAASGRAVGNYIIGWFRQAPGKEREFVATTTR DGGSTFYADSVKGRFTISRDNAKNTVNLQMNSLEPEDTAVYYCAAKSWSVPLRP G G Y G Y G Y G Y G Y T N T Y 209

[0209] QVQLQDSGGGLVQAGGSLRLSCAASGRTFSSGAMGWFRQTPGKEREFVAAIN WSVGSTYYADSVKDRFTISRDKAKNTVYLQMNSLKPEDTAVYYCAADEADGPM M I P T P R A D T P L R P 210

[0210] QVQLQESGGGLVQAGGSLRLSCAASGRTFRSGLMGWFRQAPGKEREAVALLT WSGTYTYYADSVKGRFTISRDNAKDAVYLQMNSLKPEDTGVYYCAASPRLGPIT S W S G G S R N G W Table 9. Non-limiting examples of human germline VH3 antibody sequences Descriptio Sequence 211

[0211] EVQLVESGGGLVQPGGSLRLSCAASGFTFSDHYMDWVRQAPG KGLEWVGRTRNKANSYTTEYAASVKGRFTISRDDSKNSLYLQMN DP-29 , g - g g g gand comprises, in an N-terminal to C-terminal orientation, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, wherein FR1 is selected from an amino acid sequence of SEQ ID NO: 123 to SEQ ID NO: 160, 5 wherein FR2 is selected from an amino acid sequence of SEQ ID NO: 161 to SEQ ID NO: 192, wherein FR3 is selected from an amino acid sequence of SEQ ID NO: 193 to SEQ ID NO: 253, wherein FR4 is selected from an amino acid sequence of SEQ ID NO: 254 to SEQ ID NO: 268, wherein CDR1 is selected from an amino acid sequence of SEQ ID NO: 269 to SEQ ID NO: 326, wherein CDR2 is selected from an amino acid sequence of SEQ ID NO: 327 to SEQ ID NO: 402, 10 and wherein CDR3 is selected from an amino acid sequence of SEQ ID NO: 403 to SEQ ID NO: 463. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is an amino acid sequence of SEQ ID NO: 118 to SEQ ID NO: 122 or SEQ ID NO: 674 to SEQ ID NO: 725. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises 15 an amino acid sequence of SEQ ID NO: 118, or an amino acid at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 118. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 119, or an amino acid at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein 20 Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 119. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 120, or an amino acid at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 120. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand 212

[0212] comprises an amino acid sequence of SEQ ID NO: 121, or an amino acid at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 121. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 122, or 5 an amino acid at least 95% identical thereto. In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand comprises an amino acid sequence of SEQ ID NO: 122. Table 10. Non-limiting examples of humanized IgG4 Binding Fragment sequences Sequence QVQLVESGGGLVQPGGSLRLSCSASGSIFSISAMGWYRQAPGKERELVAVITTD G D G D G D G D G Y Y Y 213

[0213] QVQLVESGGGLVQPGGSLRLSCSASGGTSIRIGSINALAWYRQALGNQRELVA AVTEGGSTNYADFVKGRFTISRDNSQNMMYLQMNSLRAEDTAVYYCNADKVLY Y Y S S A R A A S S 214

[0214] QVQLLESGGGLVQPGGSLRLSCAASGGTSIRIGSINALAWVRQAPGKGLEWVS AVTEGGSTNYADFVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDKVLYS S P E S P E P E P E S P E P E S S 215

[0215] QVQLLESGGGLVQPGGSLRLSCAASGLTVNDLYMGWFRQAPGKGLEFVGRVT PGDNTDYTYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKRRFGSS T S T S P E V S S V S S R P R P P R P 216

[0216] QVQLVESGGGLVQPGGSLRLSCAASGRAVGNYIIGWFRQAPGKEREFVATTTR DGGSTFYADSVKGRFTISRDNAKNTVNLQMNSLRAEDTAVYYCAAKSWSVPLRP P R P R P R P R P R P R P R R P R R P 217

[0217] In certain embodiments, the IgG4-binding Extracellular Protein Targeting Ligand is a humanized camelid IgG4 Binding Fragment. For example, the amino acid residues at positions 5 11, 37, 44, 45, 47, 83, 84, 103, 104, and 108 are often referred to as “Hallmark Residues” and may be comprise an amino acid selected from those listed in Table 11. Non-limiting examples of amino acid residues which commonly occur at these positions are also listed in Table 11. Table 11. Hallmark Residues in Binding Fragments Kabat Position Human VH3 Hallmark Residues 11 L, V L, M, S, V, W 10terpreted as the preferred Frequently co-occurring combinations of Hallmark Residues observed in naturally occurring Binding fragments are listed in Table 12. The Hallmark Residues of human VH3 15 germline antibody DP-47 are listed in the top row of Table 12 (M11, V37, G44, L45, W47, R83, A84, W103, G104, L108). Table 12. Frequently Co-Occurring Hallmark Residues in Naturally Occurring Binding Fragments 11 37 44 45 47 83 84 103 104 108 218

[0218] L F Q R L K P W G Q L F E R F K P W G Q occur in Human VH3 and Camelid VHH Binding fragments are listed in Table 13. Table 13. Non-limiting examples* of amino acid residues in FR1 Human VH3 Camelid VHH 1 E, Q A, D, E, H, Q, R he preferred 5 Non-limiting examples of amino acids at positions within FR2 that naturally occur in Human VH3 and Camelid VHH Binding fragments are listed in Table 14. Table 14. Non-limiting examples* of amino acid residues in FR2 Human VH3 Camelid VHH 219

[0219] 41 P, S, T A, I, L, P, Q, S, T 42 G D, E, G, R, T, V the preferred Non-limiting examples of amino acids at positions within FR3 that naturally occur in 5 Human VH3 and Camelid VHH Binding fragments are listed in Table 15. Table 15. Non-limiting examples* of amino acid residues in FR3 Human VH3 Camelid VHH 66 R R 220

[0220] 91 H, Y C, D, F, H, I, L, N, R, S, T, V, W, Y 92 C C 93 A K T A E F G H I K L M N Q R S T V Y s the preferred Non-limiting examples of amino acids at positions within FR4 that naturally occur in 5 Human VH3 and Camelid VHH Binding fragments are listed in Table 16. Table 16. Non-limiting examples* of amino acid residues in FR4 Human VH3 Camelid VHH 103 F, G, K, L, N, P, Q, R, S, V, W, Y s the preferred 10 Soluble Endoglin (sEng) CsEng (soluble Eng), caused by Eng shedding from endothelial cell surface, has antiangiogenic effects in pregnant women, which can lead to preeclampsia. It has been hypothesized that this occurs via binding to circulating TGF-β1, a protein involved in homeostasis 15 of angiogenic processes. sEng is used as a biomarker of preeclampsia during pregnancy, in particular during the second trimester. In certain embodiments, the Extracellular Protein Targeting Ligand binds sEng. In certain embodiments, the Extracellular Protein Targeting Ligand is an antibody that binds soluble endoglin. In certain embodiments, the sEng binding ligand is an antibody or antibody fragment with 20 at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with the antibody SN6, or a fragment or derivative thereof. (Haruta and Seon, 1986, PNAS 83:7898-7902). In certain embodiments, the sEng binding ligand is a humanized form of the antibody SN6, or a fragment or derivative thereof. 221

[0221] In certain embodiments, the sEng binding ligand is an antibody or antibody fragment with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with the antibody 44G4, or a fragment or derivative thereof. In certain embodiments, the sEng binding ligand is a humanized form of the antibody 44G4, or a fragment or derivative thereof. 5 In certain embodiments, the sEng binding ligand is an antibody or antibody fragment with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with the antibody MJ7 / 118, or a fragment or derivative thereof. In certain embodiments, the sEng binding ligand is a humanized form of the antibody MJ7 / 118, or a fragment or derivative thereof. In certain embodiments, the sEng binding ligand is an antibody or antibody fragment with 10 at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with the Tec-11, or a fragment or derivative thereof. In certain embodiments, the sEng binding ligand is a humanized form of the antibody Tec-11, or a fragment or derivative thereof. In certain embodiments, the sEng binding ligand is an antibody or antibody fragment described in WO2018 / 187158. 15 In certain embodiments, the sEng binding ligand is an antibody or fragment thereof comprising a heavy chain variable region having an amino acid sequence with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a sequence selected from: SEQ ID NO: 726 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDAWMDWVRQAPGKGLEWVGEIRSKASN HATYYAE K RFTI RDD K TLYL M LKTEDTA YY TT RRFFD TL T T T and a light chain variable region having an amino acid sequence with at least about 99%, 98%, 20 95%, 92%, 90%, 85%, or 80% sequence identity with a sequence selected from: SEQ ID NO: 729 DIQMTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLLIYATSNLASGVPSR S 222

