Cycling lysosomal targeting chimeras targeting immunoglobulin e (IGE)

Abstract

The present disclosure provides conjugates comprising a moiety that targets a lysosomal targeting molecule, a linker, and an antibody that specifically binds a cell surface target molecule or extracellular target molecule that is targeted for degradation.

Description

[0001] CYCLING LYSOSOMAL TARGETING CHIMERAS TARGETING IMMUNOGLOBULIN E (IGE) CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of United States Provisional Application No.63 / 669,657, filed July 10, 2024, which is hereby incorporated by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING The contents of the electronic sequence listing (92VF-385437-WO.xml; Size: 270,401 bytes; and Date of Creation: July 3, 2025) is herein incorporated by reference in its entirety. BACKGROUND Many therapeutics act by binding a functionally important site on a target protein, thereby modulating the activity of that protein, or by recruiting immune effectors, as with many monoclonal antibody drugs, to act upon the target protein. However, there is an untapped reservoir of medically important human proteins that are considered to be “undruggable” because these proteins are not readily amenable to currently available therapeutic targeting approaches. Thus, there is a need for therapies that can target a wider range of proteins. SUMMARY The present disclosure provides a class of lysosomal targeting chimeras (also referred to herein as LYTACs and conjugate compounds) that target immunoglobulin E (IgE). Structurally, such LYTACs include a ligand moiety that binds to a lysosomal targeting molecule (e.g., a receptor) and an antibody or antibody fragment that binds to a target, as disclosed herein, IgE. Cycling LYTACs are also described in International Patent Application No. PCT / US2024 / 011897. The conjugates can facilitate degradation of a target and can repeatedly “cycle” into and out of a cell. Such cycling enables duration of activity on the order of hours to days, and enables a single LYTAC to facilitate lysosomal degradation of multiple targets. A potential advantage of cycling LYTACs over other protein degraders is their ability to facilitate the degradation of targets such as IgE that are in high abundance or that regenerate rapidly. Such cycling LYTACs may offer therapeutic benefits over approved therapies or therapies currently being developed. This disclosure provides a class of conjugate compounds that include a ligand moiety, X, that binds to a lysosomal targeting molecule conjugated to target-binding moiety, Y, that binds and an antibody that specifically binds to a cell surface target molecule or extracellular target molecule. In some embodiments, the conjugate is configured to exhibit extended activity and / or super- stoichiometric clearance of a target in a biological system. The conjugates described herein facilitate transport of a target molecule into a cell and may facilitate sequestration and / or degradation of a target molecule of interest in a cell’s lysosome. In some embodiments, binding of the ligand moiety to the lysosomal targeting molecule can trigger internalization of the lysosomal targeting molecule and conjugate. In one embodiment, is provided a ligand moiety conjugated via a linker to a target-binding moiety wherein the ligand moiety binds a lysosomal targeting molecule extracellularly; the target-binding moiety binds a target molecule extracellularly; the target-binding moiety dissociates from the target molecular intraendosomally and the conjugate is externalized from a cell. In some embodiments, the conjugate comprises a target-binding moiety having a higher binding affinity for the target molecule at an extracellular pH than at an intraendosomal pH, while at the same time, having one or more of: a) a target-binding moiety having a higher affinity for FcRn at an intraendosomal pH than at an extracellular pH; b) a ligand moiety, X, having an equal binding affinity for the lysosomal targeting molecule extracellularly and intraendosomally; c) a ligand moiety, X, having an equal binding affinity for the lysosomal targeting molecule at an extracellular pH and at an intraendosomal pH; and / or d) a ligand moiety, X, having an equal binding affinity for the lysosomal targeting molecule at an extracellular Ca2+concentration and at an intraendosomal Ca2+concentration. In some embodiments, the conjugate exhibits duration of activity on the order of hours to days. In one embodiment, is provided a ligand moiety, X, conjugated via a linker, L, to a target-binding moiety, Y, wherein the ligand moiety, X, binds a lysosomal targeting molecule extracellularly; the target-binding moiety, Y, binds a target molecule extracellularly; the target-binding moiety, Y, dissociates from the target molecular intraendosomally and the conjugate is externalized from a cell. In some embodiments, Y is an antibody or an antibody fragment. The conjugates of this disclosure comprise an antibody or antigen-binding fragment moiety (Y) that exhibits pH-dependent binding characteristics towards IgE. In some embodiments, the antibody or antigen-binding fragment moiety (Y) as used herein is a mutant form of omalizumab or ligelizumab. These mutants include mutants wherein one or more amino acids of the parent omalizumab or ligelizumab sequences have been changed to a histidine. Certain mutant antibodies and antibody fragments described herein which exhibit pH-dependent binding characteristics towards IgE have weaker binding to IgE at acidic pH than at a neutral pH. Certain mutant antibodies and antibody fragments described herein which exhibit pH-dependent binding characteristics towards IgE have faster dissociation rates with IgE at acidic pH than at a neutral pH. In some embodiments, binding of the ligand moiety to the lysosomal targeting molecule can trigger internalization of the lysosomal targeting molecule and conjugate. In some embodiments, the antibody conjugate (LYTAC) is configured to exhibit extended activity and / or super-stoichiometric clearance of a target in a biological system. “Super-stoichiometric clearance” refers to conjugates facilitating a greater than stoichiometric ratio of target molecule removed from the extracellular environment to the amount of conjugate administered, i.e., where the conjugate facilitates degradation of a molar excess of target relative to the conjugate. The compound or conjugate is capable of binding a target molecule extracellularly, internalizing the target molecule, and releasing the target molecule such that the target molecule is destroyed in the lysosome, and the compound or conjugate is externalized and capable of repeating the process. As such, the ratio of compound or conjugate administered is less than the amount of target molecule cleared or removed from the extracellular environment. Also provided herein are compositions comprising such conjugates and methods of using the conjugates to target a polypeptide or molecule of interest for sequestration and / or lysosomal degradation, and methods of using the conjugates. In one aspect, provided herein is a conjugate that comprises a ligand moiety, X, conjugated to a target-binding moiety, Y, via a linker, L; wherein the ligand moiety, X, binds a lysosomal targeting molecule extracellularly; the target-binding moiety, Y, which binds IgE extracellularly; the target-binding moiety, Y, dissociates from the IgE intraendosomally; and the conjugate is externalized from a cell; further wherein the target-binding moiety comprises an antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 64, 73, 95, 99, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 49, 51, 52, 53, 54, 66, 91, 92, 93, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 33, 55 and 100b of a heavy chain variable region (VH) and 31, 94 and 50 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 100e, of a heavy chain variable region (VH) and 29, 49, 51, 53, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD(acidic pH / neutral pH) ratio greater than 20. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD(acidic pH / neutral pH) ratio greater than 50. In some embodiments, the antibody or fragment thereof binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH. In some embodiments, the antibody or fragment thereof binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH with a koff(acidic pH / neutral pH) ratio greater than 2. In some embodiments, the antibody or fragment thereof binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH with a koff(acidic pH / neutral pH) ratio greater than 3. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD(lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 210; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 211 or 216, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 211 or 216; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 212 or 217; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 213, 218, 219, 220, or 221; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 214, 222, 223, or 224; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 215 or 225, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 215 or 225, wherein each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 does not comprise SEQ ID NO: 210, 211, 212, 213, 214, and 215, respectively. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 1.1. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 1.5. In some embodiments, the antibody or fragment thereof comprises a heavy chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of K64, D73, and W100b, according to Kabat numbering. In some embodiments, the antibody or fragment thereof comprises a light chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of D27c, G29, D30, S31, Y49, A50, A51, Y53, G66, and S91, according to Kabat numbering. In some embodiments, the at least one amino acid of the antibody or fragment thereof is replaced with a histidine is selected from S31, Y49 and Y53, according to Kabat numbering. In some embodiments, the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1, 46 or an amino acid sequence having at least 90% amino acid sequence identity to SEQ ID NO: 1 or 46, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 51, 63, 67, 71, 89, 90, 91, 92 or an amino acid sequence having at least 90% amino acid sequence identity to SEQ ID NO: 51, 63, 67, 71, 89, 90, 91, 92. In some embodiments, the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1 or 46, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 51, 63, 67, 71, 89, 90, 91, or 92. In some embodiments, the antibody or fragment thereof comprises a VH / VLamino acid sequence pair comprises the amino acid sequence pair of any one of SEQ ID Nos: 1 / 89, 1 / 90, 1 / 91, 1 / 92, 46 / 63, 46 / 67, 46 / 71, 46 / 89, 46 / 90, 46 / 91, 46 / 92. In some embodiments, the antibody or fragment thereof comprises: (a) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 214, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 215; (b) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 224, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 215; (c) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO:217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 224, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 215; or (d) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO:217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 224, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 214. the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 226, 232, 233, 234, or 235, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 226, 232, 233, 234, or 235; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 227, 236, 237, 238, or 239, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 227, 236, 237, 238, or 239; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 229, 246, or 247, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 229, 246, or 247; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 230, 248, 249, 250, 251, or 281, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 230, 248, 249, 250, 251, or 281; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, wherein each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 does not comprise SEQ ID NO: 226, 227, 228, 229, 230, and 231, respectively. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD(acidic pH / neutral pH) ratio greater than 20. In some embodiments, the antibody or fragment thereof comprises a heavy chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of W31, E35, D52, G53, T54, F55, F95, S99, D100d, Y100e, and D101. In some embodiments, the antibody or fragment thereof comprises a light chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of A25, I29, A51, S52, S54, S91, W92, S93, W94, T96, and T97. In some embodiments, the antibody or fragment thereof comprises at least one amino acid substitution with a histidine at positions selected from the group consisting of W31 (heavy chain), Y100e (heavy chain), I29 (light chain), A51 (light chain), T96 (light chain), and T97 (light chain). In some embodiments, the antibody or fragment thereof comprises: (a) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256; (b) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 247, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 281, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231; (c) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 282, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257; (d) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 243, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257; or (e) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 245, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 249, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231. In some embodiments, the antibody or fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH / VLamino acid sequence pair comprises the amino acid sequence pair of any one of SEQ ID NOs: 96 / 175, 96 / 176, 96 / 180, 96 / 185, 158 / 143, 158 / 156, 158 / 179, 159 / 181, 161 / 136, 161 / 181, 162 / 143, 162 / 156, 164 / 130, 165 / 142, 165 / 157, 166 / 157, 166 / 181, 167 / 143. 