[0222] SEQ ID NO: 731 DIQLTQSPSSLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKPWIYATSNLASGVPSR FSGSGSGTDYTLTISSLQPEDFATYYCQQWSSNPLTFGGGTKVEIK identity with the following CDRs: CDR1 SEQ ID NO: 732 DAWMD CDR2 SEQ ID NO: 733 EIRSKASNHATYYAES 5 y g q SEQ ID NO: 735 EVQLVESGGGLVKPGGSLRLSCAASGFTFS or the amino acid sequence of SEQ ID NO: 735 except for one or more conservative substitutions; (ii) a heavy chain FR2 having the amino acid sequence of SEQ ID NO: 736 WVRQAPGKGLEWVG 10 or the amino acid sequence of SEQ ID NO: 736 except for a substitution of glycine (G) by alanine (A) at position 49 utilizing the Kabat numbering system; and (iii) a heavy chain FR3 having the amino acid sequence of SEQ ID NO: 737 RFTISRDDSKNTLYLQMNSLKTEDTAVYYCTT or the amino acid sequence of SEQ ID NO: 737 except for one or more substitutions selected from 15 the group consisting of: (a) a substitution of asparagine (N) by serine (S) at position 76; (b) a substitution of threonine (T) by arginine (R) at position 77; (c) a substitution of leucine (L) by valine (V) at position 78; (d) a substitution of asparagine (N) by isoleucine (I) at position 82a; 20 (e) a substitution of valine (V) by isoleucine (I) or leucine (L) at position 89; and (f) a substitution of threonine (T) by arginine (R) or glycine (G) at position 94 utilizing the Kabat numbering system; and (iv) a heavy chain FR4 having the amino acid sequence of SEQ ID NO: 268 WGQGTLVTVSS 25 or the amino acid sequence of SEQ ID NO: 268 except for one or more substitutions selected from the group consisting of: (a) a substitution of leucine (L) by threonine (T) at position 108; 223

[0223] (b) a substitution of valine (V) by leucine (L) at position 109; and (c) a substitution of serine (S) by alanine (A) at position 113 utilizing the Kabat numbering system; and said light chain variable region comprises: CDR1 SEQ ID NO: 738 RASSSVSYMH CDR2 SEQ ID NO: 739 ATSNLAS 5 g g q ce of SEQ ID NO: 741 DIQMTQSPSSLSASVGDRVTITC or the amino acid sequence of SEQ ID NO: 741 except for one or more substitutions selected from the group consisting of: 10 (a) a substitution of aspartic acid (D) by glutamine (Q) at position 1; (b) a substitution of glutamine (Q) by valine (V) at position 3; (c) a substitution of methionine (M) by leucine (L) at position 4; and (d) a substitution of threonine (T) by serine (S) at position 5; utilizing the Kabat numbering system; and 15 (ii) a light chain FR2 having the amino acid sequence of SEQ ID NO: 742 WYQQKPGKAPKLLIY or the amino acid sequence of SEQ ID NO: 742 except for one or more substitutions selected from the group consisting of: (a) a substitution of tyrosine (Y) by phenylalanine (F) at position 36; 20 (b) a substitution of leucine (L) by proline (P) at position 46; and (c) a substitution of leucine (L) by tryptophan (W) at position 47 utilizing the Kabat numbering system; and (iii) a light chain FR3 having the amino acid sequence of SEQ ID NO: 743 GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC 25 or the amino acid sequence of SEQ ID NO: 743 except for one or more substitutions selected from the group consisting of: (a) a substitution of serine (S) by valine (V) or alanine (A) at position 60; (b) a substitution of aspartic acid (D) by serine (S) at position 70; and 224

[0224] (b) a substitution of phenylalanine (F) by tyrosine (Y) at position 71 utilizing the Kabat numbering system; and (iv) a light chain FR4 having the amino acid sequence of SEQ ID NO: 744 FGGGTKVEIK 5 or the amino acid sequence of SEQ ID NO: 744 except for one or more substitutions selected from the group consisting of: (a) a substitution of glycine (G) by alanine (A) at position 100; and (b) a substitution of isoleucine (I) by leucine (L) at position 106 utilizing the Kabat numbering system. 10 In certain embodiments, the sEng binding ligand does not block ligand binding to sEng. In certain embodiments, the sEng binding ligand is a peptide comprising a sequence with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a fragment or truncated form of a peptide selected from BMP9, BMP10, TGF-β1, and / or TGF-β33. In certain embodiments, the sEng binding ligand binds to an epitope in sEng that is not 15 present in membrane-bound Endoglin (Eng). In certain embodiments, the sEng binding ligand binds to the orphan domain of human sEng. In certain embodiments, the sEng binding ligand is an antibody or antibody fragment described in WO2021 / 118955 or WO2021 / 118957. 20 In certain embodiments, the sEng binding ligand is an antibody or antibody fragment comprising a heavy chain variable region having an amino acid sequence with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a sequence selected from: CDHR1 SEQ ID NO: 745 Gly Tyr Thr Ile Thr Glu His Thr Leu His rg In certain embodiments, the sEng binding ligand is an antibody or antibody fragment 25 comprising a light chain variable region having an amino acid sequence with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a sequence selected from: CDLR1 SEQ ID NO: 748 Arg Ala Ser Ser Ser Val Asn Tyr Val Tyr 225

[0225] CDL3 SEQ ID NO: 750 Gln Gln Phe Ile Ser Phe Pro Tyr Thr ent comprising a heavy chain variable region having an amino acid sequence with at least about 99%, 98%, 95%, 92%, 90%, 85%, or 80% sequence identity with a sequence selected from: CDHR1 SEQ ID NO: 745 Gly Tyr Thr Ile Thr Glu His Thr Leu His CDHR2 SEQ ID NO: 746 Gly Ile Asn Phe Asp Asn Gly Gly Thr Thr Tyr Arg 5 %, , , , , o seque ce e y w a seque ce se ec e o : CDLR1 SEQ ID NO: 748 Arg Ala Ser Ser Ser Val Asn Tyr Val Tyr CDLR2 SEQ ID NO: 749 Tyr Thr Ser Asn Leu Ala Pro ApoE Targeting Ligand In certain embodiments the Extracellular Protein Targeting Ligand binds to apolipoprotein 10 E (ApoE). ApoE is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. It is a protein involved in the metabolism of fats in the body of mammals. In certain embodiments the Extracellular Protein Targeting Ligand is a nanobody that is 15 identified as “sdAb-ApoE-Nbx”. For example in certain embodiments the Extracellular Protein Targeting Ligand is nanobody sdAb-ApoE-Nbx which is purchased from Gulliver Biomed. In other aspects the Extracellular Protein Targeting Ligand is a lipid nanoparticle or a component of a lipid nanoparticle (LNP). For example, in certain embodiments the Extracellular Protein Targeting Ligand is a LNP which endogenously desorpts PEG lipids and enables the 20 subsequent binding of ApoE. Non-limiting examples of LNPs are described in the paper by Dillard et al. titled “On the Mechanism of Tissue-Specific mRNA Delivery by Selective Organ Targeting Nanoparticles.” PNAS 2021, 118, 52. In certain embodiments the LNP is mDLNP as described in the paper by Dillard et al. In other embodiments the LNP is DLin-MC3-DMA LNP as described in the paper by Dillard et al. 226

[0226] In other aspects the Extracellular Protein Targeting Ligand is an antibody or antibody fragment selected from ab183597, ab52607, ab51015, ab183596, ab271944, ab227993, ab1907, ab171357, ab184845, ab245999, ab271843, ab215086, ab1906, ab195855, ab24139, ab83115, ab196194, ab196463, ab307386, ab307392, ab302567, ab24274, ab55210, ab32897, ab280330, 5 ab302580, ab300743, ab242844, ab242598, ab244739, ab245008, ab241856, ab27613, ab312030, ab313170, ab312507, ab312961, ab310501, ab311685, ab310350, ab308786, ab308649, ab306401, ab310867, ab303051, ab306402, ab303052, ab306400, ab310931, ab303050, ab123749, ab226314, ab267976, ab108813, ab279714, ab279719, ab169861, ab27543, ab85975, ab85976, ab286161, ab123764, ab123766, ab50242, ab233623, and ab244096. 10 In other aspects the Extracellular Protein Targeting Ligand binds to ApoE4. Non-limiting examples of antibodies or antibody fragments that bind to ApoE4 include: ab279714, ab279719, ab169861, ab85975, ab85976, and ab123766. In other aspects the Extracellular Protein Targeting Ligand binds to ApoE3. Non-limiting examples of antibodies or antibody fragments that bind to ApoE3 include: ab27543, ab286161, 15 ab123764, and ab50242. In certain embodiments the Extracellular Protein Targeting Ligand is a sequence of greater than 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology to an ApoE Targeting antibody or antibody fragment described herein. In certain aspects the ApoE Targeting Ligand can be purchased from abcam. 20 In certain embodiments, the ApoE binding antibody binds to the C-terminal domain of ApoE. In certain embodiments, the ApoE binding antibody binds ApoE4. In certain embodiments, the ApoE binding antibody binds ApoE3. In certain embodiments, the ApoE binding antibody binds ApoE3 and ApoE4. In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an 25 antibody described in WO 2005 / 051998. In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand comprises a sequence from the tables below. In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand comprises a sequence with at least about 227

[0227] 85%, 90%, 92%, 95%, 98%, or 99% sequence homology to a sequence selected from the tables below. In certain embodiments, the ApoE Binding Extracellular Protein Targeting Ligand comprises a HCDR3 selected from SEQ ID NO: 751 to SEQ ID NO: 772. Sequence Heavy chain CDR3 SEQ ID NO: 751 Ser Xaa1Xaa2Leu Asp Tyr yr 228

[0228] Xaa1=M or I Xaa2=S or A sp et In certain embodiments, the ApoE Binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE Binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 229

[0229] 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 774, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 773 or SEQ ID NO: 775, or (iii) a variable heavy domain region comprising an amino acid sequence with 5 at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 774 and a variable light domain region with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 773 or SEQ ID NO: 775. Light Chain Sequence Heavy Chain Sequence SEQ ID NO: 773 SEQ ID NO: 774 ln ly ln er ys hr hr ly er 10 In certain embodiments, the ApoE Binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE Binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 777, (ii) a variable 15 light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 776, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of 230

[0230] SEQ ID NO: 777 and a variable light domain region with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 776. Light Chain Sequence Heavy Chain Sequence SEQ ID NO: 776 SEQ ID NO: 777 ln ly ln rp ys hr hr al sp 5 In certain embodiments, the ApoE Binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE Binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 778, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 10 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 757 or SEQ ID NO: 779, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 778 and a variable light domain region with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence 15 of SEQ ID NO: 757 or SEQ ID NO: 779. Light Chain Sequence Heavy Chain Sequence ln ly ln rp 231

[0231] Xaa3is Arg or Gly Pro Ser Gly Gly Gln Thr Trp Tyr Ala Asp Ser Val Lys Xaa4is His or Tyr Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr hr yr , an antibody, antibody fragment, or ApoE Binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 5 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 778, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 773 or SEQ ID NO: 779, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino 10 acid sequence of SEQ ID NO: 778 and a variable light domain region with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to the amino acid sequence of SEQ ID NO: 773 or SEQ ID NO: 779. Light Chain Sequence Heavy Chain Sequence ln ly ln rp ys hr hr yr 232

[0232] In certain embodiments, the ApoE Binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE Binding moiety comprising a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 92%, 95%, 98%, 99%, or 100% sequence homology to any one of the amino acid sequences of SEQ ID NO: 780 to SEQ ID 5 NO: 792. SEQ ID NO: 780 HCDR1 Met Tyr Met Met Asp SEQ ID NO: 781 HCDR2 Ser Ile Trp Pro Ser Gly Gly Gln Thr Trp Tyr Ala Asp Ser Val Lys Gly Q : g y eu e e SEQ ID NO: 786 HCDR2 Val Ile Ser Pro Ser Gl Gl Arg Thr Trp T r Ala Asp Ser Val L s Gl SEQ ID NO: 790 HCDR1 Ser Tyr Pro Met Val yr 10 In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody described in WO 2018 / 081642. In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain 15 region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 796 to SEQ ID NO: 798, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 793 to SEQ ID NO: 795, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 233

[0233] 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 796 to SEQ ID NO: 798 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 793 to SEQ ID NO: 795. 5 Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Xaa1Phe Leu Xaa2wherein or al In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, 10 or 100% sequence homology to any one of SEQ ID NO: 801 to SEQ ID NO: 803, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 799, SEQ ID NO: 794, or SEQ ID NO: 800, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ 15 ID NO: 801 to SEQ ID NO: 803 and a variable light domain region comprising an amino acid 234

[0234] sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 799, SEQ ID NO: 794, or SEQ ID NO: 800. Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Xaa1Phe Leu Xaa2wherein al 5 In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 807 to SEQ ID NO: 809, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 10 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 804 to SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 807 to SEQ ID NO: 809 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 15 804 to SEQ ID NO: 806. 235

[0235] Arg Ser Ser Gln Xaa1Ile Xaa2Xaa3Xaa4Asn Gly Asn Thr Tyr Leu Glu wherein ys y In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, 5 or 100% sequence homology to any one of SEQ ID NO: 811, SEQ ID NO: 812, or SEQ ID NO: 793, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 810, SEQ ID NO: 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence 10 homology to any one of SEQ ID NO: 811, SEQ ID NO: 812, or SEQ ID NO: 793 and a variable 236

[0236] light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 810, SEQ ID NO: 805, or SEQ ID NO: 806. Arg Ser Ser Gln Xaa1Ile Xaa2Xaa3Xaa4Asn Gly Asn Thr Tyr Leu Glu wherein ys 2 or 5 In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 816 to SEQ ID NO: 818, (ii) a variable 10 light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 237

[0237] 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813 to SEQ ID NO: 815, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 816 to SEQ ID NO: 818 and a variable light domain region comprising an amino acid sequence with at least 5 about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813 to SEQ ID NO: 815. SEQ ID NO: 813 LCDR1 His Ala Ser Gln Asn Ile Asn Ile Trp Leu Ser SEQ ID NO: 814 LCDR2 Lys Ala Ser Asn Leu His Thr al In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an 10 antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 820 to SEQ ID NO: 822, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813, SEQ ID NO: 814, or 15 SEQ ID NO: 819, or (iii) a variable heavy domain region comprising an amino acid sequence with 238

[0238] at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 820 to SEQ ID NO: 822 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813, SEQ ID NO: 814, or SEQ ID NO: 819. 5 SEQ ID NO: 813 LCDR1 His Ala Ser Gln Asn Ile Asn Ile Trp Leu Ser SEQ ID NO: 814 LCDR2 Lys Ala Ser Asn Leu His Thr er In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, 10 or 100% sequence homology to any one of SEQ ID NO: 824 to SEQ ID NO: 826, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 823, SEQ ID NO: 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ 15 ID NO: 824 to SEQ ID NO: 826 and a variable light domain region comprising an amino acid 239

[0239] sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 823, SEQ ID NO: 805, or SEQ ID NO: 806. SEQ ID NO: 823 LCDR1 Arg Ser Ser Gln Thr Ile Val His Ser Asp Gly Asn Thr Tyr Leu Glu SEQ ID NO: 805 LCDR2 Lys Val Ser Asn Arg Phe Ser 5 ce a e o e s, e po g ace u a o e a ge g ga s an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 829 to SEQ ID NO: 831, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 10 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 827, SEQ ID NO: 794, or SEQ ID NO: 828, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 829 to SEQ ID NO: 831 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any 15 one of SEQ ID NO: 827, SEQ ID NO: 794, or SEQ ID NO: 828. SEQ ID NO: 827 LCDR1 Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys His Phe Leu Ala y In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain 20 region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 833 to SEQ ID NO: 835, (ii) a variable 240