167 / 157, or 168 / 130. In one aspect, provided herein is an conjugate thereof, wherein the antibody or fragment thereof binds IgE at a higher KD(lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 210; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 211 or 216, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 211 or 216; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 212 or 217; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 213, 218, 219, 220, or 221; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 214, 222, 223, or 224; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 215 or 225, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 215 or 225, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 64 and 73 of a heavy chain variable region (VH) and 27c, 29, 30, 49, 50, 51, 53, 66, and 91of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof further comprises histidine at one or more amino acid positions selected from the group consisting of: 100b of a heavy chain variable region (VH) and 31 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 226, 232, 233, 234, or 235, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 226, 232, 233, 234, or 235; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 227, 236, 237, 238, or 239, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 227, 236, 237, 238, or 239; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 229, 246, or 247, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 229, 246, or 247; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 230, 248, 249, 250, 251, or 281, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 230, 248, 249, 250, 251, or 281; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 55, 95, 99, 100d, 100e, 101 of a heavy chain variable region (VH) and 25, 29, 51, 52, 54, 91, 92, 93, 94, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof further comprises histidine at one or more amino acid positions selected from the group consisting of: 33, 58, 100b, 100c of a heavy chain variable region (VH) and 50 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the conjugate is of Formula I: a prodrug thereof, or a or a pharmaceutically acceptable salt thereof, wherein: n is 1 to 500; m is 1 to 20; each X is independently the ligand moiety; and Y is the target-binding moiety. In some embodiments, the lysosomal targeting molecule is a cell surface receptor that provides for internalization of the conjugate. In some embodiments, the lysosomal targeting molecule is selected from asialoglycoprotein receptor (ASGPR), cation independent mannose-6-phosphate receptor (CI-M6PR also referred to herein as M6PR), folate receptor, LDLR, CD63, sortilin, IFITM3, molecules in the endosome / lysosome pathway, LIMP-1, and LIMP-2. In some embodiments, X is a moiety that binds ASGPR or M6PR. In some embodiments, X is a moiety that binds ASGPR. In some embodiments, the conjugate is of Formula I: I or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 1 to 500; m is 1 to 20; L is a linker; and X is an asialoglycoprotein receptor (ASGPR) binding moiety of Formula wherein: R1is selected from -Z1-*, -H, - OH, optionally substituted (C1-C6)alkyl, -OCH3,-OCH2CH=CH, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, and optionally substituted -S-heteroaryl; R2is selected from -Z1-*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, - NHR, and optionally substituted triazole; R6is selected from -Z1-*, -OH, -OR, optionally substituted (C1- C6)alkyl, -OC(O)R, -C(O)NHR, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl, - NHCOR, and -NRCOR; each R is independently optionally substituted (C1-C6)alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rxxand Ryyare independently H, optionally substituted (C1-C6)alkyl, or Rxxand Ryycan cyclize to form an optionally substituted heterocyclyl; wherein one of R1, R2, and R6is -Z1-*; R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally , In some embodiments, X is represented by Formula A-II: . In some embodiments, R1is –Z1–*, –H, –NHCOCH3, or (C1-C6)alkyl. In some embodiments, R3and R4are each –H. In some embodiments, X is a moiety that binds to M6PR. In some embodiments, X is of Formula IV: wherein: W is a non-hydrolyzable hydrophilic head group; Z1is selected from optionally substituted (C1-C3)alkylene and optionally substituted ethenylene; Z2is selected from S, NR21and C(R22)2, wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl, and each R22is independently selected from H, halogen and optionally substituted (C1-C6)alkyl; each A is independently an optionally substituted aryl or heteroaryl linking moiety; and each Z3is independently a linking moiety. In some embodiments, Z2is S. In some embodiments, W is phosphonate, thiophosphonate, carboxylic or malonic acid, or a salt thereof. In some embodiments, X is: wherein Ra, Rb, Rcand Rdare independently H or F. In some embodiments, X is: wherein Ra, Rb, Rcand Rdare independently H or F. In some embodiments, A is optionally substituted aryl or optionally substituted heteroaryl, preferably A is independently selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted triazole and optionally substituted phenylene-triazole. In some embodiments, L comprises of 10 to 60 consecutive branched or linear chain atoms. In some embodiments, L is of formula (IIb’): wherein: n is 1, 2, or 3; each L1to L6is independently a linker component which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** represents the point of attachment to L1of X via Z1; and *** represents the point of attachment to Y. In some embodiments, each L1to L5independently comprises one or more linker components independently selected from –C1-20-alkylene–, –NHC(O)-C1-6-alkylene–, –C(O)NH-C1-6-alkylene–, –NH- C1-6-alkylene–, –NHC(O)NH-C1-6-alkylene–, –NHC(S)NH-C1-6-alkylene–, –C1-6-alkylene–NHC(O)-, –C1-6-alkylene–C(O)NH-, –C1-6-alkylene–NH-, –C1-6-alkylene–NHC(O)NH-, –C1-6-alkylene–NHC(S)NH-, -O(CH2)p–, –(OCH2CH2)p–, –NHC(O)–, –C(O)NH–, –NHS(O)2–, –S(O)2NH–, –C(O)–, –S(O)2–, –O–, –S–, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, –NH–, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently 1 to 50; L6is a linking group comprising one or more linker components independently selected from –C1-20-alkylene–, –NR16C(O)-C1-6-alkylene–, –C(O)NR16-C1-6-alkylene–, –NR16-C1-6-alkylene–, –NR16C(O)NR16-C1-6-alkylene–, –NR16C(S)NR16-C1-6-alkylene–, –C1-6-alkylene–NR16C(O)-, –C1-6-alkylene–C(O)NR16-, –C1-6-alkylene–NR16-, –C1-6-alkylene–NR16C(O)N R16-, –C1-6-alkylene– NR16C(S)NR16-, -O(CH2)p–, –(OCH2CH2)p–, –NR16C(O)–, –C(O)NR16–, –NHS(O)2–, –S(O)2NH–, –C(O)–, –S(O)2–, –O–, –S–, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, or –NR16–; and each R16is independently –H, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted monocyclic heteroaryl or monocyclic heteroaryl. In some embodiments, each L1to L5is independently selected from –C1-20-alkylene–, –NHC(O)-C1-6- alkylene–, –C(O)NH-C1-6-alkylene–, –NH-C1-6-alkylene–, –NHC(O)NH-C1-6-alkylene–, –NHC(S)NH-C1-6-alkylene–, –C1-6-alkylene–NHC(O)-, –C1-6-alkylene–C(O)NH-, –C1-6-alkylene–NH-, –C1-6-alkylene–NHC(O)NH-, –C1-6-alkylene–NHC(S)NH-, -O(CH2)p–, –(OCH2CH2)p–, –NHC(O)–, –C(O)NH–, –NHS(O)2–, –S(O)2NH–, –C(O)–, –S(O)2–, –O–, –S–, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently 1 to 50; and , In one aspect, provided herein is a method of degrading a target molecule in a subject in need thereof, comprising administering an effective amount of a conjugate of any preceding claim to the subject. In some embodiments, at least 90% of the target is degraded at four days following the administration. In some embodiments, at least 90% of the target is degraded at seven days following the administration. In some embodiments, the extracellular concentration of the target is substantially maintained for a time period of at least four days, at an amount of at least 90% less than the initial extracellular concentration of the target prior to administering an effective amount of the conjugate. In some embodiments, the time period is seven days or more. In some embodiments, a super-stoichiometric target:conjugate ratio is degraded. In some embodiments, the ratio is at least about 5. In some embodiments, the target-binding moiety, Y, has a higher binding affinity for the target molecule extracellularly than intraendosomally. In some embodiments, the target is IgE. In one aspect, provided herein is a method of degrading a target molecule in a subject in need thereof, comprising administering an effective amount of a conjugate that comprises: a means for binding a lysosomal targeting molecule extracellularly; a means for binding a target molecule extracellularly; a means for dissociating from the target molecule intraendosomally; and wherein the conjugate is externalized from a cell. In some embodiments, the means for binding a lysosomal targeting molecule, remains bound to the lysosomal targeting molecule intraendosomally. In some embodiments, the means for binding a target molecule also binds FcRn intraendosomally; and optionally wherein the conjugate dissociates from the lysosomal targeting molecule intraendosomally. In one aspect, provided herein is a conjugate of Formula IA: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IB: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a compound of Formula IC:

[0002] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula ID: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IG: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a compound of Formula IH:

[0003] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IJ: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IK: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IL: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IM: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In some embodiments, Y is an antibody or fragment thereof comprising: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 161; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 181. In one aspect, provided herein is a conjugate of Formula IC:

[0004] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180. In one aspect, provided herein is a conjugate of Formula IC: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143. In one aspect, provided herein is a conjugate of Formula IC: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181. In one aspect, provided herein is a conjugate of Formula IC: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180. In one aspect, provided herein is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143. In one aspect, provided herein is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181. In one aspect, provided herein is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156. In one aspect, provided herein is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180. In one aspect, provided herein is a conjugate of Formula IF:

[0005] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143. In one aspect, provided herein is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181. In one aspect, provided herein is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. BRIEF DESCRIPTION OF THE DRAWINGS These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings: FIG.1 shows a graph of percent ratio of hIgE concentration to starting hIgE concentration in myeloma-transplanted mouse serum versus time following administration of LYTACs described herein. FIG.2 shows a graph of percent ratio of hIgE concentration to starting hIgE concentration in myeloma-transplanted mouse serum versus time following administration of conjugate P-421-2301 and P- 421-2327. DETAILED DESCRIPTION Definitions It is to be noted that the term “a” or “an” entity refers to one or more of that entity; for example, “an antibody,” is understood to represent one or more antibodies. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein. As used herein, the term “polypeptide” is intended to encompass a singular “polypeptide” as well as plural “polypeptides,” and refers to a molecule composed of monomers (amino acids) linearly linked by amide bonds (also known as peptide bonds). The term “polypeptide” refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product. Thus, peptides, dipeptides, tripeptides, oligopeptides, “protein,” “amino acid chain,” or any other term used to refer to a chain or chains of two or more amino acids, are included within the definition of “polypeptide,” and the term “polypeptide” may be used instead of, or interchangeably with any of these terms. The term “polypeptide” is also intended to refer to the products of post-expression modifications of the polypeptide, including without limitation glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, or modification by non- naturally occurring amino acids. A polypeptide may be derived from a natural biological source or produced by recombinant technology, but is not necessarily translated from a designated nucleic acid sequence. It may be generated in any manner, including by chemical synthesis. The term “isolated” as used herein with respect to cells, nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively, that are present in the natural source of the macromolecule. The term “isolated” as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Moreover, an “isolated nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to cells or polypeptides which are isolated from other cellular proteins or tissues. Isolated polypeptides is meant to encompass both purified and recombinant polypeptides. As used herein, the term “recombinant” as it pertains to polypeptides or polynucleotides intends a form of the polypeptide or polynucleotide that does not exist naturally, a non-limiting example of which can be created by combining polynucleotides or polypeptides that would not normally occur together. “Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence which may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non-homologous” sequence shares less than 40% identity, though preferably less than 25% identity, with one of the sequences of the present disclosure. A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) has a certain percentage (for example, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 %, 98 % or 99 %) of “sequence identity” to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in Ausubel et al. eds. (2007) Current Protocols in Molecular Biology. Preferably, default parameters are used for alignment. One alignment program is BLAST, using default parameters. In particular, programs are BLASTN and BLASTP, using the following default parameters: Genetic code = standard; filter = none; strand = both; cutoff = 60; expect = 10; Matrix = BLOSUM62; Descriptions = 50 sequences; sort by = HIGH SCORE; Databases = non-redundant, GenBank + EMBL + DDBJ + PDB + GenBank CDS translations + SwissProtein + SPupdate + PIR. Biologically equivalent polynucleotides are those having the above-noted specified percent homology and encoding a polypeptide having the same or similar biological activity. As used herein, a “target-binding moiety” refers to any antibody, antibody fragment, antigen- binding fragment, or antigen-binding polypeptide that specifically binds to a target or the antigen of a target. As used herein, an “antibody” or “antigen-binding polypeptide” refers to a polypeptide or a polypeptide complex that specifically recognizes and binds to an antigen. An antibody can be a whole antibody and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to the antigen. Examples of such include, but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein. The terms “antibody fragment” or “antigen-binding fragment,” as used herein, is a portion of an antibody such as F(ab')2, F(ab)2, Fab', Fab, Fv, scFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody. The term “antibody fragment” includes aptamers, spiegelmers, and diabodies. The term “antibody fragment” also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. A “single-chain variable fragment” or “scFv” refers to a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins. In some aspects, the regions are connected with a short linker peptide of ten to about 25 amino acids. The linker can be rich in glycine for flexibility, as well as serine or 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 the introduction of the linker. ScFv molecules are known in the art and are described, e.g., in US patent 5,892,019. The term antibody encompasses various broad classes of polypeptides that can be distinguished biochemically. Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon (γ, µ, α, δ, ε) with some subclasses among them (e.g., γ l- γ4). It is the nature of this chain that determines the “class” of the antibody as IgG, IgM, IgA IgG, or IgE, respectively. The immunoglobulin subclasses (isotypes) e.g., IgG1, IgG2, IgG3, IgG4, IgG5, etc. are well characterized and are known to confer functional specialization. Modified versions of each of these classes and isotypes are readily discernable to the skilled artisan in view of the instant disclosure and, accordingly, are within the scope of the instant disclosure. All immunoglobulin classes are clearly within the scope of the present disclosure, the following discussion will generally be directed to the IgG class of immunoglobulin molecules. With regard to IgG, a standard immunoglobulin molecule comprises two identical light chain polypeptides of molecular weight approximately 23,000 Daltons, and two identical heavy chain polypeptides of molecular weight 53,000-70,000. The four chains are typically joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region. Antibodies, antigen-binding polypeptides, variants, or derivatives thereof of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VK or VH domain, fragments produced by a Fab expression library, and anti- idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to LIGHT antibodies disclosed herein). Immunoglobulin or antibody molecules of the disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule. Light chains are classified as either kappa or lambda (Κ, λ). Each heavy chain class may be bound with either a kappa or lambda light chain. In general, the light and heavy chains are covalently bonded to each other, and the “tail” portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated either by hybridomas, B cells or genetically engineered host cells. In the heavy chain, the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain. Both the light and heavy chains are divided into regions of structural and functional homology. The terms “constant” and “variable” are used functionally. In this regard, it will be appreciated that the variable domains of both the light (VK) and heavy (VH) chain portions determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CK) and the heavy chain (CH1, CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. By convention, the numbering of the constant region domains increases as they become more distal from the antigen-binding site or amino- terminus of the antibody. The N-terminal portion is a variable region and at the C-terminal portion is a constant region; the CH3 and CK domains actually comprise the carboxy-terminus of the heavy and light chain, respectively. As indicated above, the variable region allows the antibody to selectively recognize and specifically bind epitopes on antigens. That is, the VK domain and VH domain, or subset of the complementarity determining regions (CDRs), of an antibody combine to form the variable region that defines a three dimensional antigen-binding site. This quaternary antibody structure forms the antigen- binding site present at the end of each arm of the Y. More specifically, the antigen-binding site is defined by three CDRs on each of the VH and VK chains (i.e., CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3). In some instances, e.g., certain immunoglobulin molecules derived from camelid species or engineered based on camelid immunoglobulins, a complete immunoglobulin molecule may consist of heavy chains only, with no light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993). In naturally occurring antibodies, the six “complementarity determining regions” or “CDRs” present in each antigen-binding domain are short, non-contiguous sequences of amino acids that are specifically positioned to form the antigen-binding domain as the antibody assumes its three dimensional configuration in an aqueous environment. The remainder of the amino acids in the antigen-binding domains, referred to as “framework” regions, show less inter-molecular variability. The framework regions largely adopt a β-sheet conformation and the CDRs form loops which connect, and in some cases form part of, the β -sheet structure. Thus, framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions. The antigen- binding domain formed by the positioned CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes the non-covalent binding of the antibody to its cognate epitope. The amino acids comprising the CDRs and the framework regions, respectively, can be readily identified for any given heavy or light chain variable region by one of ordinary skill in the art, since they have been precisely defined (see “Sequences of Proteins of Immunological Interest,” Kabat, E., et al., U.S. Department of Health and Human Services, (1983); and Chothia and Lesk, J. MoI. Biol., 196:901-917 (1987)). In the case where there are two or more definitions of a term which is used and / or accepted within the art, the definition of the term as used herein is intended to include all such meanings unless explicitly stated to the contrary. A specific example is the use of the term “complementarity determining region” (“CDR”) to describe the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. This particular region has been described by Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of Proteins of Immunological Interest” (1983) and by Chothia et al., J. MoI. Biol.196:901-917 (1987), which are incorporated herein by reference in their entireties. The CDR definitions according to Kabat and Chothia include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The appropriate amino acid residues which encompass the CDRs as defined by each of the above cited references are set forth in the table below as a comparison. The exact residue numbers which encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody. Kabat et al. also defined a numbering system for variable domain sequences that is applicable to any antibody. One of ordinary skill in the art can unambiguously assign this system of “Kabat numbering” to any variable domain sequence, without reliance on any experimental data beyond the sequence itself. As used herein, “Kabat numbering” refers to the numbering system set forth by Kabat et al., U.S. Dept. of Health and Human Services, “Sequence of Proteins of Immunological Interest” (1983). In addition to table above, the Kabat number system describes the CDR regions as follows: CDR- H1 begins at approximately amino acid 31 (i.e., approximately 9 residues after the first cysteine residue), includes approximately 5-7 amino acids, and ends at the next tryptophan residue. CDR-H2 begins at the fifteenth residue after the end of CDR-H1, includes approximately 16-19 amino acids, and ends at the next arginine or lysine residue. CDR-H3 begins at approximately the thirty third amino acid residue after the end of CDR-H2; includes 3-25 amino acids; and ends at the sequence W-G-X-G, where X is any amino acid. CDR-L1 begins at approximately residue 24 (i.e., following a cysteine residue); includes approximately 10-17 residues; and ends at the next tryptophan residue. CDR-L2 begins at approximately the sixteenth residue after the end of CDR-L1 and includes approximately 7 residues. CDR-L3 begins at approximately the thirty third residue after the end of CDR-L2 (i.e., following a cysteine residue); includes approximately 7-11 residues and ends at the sequence F or W-G-X-G, where X is any amino acid. Throughout this application, amino acid numbers are according to Kabat numbering system, unless specified otherwise. Antibodies disclosed herein may be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine, donkey, rabbit, goat, guinea pig, camel, llama, horse, or chicken antibodies. In another embodiment, the variable region may be condricthoid in origin (e.g., from sharks). As used herein, the term “heavy chain constant region” includes amino acid sequences derived from an immunoglobulin heavy chain. A polypeptide comprising a heavy chain constant region comprises at least one of: a CH1 domain, a hinge (e.g., upper, middle, and / or lower hinge region) domain, a CH2 domain, a CH3 domain, or a variant or fragment thereof. For example, an antigen-binding polypeptide for use in the disclosure may comprise a polypeptide chain comprising a CH1 domain; a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, and a CH2 domain; a polypeptide chain comprising a CH1 domain and a CH3 domain; a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, and a CH3 domain, or a polypeptide chain comprising a CH1 domain, at least a portion of a hinge domain, a CH2 domain, and a CH3 domain. In another embodiment, a polypeptide of the disclosure comprises a polypeptide chain comprising a CH3 domain. Further, an antibody for use in the disclosure may lack at least a portion of a CH2 domain (e.g., all or part of a CH2 domain). As set forth above, it will be understood by one of ordinary skill in the art that the heavy chain constant region may be modified such that they vary in amino acid sequence from the naturally occurring immunoglobulin molecule. The heavy chain constant region of an antibody disclosed herein may be derived from different immunoglobulin molecules. For example, a heavy chain constant region of a polypeptide may comprise a CH1 domain derived from an IgGlmolecule and a hinge region derived from an IgG3molecule. In another example, a heavy chain constant region can comprise a hinge region derived, in part, from an IgGlmolecule and, in part, from an IgG3 molecule. In another example, a heavy chain portion can comprise a chimeric hinge derived, in part, from an IgGl molecule and, in part, from an IgG4 molecule. As used herein, the term “light chain constant region” includes amino acid sequences derived from antibody light chain. Preferably, the light chain constant region comprises at least one of a constant kappa domain or constant lambda domain. A “light chain-heavy chain pair” refers to the collection of a light chain and heavy chain that can form a dimer through a disulfide bond between the CL domain of the light chain and the CH1 domain of the heavy chain. As previously indicated, the subunit structures and three dimensional configuration of the constant regions of the various immunoglobulin classes are well known. As used herein, the term “VH domain” includes the amino terminal variable domain of an immunoglobulin heavy chain and the term “CH1 domain” includes the first (most amino terminal) constant region domain of an immunoglobulin heavy chain. The CH1 domain is adjacent to the VH domain and is amino terminal to the hinge region of an immunoglobulin heavy chain molecule. As used herein the term “CH2 domain” includes the portion of a heavy chain molecule that extends, e.g., from about residue 244 to residue 360 of an antibody using conventional numbering schemes (residues 244 to 360, Kabat numbering system; and residues 231-340, EU numbering system; see Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of Proteins of Immunological Interest” (1983). The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It is also well documented that the CH3 domain extends from the CH2 domain to the C-terminal of the IgG molecule and comprises approximately 108 residues. As used herein, the term “hinge region” includes the portion of a heavy chain molecule that joins the CH1 domain to the CH2 domain. This hinge region comprises approximately 25 residues and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently. Hinge regions can be subdivided into three distinct domains: upper, middle, and lower hinge domains (Roux et al., J. Immunol 161:4083 (1998)). By “specifically binds” or “has specificity to,” it is generally meant that an antibody binds to an epitope via its antigen-binding domain, and that the binding entails some complementarity between the antigen-binding domain and the epitope. According to this definition, an antibody is said to “specifically bind” to an epitope when it binds to that epitope, via its antigen-binding domain more readily than it would bind to a random, unrelated epitope. The term “specificity” is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody “A” may be deemed to have a higher specificity for a given epitope than antibody “B,” or antibody “A” may be said to bind to epitope “C” with a higher specificity than it has for related epitope “D.” As used herein, the terms “treat” or “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the progression of cancer. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on. As used herein, phrases such as “to a patient in need of treatment” or “a subject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from administration of an antibody or composition of the present disclosure used, e.g., for detection, for a diagnostic procedure and / or for treatment. The present disclosure provides antibodies (including antigen-binding fragments thereof) that exhibit pH-dependent binding characteristics. As used herein, the expression "pH-dependent binding" means that the antibody exhibits reduced binding to IgE at acidic pH as compared to neutral pH. As used herein, the expression "acidic pH" means a pH of 6.0 or less, including pH values of about 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, and less. In some embodiments, “acidic pH” means a pH of about 6.0. In some embodiments, “lysosomal pH” can be “acidic pH.” As used herein, the expression "neutral pH" means a pH of about 7.0 to about 7.4. In some embodiments, “neutral pH” means a pH of about 7.0, 7.1, 7.2, 7.3, and 7.4. In some embodiments, “neutral pH” means a pH of about 7.4. In some embodiments, “endosomal pH” can be “neutral pH.” The "affinity" of an antibody for an antigen (e.g., IgE for purposes of the present disclosure) is expressed in terms of the KD of the antibody. The KD of an antibody refers to the equilibrium constant for the dissociation equilibrium of the antibody-antigen interaction, where KD is equal to kon / koff. The dissociation constant, KD, and affinity are inversely related; the greater the KD value for an antibody binding to an antigen, the weaker the binding affinity of that antibody to that antigen. Accordingly, as used herein, the expression "higher affinity at neutral pH than at acidic pH" (or the equivalent expression "pH-dependent binding") means that the KD for the antibody binding to IgE at acidic pH is greater than the KD for the antibody binding to IgE at neutral pH. The binding properties of an antibody for a particular antigen may also be expressed in terms of the koff of the antibody. The koff of an antibody refers to the first-order rate constant for the dissociation of the antibody-antigen complex. Assuming a constant kon, a higher koff corresponds to a higher KD and a lower affinity. A “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” means an excipient, diluent, carrier, and adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable excipient, diluent, carrier and adjuvant” as used in the specification and claims includes both one and more than one such excipient, diluent, carrier, and adjuvant. A “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general, a “pharmaceutical composition” is sterile, and typically free of contaminants that are capable of eliciting an undesirable response within the subject (e.g., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, intramuscular, subcutaneous, and the like. The term “pharmaceutically acceptable” means being approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized Pharmacopeia for use in animals, and, more particularly in humans. The term “pharmaceutically acceptable salt” refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the conjugate compounds, or separately by reacting the free base function or group of a compound with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts, or salts of an amino group formed with inorganic acids. Compounds are described using standard nomenclature. The compounds in any of the formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context. As used herein, the phrase “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. The term “independently selected from” is used herein to indicate that the recited elements, e.g., R groups or the like, can be identical or different. 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 carbonyl (C═O) group. The present disclosure includes compounds (e.g., as described herein) with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as2H,3H,11C,13C,14C,15N,18F31P,32P,35S,36Cl, and125I respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure 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 substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In some embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location. In some embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of Formulas described herein. In one non-limiting embodiment, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R1, R2, R3, R4, R6, R11, R21, R22, R23, R24, R25R, R’, and R’’ etc. For example, when any of the groups are, or contain for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non- limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). In certain other embodiments, when two substituents are combined to form a cycle, the unsubstituted carbons may be deuterated. “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions. In one embodiment, “aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In some embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. The specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species. For example, the term C1-C6 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 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-C4aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety. “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In some embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent 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 is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C1-C4 alkyl as used herein indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example and without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. “Alkenyl” is a linear or branched aliphatic hydrocarbon groups having one or more carbon- carbon double bonds that may occur at a stable point along the chain. 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 radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term “alkenyl” also embodies “cis” and “trans” alkenyl geometry, or alternatively, “E” and “Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted. The term “Alkenyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one point of unsaturation. “Alkynyl” is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. The specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term “Alkynyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one triple bond. “Alkylene” is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example C1- C2alkylene, C1-C3alkylene, C1-C4alkylene, C1-C6alkylene, or C1-C6alkylene. “Alkenylene” is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkenylene. “Alkynylene” is a bivalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C2-C4alkynylene. The term “amino” refers to the group -NRR’ wherein R and R’ are independently hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and / or heteroatom-containing variants thereof. “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain, “chain” refers to the one which leads to the simplest representation of the molecule. “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. “Halo” and “halogen” refers to fluorine, chlorine, bromine, or iodine. “Haloalkyl” is a branched or straight-chain alkyl groups substituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms. Examples include but are not limited to, trifluoromethyl and pentafluoroethyl. “Haloalkoxy” indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical). The term “heteroaliphatic” refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. “Heteroaliphatic” is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, “heteroaliphatic” is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, —O-alkyl-O-alkyl, alkyl- O-haloalkyl, etc. “Heterocycloalkyl” is an alkyl group as defined herein substituted with a heterocyclo group as defined herein. “Arylalkyl” is an alkyl group as defined herein substituted with an aryl group as defined herein. “Heteroarylalkyl” is an alkyl group as defined herein substituted with a heteroaryl group as defined herein. The term “alkynyl” refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein may contain 2 to about 18 carbon atoms, and such groups may further contain 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms. The term “substituted alkynyl” refers to alkynyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkynyl” and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkynyl” and “lower alkynyl” include linear, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyl and lower alkynyl, respectively. The term aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron, to form, for example, a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In some embodiments, the aryl group is an unsubstituted C6-14 aryl. In some embodiments, the aryl group is a substituted C6-14 aryl. An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo. The term “heterocyclyl” (or “heterocyclo”) includes saturated, and partially saturated heteroatom- containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur, and oxygen. Heterocyclic rings comprise monocyclic 3-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing —O—O—.—O—S— or —S—S— portions. Said “heterocyclyl” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples of saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]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-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′- benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl. Heterocyclo groups also include radicals where heterocyclic radicals are fused / condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms. The term “heteroaryl” denotes aryl ring systems that contain one or more heteroatoms selected from O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH- 1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. As used herein, the terms “may,” “optional,” “optionally,” or “may optionally” mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present. The term “optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C12 cycloalkyl, C3- C12 cycloalkenyl, C1-C12 heterocycloalkyl, C3-C12 heterocycloalkenyl, C1-C10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C10alkylamino, C1-C10dialkylamino, arylamino, diarylamino, C1- C10alkylsulfonamino, arylsulfonamino, C1-C10alkylimino, arylimino, C1-C10alkylsulfonimino, arylsulfonimino, hydroxyl, halo, thio, C1-C10alkylthio, C1-C10alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic ester. In one alternative embodiment any suitable group may be present on a “substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted); arylalkyl having for example, 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings with benzyloxy being an exemplary arylalkoxy group; or a saturated or partially unsaturated heterocycle having 1 to 3 separate or fused rings with one or more N, O or S atoms, or a heteroaryl having 1 to 3 separate or fused rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such groups may be further substituted, e.g., with hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, alkyl including C1- C6alkyl, alkenyl including C2-C6alkenyl, alkynyl including C2-C6alkynyl, —C1-C6alkoxy, alkanoyl including C2-C6alkanoyl, C1-C6alkylester, (mono- and di-C1-C6alkylamino)C0-C2alkyl, haloalkyl including C1-C6haloalkyl, hydoxyC1-C6alkyl, ester, carbamate, urea, sulfonamide, —C1- C6alkyl(heterocyclo), C1-C6alkyl(heteroaryl), —C1-C6alkyl(C3-C7cycloalkyl), O—C1-C6alkyl(C3- C7cycloalkyl), B(OH)2, phosphate, phosphonate and haloalkoxy including C1-C6haloalkoxy. When the term “substituted” appears prior or after a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase “substituted alkyl and aryl” is to be interpreted as “substituted alkyl and substituted aryl.” In addition to the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined herein. In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “hydroxyalkyl” refers to the group HO- (alkyl)-. As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds. In some embodiments, a substituent may contribute to optical isomerism and / or stereo isomerism of a compound. A compound of this disclosure may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the present disclosure includes a solvated form of the compound. The term “solvate” refers to a molecular complex of a compound (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent may be isotopically substituted, e.g., D2O, d6-acetone, d6- DMSO. A solvate can be in a liquid or solid form. Salts, solvates, hydrates, and prodrug forms of a compound are of interest. All such forms are embraced by the present disclosure. Thus, the compounds described herein include salts, solvates, hydrates, prodrug, and isomer forms thereof, including the pharmaceutically acceptable salts, solvates, hydrates, prodrugs, and isomers thereof. In some embodiments, a compound may be a metabolized into a pharmaceutically active derivative. Unless otherwise specified, reference to an atom is meant to include isotopes of that atom. For example, reference to H is meant to include1H,2H (i.e., D) and3H (i.e., T), and reference to C is meant to include12C and all isotopes of carbon (such as13C). Definitions of other terms and concepts appear throughout the detailed description. Target Binding Antibody Conjugates (LYTACs) In some embodiments, the compounds of this disclosure are be referred to as conjugates or LYTACs. In one embodiment, the conjugate comprises a ligand moiety conjugated via a linker to a target-binding moiety wherein the ligand moiety binds a lysosomal targeting molecule extracellularly; the target-binding moiety binds a target molecule extracellularly; the target-binding moiety dissociates from the target molecular intraendosomally and the conjugate is externalized from a cell. Such conjugates can be prepared by conjugation of a chemoselective ligation group of any one of the compounds described herein with a compatible reactive group of a molecule Y. The compatible group of the molecule Y can be introduced by modification prior to conjugation, or can be a group present in the molecule. Alternatively, such conjugates can be prepared de novo, e.g., via modification of a Y molecule of interest starting material to introduce a linker, e.g., to which a ligand or lysosomal targeting molecule binding moiety (X) can be attached. In some embodiments, the moiety of interest is a molecule that specifically binds to a target of interest, i.e., a target-binding moiety. In such cases, the conjugates of this disclosure can provide for cellular uptake of the target after it non-covalently binds to the conjugate, and / or degradation. It has been demonstrated that conjugates of this disclosure having a particular configuration of lysosomal targeting molecule binding moiety of a desired affinity, with a linker of desired valency and length, can specifically bind with high affinity to both the lysosomal targeting molecule and the target simultaneously. The conjugates of this disclosure can thus provide for sequestering of a target protein in the cell’s lysosome and degrading of the target protein. The compounds of this disclosure can, in some cases, be referred to as a conjugate, e.g., when the moiety of interest (Y) is an antibody or antibody fragment (e.g., as described herein), where the conjugate can be derived from a conjugation or coupling reaction between a chemoselective ligation group and a compatible group on the antibody or antibody fragment. In some embodiments, the antibody or antibody fragment is conjugated via a naturally occurring group of the antibody or antibody fragment. In some embodiments, the antibody or antibody fragment is conjugated via a compatible functional group that is introduced into the antibody or antibody fragment prior to chemoselective conjugation. In such cases, the linker between X and Y incorporates the residual group (e.g., Z) that is the product of the chemoselective ligation chemistry. Aspects of this disclosure include compounds or conjugates of Formula I, and subformulas thereof, where the moiety of interest Y is an antibody or antibody fragment that specifically binds to a target molecule, such as a target protein. The target protein can be the target protein is a membrane bound protein or an extracellular protein. In some embodiments of the compounds and conjugates of this disclosure, Y is an antibody or antibody fragment that specifically binds to a target protein. In some embodiments, the conjugate includes a moiety of interest Y that specifically binds a target protein, and can find use in methods of cell uptake or internalization of the target protein via binding to the cell surface receptor, and eventual degradation of