[0240] light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 832, SEQ ID NO: 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ 5 ID NO: 833 to SEQ ID NO: 835 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 832, SEQ ID NO: 805, or SEQ ID NO: 806. SEQ ID NO: 832 LCDR1 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu SEQ ID NO: 805 LCDR2 Lys Val Ser Asn Arg Phe Ser 10 In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 837 to SEQ ID NO: 839, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 15 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 836, SEQ ID NO: 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 837 to SEQ ID NO: 839 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any 20 one of SEQ ID NO: 836, SEQ ID NO: 805, or SEQ ID NO: 806. SEQ ID NO: 836 LCDR1 Arg Ser Ser Gln Asn Ile Ile His Ser Asn Gly Asn Thr Tyr Leu Glu 241

[0241] SEQ ID NO: 839 HCDR3 Ala Arg Tyr Tyr Ser Ser Ser Pro Phe Ala Tyr an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, 5 or 100% sequence homology to any one of SEQ ID NO: 841 to SEQ ID NO: 843, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 840, SEQ ID NO: 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ 10 ID NO: 841 to SEQ ID NO: 843 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 840, SEQ ID NO: 805, or SEQ ID NO: 806. SEQ ID NO: 840 LCDR1 Arg Ser Ser Gln Asn Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Glu SEQ ID NO: 805 LCDR2 L s Val Ser Asn Ar Phe Ser In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an 15 antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 833, SEQ ID NO: 844, or SEQ ID NO: 845, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 836, 20 SEQ ID NO: 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 833, SEQ ID NO: 844, or SEQ ID NO: 845 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 836, SEQ ID NO: 805, or 25 SEQ ID NO: 806. 242

[0242] SEQ ID NO: 836 LCDR1 Arg Ser Ser Gln Asn Ile Ile His Ser Asn Gly Asn Thr Tyr Leu Glu SEQ ID NO: 805 LCDR2 Lys Val Ser Asn Arg Phe Ser , an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, 5 or 100% sequence homology to any one of SEQ ID NO: 848 to SEQ ID NO: 850, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 846, SEQ ID NO: 794, or SEQ ID NO: 847, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ 10 ID NO: 848 to SEQ ID NO: 850 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 846, SEQ ID NO: 794, or SEQ ID NO: 847. SEQ ID NO: 846 LCDR1 Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Phe LeuThr y In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, 15 antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 852, SEQ ID NO: 853, or SEQ ID NO: 843, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 851, SEQ ID NO: 20 805, or SEQ ID NO: 806, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any 243

[0243] one of SEQ ID NO: 852, SEQ ID NO: 853, or SEQ ID NO: 843 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 852, SEQ ID NO: 853, or SEQ ID NO: 843. SEQ ID NO: 851 LCDR1 Arg Ser Ser Gln Ser Ile Val His Arg Asn Gly Asn Thr Tyr Leu Glu SEQ ID NO: 805 LCDR2 Lys Val Ser Asn Arg Phe Ser 5 ce a e o e s, e po g ace u a o e a ge g ga s an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 857 to SEQ ID NO: 859, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 10 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 854 to SEQ ID NO: 856, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 857 to SEQ ID NO: 859 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 15 854 to SEQ ID NO: 856. SEQ ID NO: 854 LCDR1 Ser Val Ser Ser Ser Ile Ser Ser Ser Asn Leu His In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, 20 or 100% sequence homology to any one of SEQ ID NO: 861 to SEQ ID NO: 863, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 244

[0244] 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813, SEQ ID NO: 814, or SEQ ID NO: 860, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 861 to SEQ ID NO: 863 and a variable light domain region comprising an amino acid 5 sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813, SEQ ID NO: 814, or SEQ ID NO: 860. SEQ ID NO: 813 LCDR1 His Ala Ser Gln Asn Ile Asn Ile Trp Leu Ser SEQ ID NO: 814 LCDR2 Lys Ala Ser Asn Leu His Thr sp n certan embod ments, t e po b nd ng xtrace u ar roten arget ng gand s an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain 10 region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 866 to SEQ ID NO: 868, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 864, SEQ ID NO: 805, or SEQ ID NO: 865, or (iii) a variable heavy domain region comprising an amino acid sequence with 15 at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 866 to SEQ ID NO: 868 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 864, SEQ ID NO: 805, SEQ ID NO: 865. SEQ ID NO: 864 LCDR1 Arg Ser Ser Gln Ser Leu Val His Ile Asn Gly Asn Thr Tyr Leu His 20 In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or ApoE binding moiety comprising (i) a variable heavy domain 245

[0245] region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 870 to SEQ ID NO: 872, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813, SEQ ID NO: 814, or 5 SEQ ID NO: 869, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 870 to SEQ ID NO: 872 and a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, 95% 98%, 99%, or 100% sequence homology to any one of SEQ ID NO: 813, SEQ ID NO: 814, or SEQ ID NO: 869. SEQ ID NO: 813 LCDR1 His Ala Ser Gln Asn Ile Asn Ile Trp Leu Ser SEQ ID NO: 814 LCDR2 Lys Ala Ser Asn Leu His Thr p 10 an antibody described in WO 2020 / 243346. In certain embodiments, the ApoE binding Extracellular Protein Targeting Ligand is an antibody comprising one or more complimentary determining regions selected from SEQ ID NO: 873 Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn 246

[0246] SEQ ID NO: 887 Trp Ile Asp Pro Glu Ile Asp Lys Thr Leu Tyr Asp Pro Lys Phe Gln Gly SEQ ID NO: 888 Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Glu Asn Tyr Met Asn , Soluble fms–like tyrosine kinase 1 (sFLT-1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. This receptor binds VEGFA, VEGFB, and placental growth factor 5 and controls angiogenesis in healthy and diseased tissues. sFLT-1 is upregulated in women with preeclampsia and high levels of sFLT-1 is a cause of maternal hypertension and proteinuria. During placentation, a critical process is remodeling of certain arteries to support the pregnancy. One such artery is the spiral artery (SpA). SpA remodeling involves apoptosis of certain mother cells followed by the production of specialized fetal trophoblast cells in combination with uterine 10 natural killer (uNK) cells surrpounding the SpAs. In preeclampsia pregnancies, SpA remodeling is poor and the reduced vasodilation during preeclampsia affects placental perfusion. In certain embodiments, a compound of the invention that binds sFLT-1 can be used in the treatment, prevention, or amelioration of preeclampsia. In certain embodiments, a compound of the invention that binds sFLT-1 can reduce the plasma levels of sFLT-1 by at least about 10%, 15%, 20%, 25%, 15 30%, 35%, 40%, 45%, 50%, 55%, or 60% or even more. In certain embodiments, a compound of the invention that binds sFLT-1 can reduce the plasma levels of sFLT-1 by from about 20% to about 60%. In certain embodiments, a compound of the invention that binds sFLT-1 can reduce the plasma levels of sFLT-1 by from about 30% to about 50%. In certain embodiments, a compound of the invention that binds sFLT-1 can reduce the plasma levels of sFLT-1 in less than 20 about 48 hours, less than about 36 hours, less than about 24 hours, less than about 18 hours, or even less than about 12 hours. In certain embodiments, a compound of the invention that binds sFLT-1 can reduce the plasma levels of sFLT-1 by at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or even 60% in less than about 48 hours, less than about 36 hours, less than about 24 hours, less than about 18 hours, or even less than about 12 hours. 247

[0247] In certain embodiments, the compound of the invention is of the formula: or r a pharmaceutically 5 In certain embodiments, the compound of the invention is of the formula: , 248

[0248] a 249

[0249] In certain embodiments, the compound of the invention is of the formula: or 250

[0250] ; or a In certain embodiments, the compound of the invention is of the formula: , 251

[0251] ; or a p . In certain embodiments, the compound of the invention is of the formula: 5 , 252

[0252] or or a pharmaceutically 5 Alternative splicing of the gene that encodes FLT-1 can result in the production of sFLT- 1, the soluble form of the protein. At least two splice variants, sFLT-1-1 (also known as sFlt1_v1 or sFlt-1-i13) and sFLT-1-14 (also known as sFlt1_v2 or sFlt1-e15a) are expressed in human tissues. sFLT-1-14 levels have been shown to increase dramatically in women with preeclampsia, suggesting that the sFLT-1-14 variant may be a significant factor in the pathogenesis of 10 preeclampsia. In certain embodiments, the compound of the invention is of the formula 253

[0253] or r a pharmaceutically 5 In certain embodiments, the compound of the invention is of the formula or 254

[0254] r a pharmaceutically In certain embodiments, the sFLT-1 binding ligand is a fragment or homolog of VEGFA, 5 VEGFB, or placental growth factor (Barleon, B. et al “Mapping the Sites for Ligand Binding and Receptor Dimerization at the Extracellular Domain of the Vascular Endothelial Growth Factor Receptor FLT-1” Protein Chemistry and Structure 1997, 272(16), 10382-10388). In certain embodiments, the Extracellular Protein Targeting Ligand is an antibody that binds sFLT-1. 10 In certain embodiments, the Extracellular Protein Targeting Ligand is the soluble VEGFR- 1 Targeting Ligand 01A04. The preparation of 01A04 is described in WO2016164567A1. In certain embodiments, the VEGFR-1 Targeting Ligand is an antibody described in WO 2016 / 164528. In certain embodiments, the soluble VEGFR-1 Targeting Ligand is an antibody comprising one or more complementarity determining regions (CDR) selected from the group 15 consisting of a variable heavy (VH) chain CDR1 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO: 893 to SEQ ID NO: 896, SEQ ID NO: 893 Ser Tyr Ala Met Ser SEQ ID NO: 894 Asp Tyr Ser Met Ser 20SEQ ID NO: 895 Asp Tyr Ser Ala SerSEQ ID NO: 896 Asp Tyr Ser Leu Ser a VH CDR2 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO: 897 to SEQ ID NO: 906, 255

[0255] SEQ ID NO: 897 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys SEQ ID NO: 898 Ala Ile Ser Trp Asn Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Met Lys SEQ ID NO: 899 Ala Ile Ser Trp Asn Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Leu Lys SEQ ID NO: 900 Ala Ile Ser Trp Asn Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Ala Lys 5 SEQ ID NO: 901 Ala Ile Ser Trp Asn Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Val Lys SEQ ID NO: 902 Ala Ile Thr Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Val Lys SEQ ID NO: 903 Ala Ile Ser Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Leu Lys SEQ ID NO: 904 Ala Ile Ser Trp Ser Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Val Lys SEQ ID NO: 905 Ala Ile Ser Trp Gln Gly Asp Ser Thr Tyr Tyr Ala Glu Ser Ala Lys 10SEQ ID NO: 906 Ala Ile Ser Trp Asn Ala Asp Ser Thr Tyr Tyr Ala Glu Ser Ala Lysa VH CDR3 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO: 907 to SEQ ID NO: 910; SEQ ID NO: 907 Asp Tyr 15 SEQ ID NO: 908 Ser Trp Ala Thr Pro Ile Glu Ser Leu Tyr Tyr Tyr Gly Met Asp Tyr SEQ ID NO: 909 Ser Trp Ala Thr Pro Ile Glu Ser Leu Tyr Tyr Tyr Gly Ser Asp Tyr SEQ ID NO: 910 Ser Trp Ala Thr Pro Ile Glu Ser Leu Tyr Tyr Tyr Gly Thr Asp Tyr a variable light (VL) chain CDR1 defined by an amino acid sequence having at least 80% 20 identity to any one of SEQ ID NO: 911 to SEQ ID NO: 913; SEQ ID NO: 911 Gly Gly Asn Asn Ile Gly Ser Lys Asn Val His SEQ ID NO: 912 Gly Gly Asn Asn Leu Gly Tyr Lys Ser Val His SEQ ID NO: 913 Gly Gly Asn Asn Ile Gly Ser Gln Thr Ala Gln 25 a VL CDR2 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO: 914 to SEQ ID NO: 916; and SEQ ID NO: 914 Arg Asp Ser Asn Arg Pro Ser SEQ ID NO: 915 Arg Asp Asn Asn Arg Pro Ser SEQ ID NO: 916 Ala Asn Asn Arg Arg Pro Ser 30 a VL CDR3 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO: 917 to SEQ ID NO: 926. SEQ ID NO: 917 Gln Val Val Val SEQ ID NO: 918 Gln Val Trp Asp Gly Ser Thr Gln Ala Ile Val 35 SEQ ID NO: 919 Gln Val Trp Glu Asp Ser Thr Gln Ala Ile Val 256

[0256] SEQ ID NO: 920 Gln Val Trp Asp Glu Ser Thr Gln Ala Ile Val SEQ ID NO: 921 Gln Val Trp Ala Ala Ser Thr Gln Ala Ile Val SEQ ID NO: 922 Gln Val Trp Asp Asp Ser Thr Gln Ala Ile Val SEQ ID NO: 923 Gln Val Trp Glu Ala Ser Thr Gln Ala Ile Val 5 SEQ ID NO: 924 Gln Val Trp Asp Ala Ser Thr Gln Ala Ile Val SEQ ID NO: 925 Gln Val Trp Glu Glu Ser Thr Gln Ala Ile Val SEQ ID NO: 926 Gln Val Trp Glu Gly Ser Thr Gln Ala Ile Val In certain embodiments, the VEGFR-1 Targeting Ligand is an antibody described in US 2016 / 0347843 A1 or U.S. Patent 10,426,812. 10 In some embodiments, CDRH1 comprises a sequence as set forth in SEQ ID NO: 927. In some embodiments, CDRH2 comprises a sequence as set forth in SEQ ID NO: 928. In some embodiments, CDRH3 comprises a sequence as set forth in SEQ ID NO: 929. CDRL1 comprises a sequence as set forth in SEQ ID NO: 930. In some embodiments, CDRL2 comprises a sequence as set forth in SEQ ID NO: 805. In some embodiments, CDRL3 comprises a sequence as set forth 15 in SEQ ID NO: 931. For example, in some embodiments, CDRH1 comprises a sequence as set forth in SEQ ID NO: 927, CDRH2 comprises a sequence as set forth in SEQ ID NO: 928, CDRH3 comprises a sequence as set forth in SEQ ID NO: 929. CDRL1 comprises a sequence as set forth in SEQ ID NO: 930, CDRL2 comprises a sequence as set forth in SEQ ID NO: 805, and CDRL3 comprises a sequence as set forth in SEQ ID NO: 931. 20SEQ ID NO: 927 Asp Asp Tyr Met AsnSEQ ID NO: 928 Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe Gln SEQ ID NO: 929 Gly Tyr Asp Tyr Phe Pro Phe Val Tyr SEQ ID NO: 930 Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu SEQ ID NO: 805 Lys Val Ser Asn Arg Phe Ser 25 SEQ ID NO: 931 Phe Gln Gly Ser His Val Pro Phe Thr In some embodiments, CDRH1 comprises a sequence as set forth in SEQ ID NO: 932. In some embodiments, CDRH2 comprises a sequence as set forth in SEQ ID NO: 933. In some embodiments, CDRH3 comprises a sequence as set forth in SEQ ID NO: 934. CDRL1 comprises a sequence as set forth in SEQ ID NO: 935. In some embodiments, CDRL2 comprises a sequence 30 as set forth in SEQ ID NO: 936. In some embodiments, CDRL3 comprises a sequence as set forth in SEQ ID NO: 937. For example, in some embodiments, CDRH1 comprises a sequence as set forth in SEQ ID NO: 932, CDRH2 comprises a sequence as set forth in SEQ ID NO: 933, CDRH3 comprises a sequence as set forth in SEQ ID NO: 934, CDRL1 comprises a sequence as set forth 257