the target protein. In one embodiment, the conjugate can facilitate degradation of a target and can repeatedly “cycle” into and out of a cell. Either of two cycling mechanisms are hypothesized to occur, and in some cases both mechanisms may occur with respect to a given conjugate. Utilizing these mechanisms, conjugates of the present disclosure are “cycled” in and out of a cell (internalized and externalized) and facilitate lysosomal degradation of a target. Such cycling enables duration of activity on the order of hours to days, and the ability for a single conjugate to facilitate lysosomal degradation of multiple targets. In other words, the conjugates described herein may be used to degrade super-stoichiometric ratios of target by repeatedly binding a target, internalizing with the target to facilitating its lysosomal degradation, and cycling back to the cell membrane to bind an additional target. In some embodiments, the conjugate is internalized into a cell via a lysosomal targeting molecule, for example after the conjugate binds to the lysosomal trafficking receptor. Receptor-mediated internalization is described, for example, in G. Ahn et al., Nat. Chem. Biol.2021, 17(9) 937-46 and references cited therein. As described elsewhere herein, in various embodiments, the lysosomal targeting molecule is ASGPR. In other embodiments, the lysosomal targeting molecule is M6PR. In other embodiments, the lysosomal targeting molecule is LDLR or CD63. In some embodiments, ligand moiety, X, remains bound to the lysosomal targeting molecule intraendosomally. In some embodiments, the conjugate is externalized from the cell via the lysosomal targeting molecule. In some embodiments, the ligand moiety has an equal binding affinity for the lysosomal targeting molecule extracellularly and intraendosomally. In some embodiments, the ligand moiety, X, has an equal binding affinity for the lysosomal targeting molecule at an extracellular pH and at an intraendosomal pH. In some embodiments, the ligand moiety, X, has an equal binding affinity for the lysosomal targeting molecule at an extracellular Ca2+concentration and at an intraendosomal Ca2+concentration. Externalization of the conjugate may also be mediated by FcRn. In some embodiments, the conjugate is externalized from the cell via FcRn, for example after target-binding moiety, Y, binds FcRn. In some embodiments, the ligand moiety, X, binds FcRn intraendosomally. In some embodiments, the conjugate dissociates from the lysosomal targeting molecule intraendosomally. In some embodiments, the ligand moiety, X, has a higher binding affinity for the lysosomal targeting molecule extracellularly than intraendosomally. In some embodiments, the ligand moiety, X, has a higher binding affinity for the lysosomal targeting molecule at an extracellular pH than at an intraendosomal pH. In some embodiments, the ligand moiety, X, has a higher binding affinity for the lysosomal targeting molecule at an extracellular Ca2+concentration than at an intraendosomal Ca2+concentration. In some embodiments, the ratio of binding affinity of ligand moiety, X, to the lysosomal targeting molecule intraendosomally:extracellularly is between 1:2 and 2:1. In some embodiments, the ratio of binding affinity of ligand moiety, X, to the lysosomal targeting molecule intraendosomally:extracellularly is between 1:5 and 5:1. In some embodiments, the ratio of binding affinity of ligand moiety, X, to the lysosomal targeting molecule intraendosomally:extracellularly is between 1:10 and 10:1. In some embodiments, the target-binding moiety, Y, has a higher binding affinity for FcRn intraendosomally than extracellularly. In some embodiments, the ratio of binding affinity of target- binding moiety, Y, to FcRn intraendosomally:extracellularly is between 1:100 and 1:10. In some embodiments, the target-binding moiety, Y, has a higher binding affinity for FcRn at an intraendosomal pH than at an extracellular pH. In some embodiments, Y, has enhanced binding to FcRn relative to wild- type at an endosomal pH. In some embodiments, the target-binding moiety, Y, has approximately equal binding affinity to FcRn extracellularly as wild-type IgG does extracellularly. In some embodiments, the target-binding moiety, Y, has, at pH 7.4, approximately equal binding affinity to FcRn as wild-type IgG. In some embodiments, Y is a mutant form of an antibody, Y has the YTE mutation. In one method is provided a method of degrading a target molecule in a subject in need thereof, comprising administering an effective amount of a conjugate that comprises: a means for binding a lysosomal targeting molecule extracellularly; a means for binding a target molecule extracellularly; a means for dissociating from the target molecule intraendosomally; and wherein the conjugate is externalized from a cell. In one embodiment, the means for binding a lysosomal targeting molecule, remains bound to the lysosomal targeting molecule intraendosomally. In one embodiment, the means for binding a target molecule also binds FcRn intraendosomally. In one embodiment, the conjugate dissociates from the lysosomal targeting molecule intraendosomally. In some embodiments, one Y biomolecule is conjugated to a single moiety (X) that specifically binds to the cell surface receptor (e.g., ASGPR, M6PR, FR) via a linker L. In some embodiments, one Y biomolecule is conjugated to one (Xn-L)- group, wherein when n =1 the (Xn-L)- group is referred to as monovalent, and when n > 1 the (Xn-L)- group is referred to as multivalent (e.g., bivalent, trivalent, tetravalent, etc.). It is understood that in some embodiments of Formula I, where Y is a biomolecule, Y can be conjugated to two or more (Xn-L)- groups, wherein each (Xn-L)- group may itself be monovalent or multivalent (e.g., bivalent, trivalent, tetravalent, etc.). In such cases, the ratio of linked (Xn-L)- groups to biomolecule can be referred to as 2 or more. In some embodiments, provided is a target binding conjugate of Formula I: or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: each X is independently a ligand moiety that binds to a lysosomal targeting molecule; each n is independently 1 to 20; each L is independently a linker; m is 1 to 10; and Y is an antibody or fragment thereof that specifically binds a cell surface target molecule or extracellular target molecule. In some embodiments, the conjugate is configured to facilitate degradation of the target molecule for at least one day, or at least two days, or at least four days or at least seven days after administration of the conjugate. Previously reported lysosome targeting chimeras based on an O-linked GalNac structure (see, e.g., G. Ahn et al., Nat. Chem. Biol.2021, 17(9), 937-46), while capable of facilitating lysosomal degradation of a target molecule, are not chemically or enzymatically stable in an endosomal environment and are rapidly degraded. In contrast, the conjugates described herein are stable in an endosomal environment as evidenced by, e.g., their ability to facilitate degradation of a target for over 24 hours. It is contemplated that conjugates described herein exhibit extended activity or super- stoichiometric clearance of a target in a biological system, or both. In some embodiments, the loading and / or stability of the antibody conjugates can be provided for via use of a conjugation chemistry to a specific site on the antibody, e.g., a cysteine-reactive chemoselective conjugation chemistry. In some embodiments, the ligand is M6PR or ASGPR. In some embodiments of Formula I, n is 1 to 10, such as 1 to 6, 1 to 4, or 1 to 3. In some embodiments, X is a M6PR ligand moiety, and n is 1 to 6, such as n is about 4 (i.e., an average loading of about 4). In some embodiments, X is a ASGPR ligand moiety, and n is 1 to 3, such as 1 to 2 or 2 to 3 or 1 to 3 (i.e., an average loading of about 2). In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments of Formula I, m is 1 to 6, or 1 to 4. It is understood that depending on the conjugation chemistry, m can refer to a discrete number, or m can refer to an average, e.g., loading of ligand-linker on the antibody (i.e., a DAR ratio). In some embodiments, Y exhibits a binding affinity for the target molecule that is calcium (Ca2+) dependent or pH dependent, e.g., to facilitate release of the conjugate from the molecule in the cell. In some embodiments, Y exhibits a high binding affinity for the cell surface target molecule or extracellular target molecule at neutral pH than at low pH. In some embodiments, Y is an antibody or fragment thereof,, which binds IgE and wherein the antibody or fragment comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 64, 73, 95, 99, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 49, 51, 52, 53, 54, 66, 91, 92, 93, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, provided is a target binding conjugate of Formula II: or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: X and Y are each independently as defined herein; n is 1 to 3; m is 1 to 3; a, b, and c solution of (3S,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl are each independently 1, 2, 3, 4, or 5; provided that when n is 1, b is 0; L1and L3are each independently a linker component (e.g., as described herein); L2, when present, is a branched linker component (e.g., as described herein), such that L1to L3together provide a linear or branched linker between X and Y; Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group to a compatible group of Y (e.g., as described herein), In some embodiments, provided is a target binding conjugate of Formula III: or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 1 to 3; m is 1 to 3; X and Y are each independently as defined herein; each L1to L6is independently a linker component which together provide a linear or branched linker between Z1of X (where Z1is independently as defined herein) and Y; and a, b, c, d, and e are each independently 1, 2, 3, 4, or 5. Lysosomal Targeting Molecules and Ligand Moieties A lysosomal targeting molecule is a cell surface receptor that provides for internalization of the conjugate compounds of this disclosure. The term “ligand moiety” refers to a portion of the conjugates described herein that bind to a lysosomal targeting molecule. In some embodiments, the lysosomal targeting molecule is selected from asialoglycoprotein receptor (ASGPR), cation independent mannose-6-phosphate receptor (CI-M6PR also referred to herein as M6PR), folate receptor, CD63, sortilin, IFITM3, molecules in the endosome / lysosome pathway, LIMP-1, and LIMP-2. In some embodiments, the lysosomal targeting molecule is ASGPR. In some embodiments, the lysosomal targeting molecule is CI-M6PR. In some embodiments, the lysosomal targeting molecule is folate receptor. A variety of ligand moieties (compounds or moieties that bind to a lysosomal targeting molecule) can be utilized in the conjugate compounds of this disclosure. In some embodiments, the ligand moiety comprises a monosaccharide. In some embodiments, the ligand moiety comprises a galactose. In some embodiments, the ligand moiety comprises a mannose. In some embodiments, the ligand moiety comprises a pyranose. In some embodiments, the ligand moiety is not an antibody or antibody fragment. Ligand moieties that bind to ASGPR are described in International Publication WO2023 / 288033, the disclosure of which is herein incorporated by reference in its entirety. Ligand moieties that bind to CI-M6PR are described in International Publication WO2023 / 288015, the disclosure of which is herein incorporated by reference in its entirety. Ligand moieties that bind to folate receptor are described in International Publication WO2022 / 150721, filed January 10, 2022, the disclosure of which is herein incorporated by reference in its entirety. In some embodiments of any of the conjugates disclosed herein, when the targeting moiety is bonded to the linker (L) at the C1 carbon atom of X (i.e., the anomeric carbon, such as via R1of the ASGPR targeting moieties), then the atom directly bonded to the C1 carbon atom of X is not -O-. ASGPR Ligand Moieties This disclosure provides a class of compounds (target binding conjugates) which comprise a ligand moiety that specifically binds to ASGPR. The ASGPR ligand moieties of this disclosure can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the cell surface ASGPR. The compounds of this disclosure can utilize the functions of cell surface ASGPRs in a biological system, e.g., for internalization and sequestration of a compound to the lysosome of a cell and, in some cases, subsequent lysosomal degradation. The term “asialoglycoprotein receptor” or “ASGPR,” which is also known as the Ashwell Morell receptor, refers to the transmembrane glycoprotein receptor found primarily in hepatocytes which plays an important role in serum glycoprotein homeostasis by mediating the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N-acetylgalactosamine (GalNAc) residues. ASGPR cycles between endosomes and the cell surface. In some embodiments, the ASGPR is Homo sapiens asialoglycoprotein receptor 1 (ASGR1) (see, e.g., NCBI Reference Sequence: NM_001197216). A compound or moiety or conjugate comprising such ASGPR ligand moiety (X) (e.g., as described herein), may bind to other receptors, for example, may bind with lower affinity as determined by, e.g., immunoassays or other assays known in the art. In some embodiments, the ASGPR ligand moiety X, or a compound or moiety or conjugate as described herein comprising such X, specifically binds to the cell surface ASGPR with an affinity that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the affinity when X or the compound or the conjugate bind to another cell surface receptor. In one embodiment, X or a compound or moiety as described herein comprising X, specifically binds to ASGPR with an affinity (Kd) 20 mM or less. In some embodiments, such binding is with an affinity (Kd) is 10 mM or less, 1 mM or less, 100 uM or less, 10 uM or less, 1 uM or less, 100 nM or less, 10 nM or less, or 1 nM or less. The terms “binds,” “binds to,” “specifically binds” or “specifically binds to” in this context are used interchangeably. The ASGPR binding compounds or ASGPR ligand moieties of this disclosure include a moiety (X) that specifically binds to the cell surface receptor ASGPR. The ASGPR binding compounds or ASGPR ligand moieties can be monovalent or multivalent (e.g., bivalent, or trivalent or of higher valency), where a monovalent compound includes a single ASGPR ligand moiety, and a multivalent compound includes two or more such moieties. In certain embodiments, the ASGPR ligand moiety, X, is able to bind to a specific cell surface ASGPR, and direct (or target) the molecule to this receptor. In certain embodiments, the ASGPR ligand moiety, X, is capable of binding to the ASGPR and directing (or targeting) a compound or conjugate described herein for internalization and sequestration to the lysosome, and / or subsequent lysosomal