[0257] in SEQ ID NO: 935, CDRL2 comprises a sequence as set forth in SEQ ID NO: 936, and CDRL3 comprises a sequence as set forth in SEQ ID NO: 937. SEQ ID NO: 932 Thr Ser Gly Met Ser SEQ ID NO: 933 Trp Ile Asn Thr Tyr Ser Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys 5 SEQ ID NO: 934 Ser Arg Asn Asn Tyr Glu Gly Phe Ala Tyr SEQ ID NO: 935 Lys Ser Ser Gln Ser Leu Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala SEQ ID NO: 936 Trp Ala Ser Thr Arg Glu Ser SEQ ID NO: 937 Gln Gln Tyr Tyr Leu Tyr Pro Leu Thr In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand 10 comprises an antibody, antibody fragment, or sFLT-1 binding moiety described in WO2004 / 008946. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand comprises an antibody, antibody fragment, or sFLT-1 binding moiety described in U.S. Patent Application Publication Numbers 20040126828, 20050025762, and 20050170444 and PCT Publication Numbers WO 2004 / 008946 and WO 2005 / 077007. 15 In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand may contain one or more non-classical amino acids. Non-classical amino acids include, but are not limited to, to the D-isomers of the common amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, g-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, omithine, norleucine, norvaline, 20 hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β- methyl amino acids, Ca-methyl amino acids, Na-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary). In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand may 25 comprise a chemically modified derivative of the targeting ligands described herein, which may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337) are also included. The chemical moieties for derivatization may be selected from water soluble polymers such as, for example, polyethylene glycol, ethylene glycol / propylene glycol copolymers, 30 carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The compound may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties. 258

[0258] In certain embodiments, the sFLT-1 ligand identified by a SEQ ID NO can be a cyclic or stapled form of the sequence. For example, the first amino acid in the sequence can be bound to the last amino acid in the sequence, forming a head-to-tail cyclized binding ligand. In certain embodiments, two or more side chains of the sequence listed can be bound together, for example 5 through a disulfide or amide bond to form a side chain cyclized peptide. In certain embodiments the sFLT-1 binding ligand is a stapled form of the sequence listed. In certain embodiments, the sFLT-1 binding moiety is an scFv, Fv, scFab, Fab’, or Fab that binds to sFLT-1. In certain embodiments, the sFLT-1 binding moiety is a peptide ligand, for example a cyclic peptide ligand. In certain embodiments, the sFLT-1 binding moiety is a peptide10 that comprises one, two, three, four, five, or six complementary determining regions of an anti- sFLT-1 antibody as described herein. In certain embodiments, a peptide Extracellular Protein Targeting Ligand that binds to sFLT-1 according to any SEQ ID NO described herein is in cyclized form. A cyclized form of a SEQ ID NO described herein includes but is not limited to head-to-tail cyclized forms (i.e. the first 15 and the last amino acid in a sequence covalently bound to each other), side chain cyclized forms (i.e. a disulfide bond between two cysteine residues in the sequence), and stapled peptide forms (i.e. two amino acid residues in the chain are linked together by a covalently bound linker). In certain embodiments, the Extracellular Protein Targeting Ligand is an sFLT-1 binding moiety described in U.S. Patent 10,421,812. 20 In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising (i) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 938, (ii) a variable light domain region comprising the amino acid sequence of SEQ ID NO: 944, or (iii) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 938 and a variable light domain region 25 comprising the amino acid sequence of SEQ ID NO: 944. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of SEQ ID NO: 938, (ii) a variable light domain region 30 comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of SEQ ID NO: 944, or (iii) a variable heavy domain region comprising 259

[0259] an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of SEQ ID NO: 938 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 944. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an 5 antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of any one of SEQ ID NO: 939 to SEQ ID NO: 943, or any one of SEQ ID NO: 927 or SEQ ID NO: 929. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least 10 about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of any one of SEQ ID NO: 945 to SEQ ID NO: 948, or any one of SEQ ID NO: 930, SEQ ID NO: 805, or SEQ ID NO: 931. EVQLQQSGAELVRPGASVKLSCTASGVNIKDDYMNWVNQRPEQG Heavy chain SEQ ID NO: 938 LEWIGWIDPENGDTEYASKFQGKATITADTSSNTAYLQLSSLTSED variable g in SEQ ID NO: 944 QSPKLLIHKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYY variable 15 In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising (i) a variable heavy domain 260

[0260] region comprising the amino acid sequence of SEQ ID NO: 949, (ii) a variable light domain region comprising the amino acid sequence of SEQ ID NO: 955, or (iii) a variable heavy domain region comprising the amino acid sequence of SEQ ID NO: 949 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 955. 5 In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising (i) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of SEQ ID NO: 949, (ii) a variable light domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology 10 to the amino acid sequence of SEQ ID NO: 955, or (iii) a variable heavy domain region comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to the amino acid sequence of SEQ ID NO: 949 and a variable light domain region comprising the amino acid sequence of SEQ ID NO: 955. QIQLVQSGPELKKPGETVKISCTTSGYIFTTSGMSWVKQAPGKGLQWM Heavy chain SEQ ID NO: 949 GWINTYSGEPTYADDFKGRFAFSLETSASTAYLHINDLKNEDTATYFCA variable Q Q Q QQ Q g c ain SEQ ID NO: 955 SPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQY variable 15 261

[0261] In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising any one of SEQ ID NO: 960 to SEQ ID NO: 1039. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid 5 sequence with at least about 80%, 85%, 90%, or even 95% homology to any one of SEQ ID NO: 960 to SEQ ID NO: 1039. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least about 90% homology to any one of SEQ ID NO: 960 to SEQ ID NO: 1039. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is 10 an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least about 95% homology to any one of SEQ ID NO: 960 to SEQ ID NO: 1039. QVQLVQSGAEVKKPGASVKVSCKAS GYIFTTSGMS WVRQAPGQRLEWMG SEQ ID NO: 960 WINTYSGEPT YSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCAR G R G R G R G R G R G R G R G R G R G R 262

[0262] EIQLVQSGAEVKKPGASVKVSCKTS GYIFTTSGMS WVRQAPGQRLEWMG SEQ ID NO: 971 WINTYSGEPT YSQKFQGRVTITLDTSASTAYMELSSLRSEDTAVYYCAR SRNNYEGFAY WGQGTLVTVSS G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R 263

[0263] EVQLVQSGAEVKKPGASVKVSCKTS GYIFTTSGMS WVRQAPGQRLEWMG SEQ ID NO: 988 WINTYSGEPT YADSFKGRVTITLDTSASTAYMELSSLRSEDTATYYCAR SRNNYEGFAY WGQGTLVTVSS G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R 264

[0264] EVQLVQSGAEVKKPGASVKVSCKAS GYIFTTSGMS WVRQAPGQRLEWMG SEQ ID NO: 1005 WINTYSGEPT YSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYFCAR SRNNYEGFAY WGQGTLVTVSS G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R 265

[0265] QVQLVQSGAEVKKPGASVKISCKTS GYIFTTSGMS WVRQAPGQRLEWMG SEQ ID NO: 1022 WINTYSGEPT YSQKFQGRFTFTLDTSASTAYLEISSLRSEDTATYFCAR SRNNYEGFAY WGQGTLVTVSS G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R G R 266

[0266] In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising any one of SEQ ID NO: 1040 to SEQ ID NO: 1055. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising a CDRH2 5 selected from any one of SEQ ID NO: 1040 to SEQ ID NO: 1055. SEQ ID NO: 1040HINTYSGEPTSEQ ID NO: 1041YINTYSGEPT In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising any one of SEQ ID NO: 1056 to SEQ ID NO: 1070. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting 10 Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising a CDRH3 selected from any one of SEQ ID NO: 1056 to SEQ ID NO: 1070. SEQ ID NO: 1056 SRQNYEGFAY 267

[0267] SEQ ID NO: 1063 SRNSYEGFAY SEQ ID NO: 1064 SRQSYEGFAY , - nding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising any one of SEQ ID NO: 1071 to SEQ ID NO: 1190. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting 5 Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least about 80%, 85%, 90%, or even 95% homology to any one of SEQ ID NO: 1071 to SEQ ID NO: 1190. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least about 90% homology to any one of SEQ ID NO: 1071 to SEQ 10 ID NO: 1190. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising an amino acid sequence with at least about 95% homology to any one of SEQ ID NO: 1071 to SEQ ID NO: 1190. DIVMTQSPDSLAVSLGERATINC KSSQSLLYSSNQKNYLA WYQQKPGQPPKLLIY 268

[0268] WASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC QQYYLYPLT FGQGTKLEIK 269

[0269] WASTRES GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC QQYYLYPLT FGQGTKLELK Q, Q, 270

[0270] DIVMTQSPDSLAVSLGERVTMNC KSSQSLLYSSXQKNYLA WFQQKPGQPPKLLIY SEQ ID NO: 1097 WASTRES Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, 271

[0271] DIVMTQSPDSLAVSLGERATINC KSSQSLLYSSXQKNYLA WFQQKPGQPPKLLIY SEQ ID NO: 1108 WASTRES Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, 272

[0272] DIVMTQSPDSLAVSLGERATINC Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, 273

[0273] GVPDRFSGSGSGTDFTLTISSLQAEDLAVYYC QQYYLYPLT FGQGTKLEIK DIVMTQSPDSLAVSLGERVTMNC Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, Q, 274

[0274] GVPDRFSGSGSGTDFTLTISSLQAEDLAVYYC QQYYLYPLT FGQGTKLELK DIVMTQSPDSLAVSLGERATINC Q, Q, re N, re N, re N, re N, re N, re N, re N, re N, 275

[0275] DIVMTQSPDSLAVSLGERVTMNC KSSQSLLYSSXQKX2YLA WFQQKPGQPPKLLIY SEQ ID NO: 1151 WASTRES wherein X and X2are N, re N, re N, re N, re N, re N, re N, re N, re N, re N, re N, 276

[0276] DIVMTQSPDSLAVSLGERATINC KSSQSLLYSSXQK X2YLA WFQQKPGQPPKLLIY SEQ ID NO: 1162 WASTRES wherein X and X2are N, re N, re N, re N, re N, re N, ed re N, ed re N, ed re N, ed re N, ed re N, 277

[0277] GVPDRFSGSGSGTDFTLTISSVQAEDVAVYYC Q, S, A, and D; and X3is selected QQYYLYPLT FGQGTKLEIK from W, H, Y, and F DIVMTQSPDSLAVSLGERATINC re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed re N, 278

[0278] GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC Q, S, A, and D; and X3is selected QQYYLYPLT FGQGTKLELK from W, H, Y, and F DIVMTQSPDSLAVSLGERVTMNC re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed re N, ed In certain embodiments, X is N. In certain embodiments, X is Q. In certain embodiments, X is S. 5 In certain embodiments, X is A. In certain embodiments, X2is D. In certain embodiments, X2is N. In certain embodiments, X2is Q. In certain embodiments, X2is S. 10 In certain embodiments, X2is A. 279

[0279] In certain embodiments, X2is D. In certain embodiments, X3is W. In certain embodiments, X3is H. In certain embodiments, X3is Y. 5 In certain embodiments, X3is F. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising any one of SEQ ID NO: 1191 to SEQ ID NO: 1194. In certain embodiments, the sFLT-1 binding Extracellular Protein Targeting Ligand is an antibody, antibody fragment, or sFLT-1 binding moiety comprising a CDRL2 selected 10 from any one of SEQ ID NO: 1191 to SEQ ID NO: 1194. SEQ ID NO: 1191WASTRFSSEQ ID NO: 1192HASTRES In certain embodiments, the Extracellular Protein Targeting Ligand is an sFLT-1 binding moiety described in WO 2021 / 118957. In certain embodiments, the Extracellular Protein Targeting Ligand is an sFLT-1 antibody 15 or sFLT-1-binding fragment thereof that binds to an epitope on hum...

Claims

1. CLAIMS We Claim:

1. An extracellular protein degrading compound of Formula: ) ) B) 678wherein the ASGPR Binding Ligand is selected from: , ;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 one of R1, R1b, and R5is replaced with a bond to LinkerA; zz is selected from 1, 2, 3, 4, 5, or 6; Lis selected from ;R3, R3a, R3b, andhydrogen, 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; 679R10is 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; R76is selected from 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; 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, 680C0-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; is heteroaryl or phenyl;is selected from ndth n substituents independently selected from R75and one R1substituent; 6-membered heteroaryl optionaselected 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; and 681Extracellular Protein Targeting Ligand is a peptide or antibody described herein that binds to an extracellular protein described herein.

2. The compound of claim 1, wherein the ASGPR Binding Ligand is selected from: ,.. , of Formula .6825. The compound of any one of claims 1-3, of Formula . 6.e co pou o ay oe o ca s -, wee g igand is selected from: .

7. The compound of any one of claims 1-6, wherei .

8. The compound of any one of claims 1-6, wherei .

9. The compound of any one of claims 1-6, wherei is a 6-membered heteroaryl.

10. An extracellular protein degrading compound oformula I-X, Formula II-X, or Formula III- X: X)) X);ywherein the ASGPR Binding LigandB is selecte,;,686or ASGPR Binding LigandBis selected from: ; yl, 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; 687L is selected from and ;R3, R3a, R3b, R3c, e 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, ,C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, and C2-C4 alkynyl; , and R67Bare independently selected at each instance from hydrogen,o, 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 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, 688and 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; q is 1, 2, or 3; s heteroaryl or phenyl;is aryl, heterocycle, cycloalkyl, or heteroaryl, optionally substituted with R75B, R76B, R77B, a8B; is aryl, heterocycle, cycloalkyl, bicycle, or heteroaryl;is aryl or heteroaryl;is a bicycle or spirocycle;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.

11. The compound of claim 10, wherein ASGPR Binding LigandBis selected from: ,, ,,,; ,; or A s selected from:.

12. The compound of claim 10, wherei .69213. The compound of claim 10, wherei .

14. The compound of claim 10, wherei .

15. The compound of any one of claims 1-14, wherein L is selected fro ,.

16. The compound of any one of claims 1-14, wherein L is selected fro and.

17. The compound of claim 10, wherein ASGPR LigandBis9318. The compound of any one of claims 10-14, wherei is selected fromnd19. The compound of any one of claims 10-14, wherei is selected fromnd20. The compound of any one of claims 10-14, wherei is selected from.

421. The compound of any one of claims 10-14, wherei is selected from,kyl, 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.

24. The compound of any one of claims 10-22, 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.

25. The compound of any one of claims 10-22, 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 695which is optionally substituted with 1 or 2 substituents independently selected at each occurrence from R102.

26. The compound of any one of claims 10-22, 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.

27. The compound of any one of claims 1-26, wherei is a 6-membered heteroaryl.

28. The compound of any one of claims 1-26, wherei is selected from,29. The compound of any one of claims 1-26, wherei is selected from, ,696,30. The compound of any one of claims 1-26, wherei is a 5-membered heteroaryl.

31. The compound of any one of claims 1-26, wherei is a bicyclic heteroaryl.

32. The compound of any one of claims 1-26, wherei .

33. The compound of any one of claims 1-31, wherei34. The compound of any one of claims 1-33, wherein R10is hydrogen.

35. The compound of any one of claims 1-34, 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.

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

39. The compound of any one of claims 1-38, 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. 69740. The compound of any one of claims 1-38, wherein R7is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

41. The compound of any one of claims 1-38, wherein R7is independently selected at each occurrence from hydrogen, alkyl, heterocycle, -alkyl-OR8, -alkyl-NR8R9, and C(O)R3.

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

43. The compound of any one of claims 1-42, wherein R8is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, and heterocycle.

44. The compound of any one of claims 1-42, wherein R8is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, and heterocycle.

45. The compound of any one of claims 1-42, wherein R8is independently selected at each occurrence from hydrogen and alkyl.

46. The compound of any one of claims 1-45, wherein R9is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, and heterocycle.

47. The compound of any one of claims 1-45, wherein R9is independently selected at each occurrence from hydrogen, alkyl, aryl, heteroaryl, and heterocycle.

48. The compound of any one of claims 1-45, wherein R9is independently selected at each occurrence from hydrogen and alkyl.

49. The compound of any one of claims 1-48, wherein R1is replaced with a bond to LinkerA.

50. The compound of any one of claims 1-48, wherein R1bis replaced with a bond to LinkerA.

51. The compound of any one of claims 1-48, wherein R5is replaced with a bond to LinkerA.

52. The compound of any one of claims 1-51, wherein LinkerAis bond and LinkerBis ; wheR11, 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-, 698-[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.