degradation. In some embodiments, the ASGPR ligand moiety, X, includes an amino sugar ring derivative of galactose (e.g., N-acetylgalactosamine, and analogs thereof), that is linked via a linking moiety (such as those described herein) to the 1, 6 or 2-position of the sugar ring. In some embodiments, the ASGPR ligand moiety, X, is linked via a linking moiety to an oxygen, sulfur, nitrogen, or carbon atom the 1- position of the ring. In some embodiments, the ASGPR ligand moiety, X, is linked via a linking moiety to an oxygen, sulfur, nitrogen, or carbon atom the 6-position of the ring. In some embodiments, the ASGPR ligand moiety, X, is linked via a linking moiety to an oxygen, sulfur, nitrogen, or carbon atom the 2-position of the ring. In certain embodiments, the ASGPR ligand moiety, X, is linked via a linking moiety to a heteroaryl group at the 1, 6 or 2 position of the ring. In certain embodiments, the ASGPR ligand moiety, X, is a bicyclic structure. In some embodiments, the ASGPR binding portion of the target binding conjugate is monovalent (e.g., of a Formula disclosed herein, n is 1), such that the ASGPR ligand moiety includes a single ASGPR ligand moiety (X) that is linked to a moiety of interest or target-binding moiety (Y) via a linking moiety, L, at the 1, 6, or 2-position of (X). In certain embodiments of a Formula disclosed herein, n is 1, and L comprises a linear linker having a backbone of 20 or more consecutive atoms covalently linking the ASGPR ligand (X) to Y via a linking moiety at any of the 1, 2 or 6-positions of X. In certain cases, n is 20 to 100 consecutive atoms, such as 25 to 80, 25 to 60, or 25 to 50. In certain embodiments, n is 1, and L comprises a backbone of 25 or more consecutive atoms covalently linking the ASGPR ligand moiety (X) to Y. In some embodiments, the ASGPR binding portion of the conjugate are multivalent (e.g., of a Formula disclosed herein, n is 2 or more, such that the ASGPR binding portion of the conjugate includes two or more ASGPR ligand binding moieties (X) that are each covalently linked to a moiety of interest (Y) via a branched linker (e.g., L is a branched linker). In some embodiments, the ASGPR binding compound is divalent (e.g., n is 2 in a Formula disclosed herein). In some embodiments, the ASGPR binding compound is trivalent (e.g., n is 3 in a Formula disclosed herein). In some embodiments, each branch of the branched linker comprises a liner linker of 14 or more consecutive atoms to covalently link a linking moiety of each X to a branching point in the linker. In some embodiments, each branch of the linker includes 14 to 50 consecutive atoms, such as 14 to 40, 14 to 30, or 14 to 20 atoms. In some embodiments, each branch of the linker includes a linear linker of 20 or more consecutive atoms. In some embodiments, the linker comprises a linear linker of 12 or more consecutive atoms to covalently link the branching point of L to a moiety of interest (Y), such as 15 or more, 20 or more, 30 or more, or even more consecutive atoms to covalently link the branching point of L to Y. ASGPR ligand moieties which can be adapted for use in the conjugates of this disclosure are described in WO / 2023288033, filed July 14, 2022, the disclosure of which is herein incorporated by reference in its entirety. Exemplary ASGPR ligand moieties are described below. In some embodiments, the ASGPR ligand moiety (X) of the ASGPR binding portion (e.g., Xn-L or (X-L)n) of a Formula disclosed herein), are designed to specifically bind to ASGPR with an affinity (Kd) of 300 nM or less, such as 100 nM or less, 30 nM or less, 10 nM or less, 3 nM or less, or 1 nM or less. The terms “binds,” “binds to,” “specifically binds,” or “specifically binds to” in this context are used interchangeably. In some embodiments of the conjugates described herein, X is an asialoglycoprotein receptor (ASGPR) binding moiety of Formula A-I: wherein: R1is selected from -Z1-*, -H, -OH, optionally substituted (C1-C6)alkyl, -OCH3, -OCH2CH=CH, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, and optionally substituted -S-heteroaryl; R2is selected from -Z1-*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, -NHR, and optionally substituted triazole; R6is selected from -Z1-*, -OH, -OR, optionally substituted (C1-C6)alkyl, -OC(O)R, -C(O)NHR, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, and -NRCOR; each R is independently optionally substituted (C1-C6)alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rxxand Ryyare independently H, optionally substituted (C1-C6)alkyl, or Rxxand Ryycan cyclize to form an optionally substituted heterocyclyl; wherein one of R1, R2, and R6is -Z1-*; R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc: IIc wherein: R1is hydrogen, -OH, optionally substituted (C1-C6)alkyl, or -OCH3, and R11is hydrogen; or R1and R11together with the carbon atoms to which each is attached form a bridging moiety; R2is -NHR; where R is optionally substituted pyrimidinyl or optionally substituted pyrazinyl; R3and R4are hydrogen; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, R2is: In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-1: wherein: R1is hydrogen, -OH, optionally substituted (C1-C6)alkyl, or -OCH3, and R11is hydrogen; or R1and R11together with the carbon atoms to which each is attached form a bridging moiety; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-2: wherein: R1is hydrogen, -OH, optionally substituted (C1-C6)alkyl, or -OCH3, and R11is hydrogen; or R1and R11together with the carbon atoms to which each is attached form a bridging moiety; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-1A:

[0006] In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc-2A: . In some embodiments, the lysosomal targeting bifunctional molecules of this disclosure (e.g., of Formula I) can include an ASGPR ligand moiety of Formula A-I: wherein: R1is selected from -Z1-*, -H, -OH, -CH3, -OCH3, and -OCH2CH=CH; R2is selected from -Z1-*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, and optionally substituted triazole; R6is selected from -Z1-*, -OH, -OC(O)R, -C(O)NHR, and optionally substituted triazole, where R is optionally substituted (C1-C6)alkyl or optionally substituted aryl; wherein one of R1, R2, and R6is -Z1-*; R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H, or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2-*, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted arylene or optionally substituted heteroarylene; each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl. In some embodiments, X is represented by Formula A-II: In some embodiments, R1is -Z1-*, -H, or (C1-C6)alkyl. In some embodiments, R1is -Z1-*, -H, or n-propyl. In some embodiments, R2is -Z1-* or -NHCOCH3. In some embodiments, R3and R4are each -H. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIa: wherein R2, R3, R4, R6and Z1are as defined herein. In some embodiments of Formula IIa, R6is selected from -OH, -OC(O)R, and -C(O)NHR; and R2is selected from -NHCOCH3, -NHCOCF3, and -NHCOCH2CF3. In some embodiments of Formula II, Z1is in a beta configuration, and can be described by Formula IIa-1: . In some embodiments of Formula II, Z1is in an alpha configuration, and can be described by Formula IIa-2: . In some embodiments of Formula IIa, IIa-1, or IIa-2, Z1is -Z11-A1-, wherein A1- is optionally substituted arylene or optionally substituted heteroarylene. In some embodiments, A1is an optionally substituted heteroarylene. In some embodiments, the heteroarylene is a 5 or 6-membered heteroarylene. In some embodiments, the heteroarylene is a 5-membered heteroarylene. In some embodiments, the 5- membered heteroarylene is a triazole. In some embodiments, the triazole is a 1,2,3-triazole moiety. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIIa or IIIb: wherein: -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2-, where each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl, and R21is H or optionally substituted (C1-C6)alkyl; and -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. In some embodiments, -A1- is arylene or heteroarylene; wherein each is independently optionally substituted with one to three halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments of Formula IIIa or IIIb, Z11is -S-. In some embodiments, Z11is -C(R22)2-. In some embodiments, Z11is -CH2-. In some embodiments, Z11is -C(R22)2, where at least one R22is H. In some embodiments, both R22are H. In some embodiments Z11is -O-. In some embodiments, Z11is -S-. In some embodiments cases, Z11is -N(R21), where R21is H or C1-3alkyl. In some embodiments, -A1- is triazole. In some embodiments, Z1is -C(R22)2-triazole-. In some embodiments, Z1is: . In some embodiments, Z1is: . In some embodiments of Formula IIa, IIa-1, or IIa-2, Z1is Z11. In some embodiments, Z11is - C(R22)2. In some embodiments, at least one R22is H. In some embodiments, both R22are H, and Z11is - CH2-. In some embodiments Z11is -O-. In some embodiments, Z11is -S-. In certain other cases, Z11is - N(R21), where R21is H or C1-3alkyl. In some embodiments of Formula IIa, IIa-1, or IIa-2, Z1is monocyclic 5 or 6-memberedheteroaryl or aryl. In some embodiments, Z1 is . 1 In some embodiments, Z is .In some embodiments of Formula IIa, IIa-1, or IIa-2, Z1is selected from -O-, -S-, -C(R22)2-, - wherein: X1is O or S; t is 0 or 1; R21and each R23is independently selected from H, and optionally substituted (C1-C6)alkyl (e.g., C(1-3)-alkyl, such as methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl. In some embodiments of Formula IIa, IIa-1, or IIa-2, Z1is optionally substituted (C1-C6)alkyl. In some cases of Z1the alkyl is methyl. In some cases of Z1, the alkyl is ethyl. In some cases of Z1, the alkyl is propyl. In some cases of Z1, the alkyl is butyl. In some cases of Z1, the alkyl is pentyl. In some cases of Z1, the alkyl is hexyl. In some embodiments, the ASGPR ligand moiety (X) of Formula IIa-1 is selected from one of the following structures: , In some embodiments of Formula IIa-2, Z1is in a beta configuration and X is of Formula IIIb-2: wherein: -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. In some embodiments of Formula IIIb-2, A1is a triazole. In some embodiments of Formula IIIb- 2, X is of Formula XA-4. In some embodiments of Formula IIa-1, Z1is in a beta configuration at the 1-position carbon of the galactosamine ring. In some embodiments of Formula IIa-1, Z1is S, and each X is of Formula XA-1. In some embodiments of Formula IIa-1, each X is of formula XA-2. In some embodiments of Formula IIa- 1, each X is of Formula XA-3. In some embodiments of Formula IIa-1, each X is of Formula XA-4. In some embodiments of Formula IIa-1, each X is of Formula XA-5. In some embodiments, the compound of Formula IIa-2 is selected from one of the following structures: In some embodiments of Formula IIa-2, Z1is in an alpha configuration and X is of Formula IIIb-1: wherein -A1- is arylene, substituted arylene, heteroarylene, or substituted heteroarylene. In some embodiments of Formula IIIb-1, A1is an optionally substituted heteroarylene. In some embodiments, the heteroarylene is a 5 or 6-membered heteroarylene. In some embodiments, the heteroarylene is a 5-membered heteroarylene. In some embodiments, the 5-membered heteroarylene is a triazole. In some embodiments, the triazole is a 1,2,3-triazole moiety. In some embodiments, each is independently optionally substituted with one to three halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, the X of Formula IIIb-1 is selected from one of the following structures: In some embodiments of Formula IIa: R6is -OH, R2is -NHC(O)CH3, R3is H or -C(O)CH(CH3)2, R4is H, and Z1is -O-, -S-, -CH2-, -NH-, or a 1,2,3-triazolyl. In some embodiments, Z1is in the alpha configuration such that the ASGPR ligand moiety is derived from Formula IIa-2: In some embodiments, the ASGPR ligand moiety (X) is linked via the 2-postion of the sugar analog. In some embodiments, the ASGPR ligand moiety (X) has a reduced ring carbon at the 1-position relative to a galactosamine derived sugar. In some embodiments, the ASGPR ligand moiety (X) of the bifunctional molecules of this disclosure is described by Formula IIb:

[0007] wherein R1, R3, R4, R6, R11, and Z1are as defined herein. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure are described by Formula IIb’: IIb’ wherein R3-R4, R6, and Z1are as defined herein. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure are described by Formula IVa: wherein R1, R11, and Z1are as defined herein. In some embodiments of Formula IIb, IIb’, or IVa, Z1is selected from optionally substituted-(C(R22)2)q-heteroarylene, a , wherein t is 0 or 1.In some embodiments of Formula IIb, IIb’ or IVa, Z1is optionally substituted -(C(R22)2)q-triazole, wherein q is 0 or 1. In some embodiments of Formula IIb, IIb’ or IVa, Z1is -(C(R22)2)q-1,2,3-triazolyl, wherein q is 0 or 1. In some embodiments of Formula IIb, IIb’ or IVa, Z1 . In some embodiments, Z1is In some embodiments of Formula IIb, IIb’ or IVa, Z1is , wherein R23is H, or C(1-3)-alkyl. In some embodiments of Formula IIb, IIb’ or IVa, Z1is -NR23CO-, wherein R23is H or C(1-3)- alkyl. In some embodiments of Formula IIb, IIb’ or IVa, Z1is selected from -O-, -S-, -C(R22)2-, -NR21-, - wherein: X1is O or S; t is 0 or 1; R21and each R23is independently selected from H, and optionally substituted C1-6alkyl (e.g., C(1-3)-alkyl, such as methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted C1-6alkyl. In some embodiments, each is independently optionally substituted with one to three halo, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. In some embodiments, each X is independently selected from: wherein R1Ais independently H or (C1-3)alkyl. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IVb or IVc: wherein: -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted arylene or optionally substituted heteroarylene; each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1- C6)alkyl. In some embodiments of Formula IVb or IVc, R1is H. In some embodiments, -Z1-* or -Z1-L1- comprises , , , In some embodiments, Z11is -C(R22)2. In some embodiments, at least one R22is H. In some embodiments, both R22are H. In some embodiments, Z11is -O-. In some embodiments, Z11is -S-. In some embodiments, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In some embodiments of Formula IVb, IVc, IVb-1, or IVc-1, -A1- and -A2- are each independently an optionally substituted heteroarylene. In some embodiments, the heteroarylene is a 5 or 6-membered heteroarylene. In some embodiments, the heteroarylene is a 5-membered heteroarylene. In some embodiments, the heteroarylene is a 6-membered heteroarylene. In some embodiments of Formula IVb, or IVb-1, the A1ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In some embodiments, the A1ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In some embodiments, the A1ring is triazole. In some embodiments, the A1ring is pyridine. In some embodiments, the A1ring is pyrimidine. In some embodiments, the A1ring is thiadiazole. In some embodiments, the A1ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A1ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1- C6)alkyl (e.g., CF3). In some embodiments, the A2ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In some embodiments, the A2ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In some embodiments, the A2ring is triazole. In some embodiments, the A2ring is pyridine. In some embodiments, the A2ring is pyrimidine. In some embodiments, the A2ring is thiadiazole. In some embodiments, the A2ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A2ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments, -Z11-A1- is a monocyclic 5 or 6-memebered heteroarylene of one of the following structures: , In some embodiments, -A2- is a monocyclic 5 or 6-membered heteroarylene of the structure: It is understood that a variety of substituents can be utilized to connect a particular -Z11-A1- group to an adjacent linker. In some embodiments of Formula IIb, or IVa-IVc, R1is H, such that the compound of Formula IIb, or IVa-IVc has no non-hydrogen substituents at the 1-position of the sugar ring. In some embodiments, the compound of Formula IIb is of any one of Formula IVd-IVg: wherein the A1and A2rings, R6, R4, R3, R11, and R21are as defined herein. In some embodiments of any one of Formula IVd-IVg, the A1ring is a 5 or 6-membered arylene or heteroarylene. In some embodiments, the A1ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In some embodiments, the A1ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In some embodiments, the A1ring is triazole. In some embodiments, the A1ring is pyridine. In some embodiments, the A1ring is pyrimidine. In some embodiments, the A1ring is thiadiazole. In some embodiments, the A1ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A1ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments of any one of Formula IVd-IVg, the A2ring is a 5 or 6-membered arylene or heteroarylene. In some embodiments, the A2ring is a 5-membered heteroarylene selected from triazole, thiadiazole, thiophene, oxazole, isoxazole, isothiazole, thiazole, oxadiazole, and furan. In some embodiments, the A2ring is a 6-membered heteroarylene selected from pyridine, pyrimidine, pyridazine, pyrazine, and triazine. In some embodiments, the A2ring is triazole. In some embodiments, the A2ring is pyridine. In some embodiments, the A2ring is pyrimidine. In some embodiments, the A2ring is thiadiazole. In some embodiments, the A2ring is a 5 or 6-membered arylene or heteroarylene that is further substituted with one or more substituents. In some cases, the A2ring is further substituted with one or more substituents selected from halogen, (C1-C6)alkyl and substituted (C1-C6)alkyl (e.g., CF3). In some embodiments of any one of Formula IVd-IVg, the A1or A2ring is absent. In some embodiments of any one of Formula IVd-IVg, the A1or A2ring is phenylene or substituted phenylene. In some embodiments of Formula IVd, the A2ring is a 5 or 6-membered heteroarylene. In some embodiments of Formula IVd, the A2ring is a 5-membered heteroarylene. In some embodiments of Formula IVd, the A2ring is triazole. In some embodiments of Formula IVd, the A2ring is absent. In some embodiments of Formula IVe, the A1ring is a 5 or 6-membered heteroarylene and R21is H. In some embodiments of Formula IVe, the A ring is triazole. In some embodiments of Formula IVe, the A1ring is pyridine. In some embodiments of Formula IVe, the A1ring is pyrimidine. In some embodiments of Formula IVe, the A1ring is thiadiazole. In some embodiments of Formula IVe, the A1ring is absent and R21is H or optionally substituted acyl. In some cases, R21is -COCH3. In some cases, R21is H. In some embodiments of Formula IVf, the A1ring is a 5 or 6-membered heteroarylene. In some embodiments of Formula IVf, the A1ring is a 5-membered heteroarylene. In some embodiments of Formula IVf, the A1ring is triazole. In some embodiments of Formula IVf, the A1ring is absent. In some embodiments of Formula IVg, the A2ring is a 5 or 6-membered heteroarylene. In some embodiments of Formula IVg, the A2ring is a 5-membered heteroarylene. In some embodiments of Formula IVg, the A2ring is triazole. In some embodiments of Formula IVg, the A2ring is absent. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by any one of Formula IVl-IVm: wherein: R6, R4, R3, and R21are as defined herein; Y1-Y3are each independently N or CR25; Y4is N or CR24; Y5is S, O, or NH; and R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In some embodiments of Formula IVi at least one of Y1to Y3is N. In some cases, at least two of Y1to Y3are N. In some embodiments, Y1and Y3are N and Y2is CR25. In some embodiments, Y1and Y2are N and Y3is CR25. In some embodiments, Y1and Y2are CR25and Y3is N. In some embodiments of any one of formulae IVd-IVk R6is H. In some embodiments of any one of Formula IVd-IVk, R4and R3are each H. In some embodiments, at least one of R4-R3is a promoiety. In some embodiments, R4and R3are cyclically linked to form a promoiety (e.g., as described herein). In some embodiments, X is of Formula IVi-1: wherein R24and R25are independently selected from H, halogen, C1-6-alkyl and substituted C1-6-alkyl (e.g., CF3). In some embodiments of Formula IVi - IVi-1, R25is H. In some embodiments, R25is C1-3-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is -CF3. In some embodiments of Formula IVi or IVi- 1, R24is H. In some embodiments, R24is C1-3-alkyl, or C1-3-fluoroalkyl. In some cases, the fluoroalkyl is -CF3. In some embodiments, X is of Formula XD1: In some embodiments, X is of Formula XD2:

[0008] In some embodiments, X is of Formula XE: In some embodiments, X is of Formula IVl-1: wherein: R6, R4, R3, and R21are as defined herein; Y1-Y4are each independently N or CR25; Y5is S, O, or NH; and each R25is independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In some embodiments, each R25is H. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by one of the following structures: . In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by one of the following structures: In some embodiments of Formula IIb, R1R3, R4, and R11are H, and R6is OH: wherein Z1is -NH-, -CH2-, -S- or -O-. In some embodiments, the ASGPR ligand moiety (X) is linked via the 6-postion of the sugar analog. In some embodiments, the ASGPR ligand moiety (X) has a reduced ring carbon at the 1-position relative to a galactosamine derived sugar. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IIc: wherein R1-R4and Z1are as defined herein. In some embodiments of Formula IIc, Z1is selected from -O-, -S-, -CONR21-, and optionally substituted -(C(R22)2)q- heteroarylene, wherein q is 0 or 1. In some embodiments, Z1is -O-. In certain other cases, Z1is optionally substituted -(C(R22)2)q-triazole wherein q is 0 or 1. In some embodiments, In some embodiments of Formula IIc, Z1is -Z11-A1-, wherein -A1- is or optionally substituted - A1- or optionally substituted arylene. In some embodiments, -A1- is an optionally substituted heteroarylene. In some embodiments, the heteroarylene is a 5 or 6-membered heteroarylene. In some embodiments, the heteroarylene is a 5-membered heteroarylene. In some embodiments, the 5-membered heteroarylene is a triazole. In some embodiments, the triazole is a 1,2,3-triazole moiety. In some embodiments, Z11is -C(R22)2. In some embodiments, at least one R22is H. In some embodiments, both R22are H. In some embodiments Z11is -O-. In some embodiments, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or C1-3alkyl. In some embodiments, Z1is -C(R22)2-triazole-. In some embodiments, In some embodiments of Formula IIc, Z1is Z11. In some embodiments, Z11is -C(R22)2. In some embodiments, at least one R22is H. In some embodiments, both R22are H, and Z11is -CH2-. In some embodiments Z11is -O-. In some embodiments, Z11is -S-. In certain other cases, Z11is -N(R21), where R21is H or (C1-C3)alkyl. In some embodiments of Formula IIc, Z1is monocyclic 5 or 6-membered heteroarylene or arylene. In some embodiments, In some embodiments of Formula IIc, Z1is selected from -O-, -S-, -C(R22)2-, -N(R21) - wherein: X1is O or S; t is 0 or 1; R21and each R23is independently selected from H, and optionally substituted C1-6alkyl (e.g., C1-3- alkyl, such as methyl); and each R22is independently selected from H, halogen (e.g., F) and optionally substituted C1-6alkyl. In some embodiments, the compound of Formula IIc i . In some embodiments, the compound of Formula IIc i . In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IId: IId wherein: R6, R4, R3, and Z1are as defined herein; Y6and Y5are each independently selected from -O-, -S-, NR21-, and -C(R22)2; R21is selected from H, optionally substituted C1-6alkyl, and -C(O)R22; each R22is independently selected from H, halogen and optionally substituted C1-6alkyl; and ring B is a 5 or 6-membered optionally substituted cyclic group. In some embodiments of Formula IId, Y5is connected to the sugar ring via an alpha configuration. In some embodiments of Formula IId, Y5is connected to the sugar ring via a beta configuration. In some embodiments, the ASGPR ligand moiety (X) of the compounds of this disclosure can be described by Formula IId’: wherein: R6, R4, R3, and Z1are as defined herein; Y5and Y6are each independently selected from -O-, -S-, NR21-, and -C(R22)2; R21is selected from H, optionally substituted (C1-C6)alkyl, and -C(O)R22; each R22is independently selected from H, halogen and optionally substituted (C1-C6)alkyl; and ring B is a 5 or 6-membered optionally substituted cyclic group. In some embodiments of Formula IId-IId’, Y5is O. In some embodiments, Y5is S. In some embodiments, Y5is -NR21-. In some embodiments, Y5is -C(R22)2 and each R22is H. In some embodiments of Formula IId-IId’, Y6is -NR21- where R21is H. In some embodiments, Y6is -NR21- where R21is -C(O)R22. In some cases, R22is methyl. In some embodiments of Formula IId-IId’, the B ring is a 5 or 6-membered heterocycle. In some cases, the B ring is a 5-membered heterocycle. In some cases, the B ring is a 6-membered heterocycle. In some embodiments of Formula IId-IId’, Z1is Z11, where Z11is selected from -O-, -S-, NR21-, and -C(R22)2. In some cases, Z1is -O-. In some cases, Z1is -S-. In some cases, Z1is NR21where R21is H. In some cases, Z1is -C(R22)2where each R22is H. In some embodiments of Formula IId-IId’, Z1is optionally substituted Z11-heteroarylene or optionally substituted Z11-arylene. In some embodiments, Z1is CH2-heteroarylene or CH2-arylene. In some embodiments of Formula IId-IId’, Z1is optionally substituted amide. In some embodiments of Formula IId-IId’, Z1is optionally substituted sulfonamide. In some embodiments of Formula IId-IId’, Z1is optionally substituted urea or optionally substituted thiourea. In some embodiments, X has one of the following structures: . In some embodiments of Formula IIa, IIb, or IId, R6is OH. In certain other cases, R6is -OC(O)R. In some embodiments, R6is -C(O)NHR, where R is an optionally substituted alkyl. In some embodiments, R terminates in an alkenyl or an alkynyl group. In certain other cases R6is optionally substituted triazole. In some embodiments, the triazole is . In some embodiments of Formula IIa or IIc, R2is -NHCOCH3. In some embodiments, R2is - NHCOCF3. In certain other embodiments, R2is -NHCOCH2CF3. In some embodiments, R2is -OH. In some embodiments, R2is an optionally substituted triazole. In some embodiments, the triazole is . In some embodiments, when R6or R2is a substituted triazole, the triazole is a 1,2,3-trizole, and the substituent is at the 4 or 5-position. In some embodiments, the substituent on the triazole moiety includes but is not limited to, an optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkaryl, and an optionally substituted alkyheteroaryl. It will be understood that any convenient substituent can be included in the triazole moiety, see, e.g., triazole moieties disclosed in Mamidayala et al, J. Am. Chem. Soc.2012, 134, 1978-1981. It is understood that the Z1, Z11, and Z11-Ar linking moieties can be considered part of the X group of Formula I. In the ASGPR binding moieties (X) as described herein, -Z1- can be linked to an -L1- moiety (e.g., of the linker as described herein) via a variety of bonds and linking moieties, depending on the method of preparation. In some embodiments, the subject compounds comprise a -Z1-L1- moiety selected from: , wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl; each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl; and o, p, q, r, s, t, u, v, w, x, y, z and z1 are each independently 1 to 6. In some embodiments, o, p, q, r, s, t, u, v, w, x, y, z and z1 are each independently 1 to 6. In some embodiments, the subject compounds comprise a -Z1-L- group selected from: ,

[0009] . In some embodiments, the Z1-L1- group is , where q is 1-3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, the Z1-L1- group is .In some embodiments, the Z1-L1- group is .In some embodiments, the Z1-L1- group is . In some embodiments, -Z1-L1- comprises an optionally substituted -NH-heteroarylene-. In some embodiments the heteroarylene is a triazole. In some embodiments, the heteroarylene is pyridine. In some embodiments, the heteroarylene is pyrimidine. In some embodiments, the heteroarylene is thiadiazole. In some embodiments, the -Z1-L1- comprises a group selected from: , wherein each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl; and R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen. In some embodiments, the -Z1-L1- comprises a group selected from: wherein R24and R25are each independently selected from H, optionally substituted C(1-6)-alkyl, optionally substituted fluoroalkyl, and halogen; and each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted acyl. In some embodiments, R21is H. In some embodiments, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. It is understood that a variety of substituents and chemistries can be utilized to connect a particular X ligand moiety (e.g., as described herein) to an adjacent linker. In some embodiments, a linking moiety of the linker comprises a triazole that derives from a Click chemistry conjugation. In some embodiments, the ASGPR ligand moiety (X) is attached to a linking moiety as shown in one of the following structures: ,

[0010] In some embodiments, R1R3, R4, and R11are H, and R6is OH: wherein Z1is triazole, -NH-heteroaryl (e.g., -NH- attached to pyridine or pyrimidine), -NH-, -O-, or -CH2- , and / or Z1is attached to a linking moiety as shown in one of the following structures: ,