53. The compound of any one of claims 1-51, wherein LinkerBis bond and LinkerAis ; wheR11, 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.

54. The compound of any one of claims 52-53, wherein is55. The compound of any one of claims 52-53, wherein is 56.ein is 57.ein is ein , , , ,, , and 59. Thare independently selected from bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR6-, -NR6C(O)-, -O-, -S-, -NR6-, -C(R21R21)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, and -CH2CH2-[O-(CH2)2]n-O-.

60. The compound of any one of claims 52-58, wherein R11is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-.

61. The compound of any one of claims 52-58, wherein R20is selected from the group consisting of bond, CH2, -O-, -C(O)NR6- and -C(O)O-.

62. The compound of any one of claims 52-61, wherein ofxx ein is 17, R18, R19, and R20are bond.

65. The compound of any one of claims 52-63, wherein two of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

66. The compound of any one of claims 52-63, wherein three of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

67. The compound of any one of claims 52-63, wherein four of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

68. The compound of any one of claims 52-63, wherein five of R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20are bond.

69. The compound of any one of claims 1-68, wherein LinkerCis selected from: .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.

70. The compound of claim 69, wherein R22is selected from -C(O)N-, -NC(O)-, -N-, and -C(R21)- . ted.

73. ms 1-68, 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-;.

74. The compound of 73, wherein is selected fro ,. 4om705.

76. The g Ligandbinds to an immunoglobulin.

77. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgG.

78. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgG1.

79. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgG2.

80. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgG3.

81. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgG4.

82. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgG1, IgG2, and IgG4.

83. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgA.

84. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgA1.

85. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to (i) a galactose-deficient IgA1, (ii) a galactose-deficient fragment of IgA1, (iii) a galactose-deficient polypeptide corresponding to the hinge region of IgA1 or (iv) a galactose-deficient fragment of a polypeptide corresponding to the hinge region of IgA1. 70686. The compound of any one of claims 1-75 or 85, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient IgA1.

87. The compound of any one of claims 1-75 or 85, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient fragment of IgA1.

88. The compound of any one of claims 1-75 or 85, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient polypeptide corresponding to the hinge region of IgA1.

89. The compound of any one of claims 1-75 or 85, wherein the Extracellular Protein Targeting Ligand has at least 95% sequence identity to a galactose-deficient fragment of a polypeptide corresponding to the hinge region of IgA1.

90. The compound of any one of claims 1-75 or 85-89, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 95% sequence identity to a polypeptide selected from any one of SEQ ID NOs 42-92.

91. The compound of any one of claims 1-75 or 85-89, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 96% sequence identity to a polypeptide selected from any one of SEQ ID NOs 42-92.

92. The compound of any one of claims 1-75 or 85-89, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 97% sequence identity to a polypeptide selected from any one of SEQ ID NOs 42-92.

93. The compound of any one of claims 1-75 or 85-89, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 98% sequence identity to a polypeptide selected from any one of SEQ ID NOs 42-92.

94. The compound of any one of claims 1-75 or 85-89, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that has at least 99% sequence identity to a polypeptide selected from any one of SEQ ID NOs 42-92.

95. The compound of any one of claims 1-75 or 85-89, wherein the Extracellular Protein Targeting Ligand is or comprises an amino acid that is a polypeptide selected from any one of SEQ ID NOs 42-92.

96. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises one GalNAc. 70797. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises two GalNAcs.

98. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises three GalNAcs.

99. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises four GalNAcs.

100. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises five GalNAcs.

101. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises six GalNAcs.

102. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises seven GalNAcs.

103. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises eight GalNAcs.

104. The compound of any one of claims 1-75 or 85-95, wherein the Extracellular Protein Targeting Ligand comprises nine GalNAcs.

105. The compound of any one of claims 96-104, wherein the GalNAcs are O-linked through serines.

106. The compound of any one of claims 96-104, wherein the GalNAcs are O-linked through threonines.

107. The compound of any one of claims 96-104, wherein the GalNAcs are O-linked through serines and threonines.

108. The compound of any one of claims 1-75 or 85-107, wherein the Extracellular Protein Targeting Ligand is attached to the Linker through the C-terminus.

109. The compound of any one of claims 1-75 or 85-107, wherein the Extracellular Protein Targeting Ligand is attached to the Linker through the N-terminus.

110. The compound of any one of claims 1-75 or 85-107, wherein the Extracellular Protein Targeting Ligand is an antibody which is attached to the Linker through a nonbinding portion of the antibody.

111. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IgE. 708112. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to an autoantibody.

113. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to an autoantibody that binds to the beta-1 adrenergic receptor.

114. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to an autoantibody that binds to VEGFR-1 115. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to an autoantibody that binds to ACPA.

116. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to an autoantibody that binds to desmoglein-2.

117. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to an autoantibody that binds to ApoE.

118. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to anti-nicotinic acetylcholine receptor (AChR) autoantibodies.

119. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to anti-muscle-specific kinase (MUSK) autoantibodies.

120. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to anti-aquaporin-4 autoantibodies.

121. The compound of any one of claims 1-75 or 112, wherein the Extracellular Protein Targeting Ligand binds to anti-phospholipase A2 receptor autoantibodies.

122. The compound of any one of claims 112-121, wherein the Extracellular Protein Targeting Ligand binds to IgG autoantibodies.

123. The compound of any one of claims 112-121, wherein the Extracellular Protein Targeting Ligand binds to IgA autoantibodies.

124. The compound of any one of claims 112-121, wherein the Extracellular Protein Targeting Ligand binds to IgM autoantibodies.

125. The compound of any one of claims 112-121, wherein the Extracellular Protein Targeting Ligand binds to IgE autoantibodies.

126. The compound of any one of claims 1-75, wherein the Extracellular Protein Targeting Ligand binds to IL-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-17, IL-21, or IL-22. 709127. A pharmaceutical composition comprising a compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

128. The pharmaceutical composition of claim 127, for oral administration.

129. The pharmaceutical composition of claim 127, for subcutaneous administration.

130. The pharmaceutical composition of claim 127, for intramuscular administration.

131. The pharmaceutical composition of claim 127, for intravenous administration.

132. A method of treating a disease mediated by an extracellular protein comprising administering an effective amount of a compound of any one of claims 1-126 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 127-131, to a patient in need thereof.

133. The method of treatment of claim 132, wherein the disease is an autoimmune disease.

134. The method of treatment of claim 132, wherein the disease is a hyperproliferative disease.

135. The method of treatment of claim 132, 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.

136. The method of treatment of claim 132, 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 710of undetermined significance (MGUS), linear IgA bullous dermatosis, rheumatoid arthritis, ulcerative colitis, and primary glomerulonephritis.

137. The method of treatment of claim 132, 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.

138. The method of treatment of claim 132, 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 711syndrome, 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.

139. The method of treatment of claim 132, wherein the extracellular protein is TNF-α and the disease is selected from rheumatoid arthritis, inflammatory bowel disease, graft-vs-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupis erthyematosus, diabetes, and the induction of cachexia.

140. The method of treatment of claim 132, wherein the disorder is dilated cardiomyopathy.

141. Use of a compound of any one of claims 1-126 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 127-131, in the treatment of a disease mediated by an extracellular protein.

142. Use of a compound of any one of claims 1-126 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 127-131, in the manufacture of a medicament to treat a disease mediated by an extracellular protein.

143. The use of claim 141 or 142, wherein the disease is an autoimmune disease. 712144. The use of claim 141 or 142, wherein the disease is a hyperproliferative disease.

145. The use of claim 141 or 142, 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.

146. The use of claim 141 or 142, 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.

147. The use of claim 141 or 142, 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, 713monoclonal 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.

148. The use of claim 141 or 142, 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 714conjunctivitis, 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.

149. The use of claim 141 or 142, wherein the extracellular protein is TNF-α and the disease is selected from rheumatoid arthritis, inflammatory bowel disease, graft-vs-host disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, refractory asthma, systemic lupis erthyematosus, diabetes, and the induction of cachexia.

150. The use of claim 141 or 142, wherein the disorder is dilated cardiomyopathy. 715

Images