[0011] , In some embodiments, R1R3, R4, and R11are H, and R6is OH: wherein Z1is attached to a linking moiety as shown in one of the following structures M6PR Ligand Moieties In some embodiments, the ligand moiety is a M6PR binding moiety. M6PR binding moieties of the present disclosure (also referred to as M6PR ligand moieties) can be linked to a variety of moieties of interest without impacting the specific binding to, and function of, the cell surface M6PR. The M6PR binding moieties having particular structures described below provide for high affinity binding to cell surface M6PRs, and when configured via a linker according to the bifunctional compounds of this disclosure can utilize the functions of cell surface M6PRs in a biological system, e.g., for internalization, and / or degradation of a target molecule. The terms “mannose-6-phosphate receptor” and “M6PR” refer to receptors of the family of mannose-6-phosphate receptors. M6PRs are transmembrane glycoprotein receptors that target enzymes to lysosomes in cells. MP6R endogenously transports proteins bearing N-glycans capped with mannose-6- phosphate (M6P) residues to lysosomes, and cycles between endosomes, the cell surface, and the Golgi complex. See, e.g., Ghosh et al., Nat. Rev. Mol. Cell Biol.2003; 4: 202-213. The family of M6PRs includes the cation independent mannose-6-phosphate receptor (CI-M6PR). The CI-M6PR is also referred to as the insulin-like growth factor 2 receptor (IGF2R) and is encoded in humans by the IGF2R gene (see, e.g., NCBI Reference Sequence: NM_000876.3, and NCBI Gene ID: 3482). The CI-M6PR binds insulin- like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P)-tagged proteins. The compounds of this disclosure can specifically bind to a cell surface M6PR, for example, an internalizing CI-M6PR cell surface receptor. In particular embodiments, the surface CI-M6PR is a human CI-M6PR. It is understood that the terms M6PR and CI-M6PR are used interchangeably when referring to the binding properties of the M6PR binding moieties and compounds of this disclosure. A compound comprising such M6PR binding moiety (X) (e.g., as described herein), may bind to other receptors, for example, may bind with lower affinity as determined by, e.g., immunoassays or other assays known in the art. In a specific embodiment, X, or a compound as described herein including such X specifically binds to a cell surface CI-M6PR with an affinity that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the affinity when X or the compound bind to another cell surface receptor. In a specific embodiment, X, or a compound as described herein comprising X, specifically binds to CI-M6PR with an affinity (Kd) 20 mM or less. In particular embodiments, such binding is with an affinity (Kd) is 10 mM or less, 1 mM or less, 100 µM or less, 10 µM or less, 1 µM or less, 100 nM or less, 10 nM or less, or 1 nM or less. The terms “binds,” “binds to,” “specifically binds” or “specifically binds to” in this context are used interchangeably. The M6PR binding compounds of this disclosure include a moiety (X) (e.g., as described herein) which is a D-mannopyranose analog that specifically binds to the cell surface receptor M6PR. The M6PR binding compounds can be monovalent or multivalent (e.g., bivalent, or trivalent or of higher valency), where a monovalent compound includes a single M6PR ligand moiety, and a monovalent compound includes two or more such moieties. In some embodiments, the M6PR binding moiety of the compounds of this disclosure can include a linked pyranose ring described by Formula II′′: where: W is a hydrophilic head group; Z1is selected from optionally substituted (C1-C3)alkylene and optionally substituted ethenylene; Z2is selected from O, S, NR21and C(R22)2, wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl, and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl. In some embodiments Z2is not O. In some embodiments, Z2is a linking moiety connected to the pyranose sugar ring at the anomeric or 1-position with an alpha-configuration as shown in Formula IIa′′ below: Although it has been demonstrated that M6PR binding compounds having a M6PR binding moiety with an anomeric alpha-configuration of Formula IIa′′ can provide good binding and internalization activity at the receptor, in some cases it is possible to impart more potent binding and internalization activity at the M6PR by configuring the central pyranose sugar ring of the M6PR binding moiety with a beta-configuration at the anomeric position. In some embodiments, such M6PR binding moieties can provide for increased stability at the pyranose ring. Accordingly, in some embodiments of Formula IIa′′, Z2is a linking moiety connected to the sugar ring at the anomeric or 1-position with a beta-configuration as shown in Formula IIb′′ below: Although moieties of Formula II′′ can exhibit binding activity for the M6PR, it has been demonstrated that when particular types of cyclic groups are linked with a particular configuration adjacent to the pyranose ring of Formula II′′ via the linking moiety Z2, a M6PR binding moiety of desirable binding activity can be produced. Accordingly, in some embodiments of Formula II′′, the M6PR binding moiety (X) can be described by Formula III′′: or a prodrug thereof, or a salt thereof, wherein: W is a hydrophilic head group; Z1is selected from optionally substituted (C1-C3)alkylene and optionally substituted ethenylene; Z2is selected from O, S, NR21and C(R22)2, wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl, and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl; A is independently an optionally substituted cyclic group; and Z3is independently a linking moiety. In some embodiments of Formula II′′-III′′, W is a non-hydrolyzable hydrophilic head group. In some embodiments of Formula II′′-III′′, Z2is optionally substituted ethylene. In some embodiments of Formula II′′-III′′, Z2is optionally substituted ethenylene. In some embodiments, Z2is O. In some embodiments, Z2is S. In some embodiments, Z2is -NR21- . In some embodiments, Z2is -C(R22)2-, wherein each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl. In some embodiments, Z2is -CH2-. In some embodiments, A is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, or optionally substituted cycloalkyl. In some embodiments, A is independently an optionally substituted aryl or heteroaryl linking moiety (e.g., monocyclic or bicyclic aryl or heteroaryl, optionally substituted). Exemplary Z3linking moieties are described herein. M6PR-binding moieties disclosed herein can be attached to a moiety or molecule of interest to produce a bifunctional compound that undergoes effective M6PR-mediated cell internalization. The inventors have further demonstrated that when the moiety or molecule of interest is a target protein- binding moiety, the M6PR binding compound also provides for M6PR mediated internalization and / or degradation of bound target protein. Accordingly, the M6PR binding compound is of Formula XII: or a prodrug thereof, or a salt thereof, wherein: W is a hydrophilic head group; Z1is selected from optionally substituted (C1-C3)alkylene and optionally substituted ethenylene; Z2is selected from O, S, NR21and C(R22)2; wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl, and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl; A is independently an optionally substituted cyclic group; Z3is independently a linking moiety; n is 1 to 500; L is a linker; Y is a moiety of interest; and m is 1 to 100. In some embodiments, the cell surface M6PR binding compound is of Formula XIII: or a prodrug thereof, or a salt thereof, wherein: W is a hydrophilic head group; Z1is selected from optionally substituted (C1-C3)alkylene and optionally substituted ethenylene; Z2is selected from O, S, NR21and C(R22)2, wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl, and each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl; A is independently an optionally substituted cyclic group; Z3is independently a linking moiety; n is 1 to 500; L is a linker; and Y is a moiety of interest (e.g., as described herein). In some embodiments, n is 1. In some embodiments, n is 2, 3, 4, or 5. In some embodiments, n is 5-10. In some embodiments, n is 10-100, such as 20-80, or 20-50. In some embodiments, when n is 5 or more, then L is a polypeptide containing linker (e.g., as described herein). In some embodiments of Formula XII-XIII, when n is 1 and A is phenyl, then: i) L comprises a backbone of at least 16 consecutive atoms (e.g., at least 18 consecutive atoms, or at least 20 consecutive atoms, in some cases up to about 200 consecutive atoms); ii) Y is a biomolecule; and / or ii) Z3is amide, sulfonamide, urea or thiourea linking moiety to linker L. In some embodiments, Z2is a linking moiety connected to the sugar ring at the anomeric or 1- position with an alpha-configuration such that the compound is of Formula XIIa: XIIa. In some embodiments, Z2is a linking moiety connected to the sugar ring at the anomeric or 1- position with a beta-configuration, such that the compound is of Formula XIIb: XIIb. In some embodiments of Formula XI-XIIb, multiple M6PR binding moieties, e.g., of Formula III, are linked via multiple linkers L to different ligation sites on a moiety of interest Y. Hydrophilic Head Groups and Linking Moieties In some embodiments of the M6PR binding moiety, X includes an analog of a D-mannopyranose ring, with a hydrophilic head group, or a precursor or prodrug thereof, that is connected via a linking moiety (Z1) to the 5-position of the sugar ring. The linking moiety can be of 1-6 atoms in length, such as 1-5, 1-4 or 1-3 atoms in length, e.g., 1 or 2 atoms in length. It is understood that the length of the linking moiety can be selected in conjunction with the hydrophilic head group. The hydrophilic head group (W) can be any suitable negatively charged group, or salt thereof. In some embodiments, the hydrophilic head group is a neutral, polar, hydrophilic group. In general, the hydrophilic head group is capable of hydrogen bonding or electrostatic interactions with the M6PR, under aqueous or physiological conditions, similar to those of the phosphate group of M6P. The hydrophilic head group can be a bioisostere (e.g., a structural or functional mimic) of the 6-phosphate group of the naturally occurring mannose-6-phosphate ligand. In some embodiments, the hydrophilic head group is non-hydrolyzable, i.e., a functional group that is stable against its cleavage (e.g., chemically or enzymatically) under physiological conditions, from the Z1linking moiety and / or pyranose ring of X to which the hydrophilic head group is attached. The hydrophilic head group is generally a small group, such as a heteroatom containing functional group, or single heterocyclic ring, and in some cases has a MW of less than 200, such as less than 150, or less than 100. In some embodiments, the hydrophilic head group is a phosphonate, or a bioisostere thereof, such as a carboxylate or malonate. In some embodiments, the hydrophilic head group is a thiophosphonate. In some embodiments, the hydrophilic head group is not a phosphate, thiophosphate or dithiophosphate, as such groups would have phosphate ester linkages to the compound which can be unstable and susceptible to cleavage under physiological conditions (e.g., by phosphatases in a biological system or chemically). For example, the 6-phosphate ester group of M6P exhibits undesirable stability as compared to a phosphonate analog, or other more stable head group. This disclosure provides alternative non-hydrolyzable head groups in addition to phosphonate which retain binding and internalization activity of the resulting M6PR binding compound. In some embodiments, the hydrophilic head group W is selected from –OH, –CR2R2OH, , thereof, wherein: R1and R2are independently hydrogen, SR3, halo, or CN, and R3and R4are independently H, C1-6 alkyl or substituted C1-6alkyl (e.g., -CF3or -CH2CF3); A, B, and C are each independently CH or N; and D is each independently O or S. In some embodiments, the hydrophilic head group W is phosphate or thiophosphate, e.g., – OP=O(OH)2, –SP=O(OH)2, –OP=O(SH)(OH), –SP=O(SH)(OH), –OP=S(OH)2, –OP=O(N(R3)2)(OH), or –OP=O(R3)(OH), or a salt thereof. In some embodiments of formula (II)-(XIII), the hydrophilic head group W is non-hydrolyzable, and accordingly, is not selected from phosphate or thiophosphate, e.g., – OP=O(OH)2, –SP=O(OH)2, –OP=O(SH)(OH), –SP=O(SH)(OH), –OP=S(OH)2, –OP=O(N(R3)2)(OH), or –OP=O(R3)(OH), or a salt thereof. In some embodiments, the hydrophilic head group W is charged, e.g., capable of forming a salt under aqueous or physiological conditions. In some embodiments of formula (II)-(XIII), the hydrophilic head group W is selected from –NR3P=O(OH)2, –P=O(OH)2, –P=S(OH)2, –P=O(SH)(OH), – P=S(SH)(OH), P(=O)R1OH, -PH(=O)OH, –(CR2R2)-P=O(OH)2 ,–COOH, –CH(COOH)2, – CR1R2COOH, and -NHC(O)CO2H. In some embodiments, the hydrophilic head group W is phosphonate or thiophosphonate (e.g., – P=O(OH)2, –P=S(OH)2, –P=O(SH)(OH), or –P=S(SH)(OH), or a salt thereof). In some embodiments of formula (II)-(XIII), the hydrophilic head group W is phosphonate or a salt thereof. In some embodiments of formula (II)-(XIII), the hydrophilic head group W is –CO2H or a salt thereof. In some embodiments of formula (II)-(XIII), the hydrophilic head group W is malonate (e.g., –CH(COOH)2 or a salt thereof). In some embodiments of formula (II)-(XIII), the hydrophilic head group W is selected from – SO2OH (i.e., –SO3H), –S(O)OH, –OSO2OH, and –NHSO3H. In some embodiments of formula (II)- (XIII), the hydrophilic head group W is sulfonate (e.g., –SO3H or a salt thereof). In some embodiments, the hydrophilic head group W is neutral hydrophilic. In some embodiments of formula (II)-(XIII), the hydrophilic head group W is selected from –OH, –CR2R2OH, – CN, -CONH2, –CONHR3, –CONR3R4, –CONH(OH), –CONH(OR3), –CONHSO2R3, –SO2R3,–SOR3R4, – SO2NH2, –SO2NHR3, –SO2NR3R4, –SO2NHCOR3, –NHCOR3, –NHSO2NHR3, -NHC(O)NHS(O)2R3, and –NHSO2R3. In some embodiments, the hydrophilic head group W comprises a heterocycle, such as, wherein A, B, and C are each independently CH or N; and D is each independently O or S. In some embodiments, the hydrophilic head group W comprises a 5-membered heterocycle, such .In some embodiments, the hydrophilic head group W is linked to the pyranose ring via a Z1that is selected from optionally substituted (C1-C2)alkylene and optionally substituted ethenylene. The Z1can be selected in conjunction with W so as to provide a desired spacing between the 5-position of the ring and the charged or polar center of W. For example, when W is a malonate having a CH atom linking the two carboxylic acid groups, Z1can be methylene, which together provide a desirable two carbon spacer between the ring and the COOH groups. In some embodiments, Z1is methylene or substituted methylene. In some embodiments of formula (II)-(XIII), Z1is ethyl or substituted ethyl. In some embodiments, Z1is ethenylene or substituted ethenylene. In some embodiments, Z1is substituted with one or more halogen, e.g., fluoro. In some embodiments, the M6PR binding moiety (X) is of Formula IV-1 to IV-3: IV-1 IV-2 IV-3 wherein Ra, Rb, Rcand Rdare independently H or F. In some embodiments, Z2is O. In some embodiments, Z2is S. In some embodiments, Z2is -NR21-. In some embodiments, Z2is -C(R22)2-, wherein each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl. In some embodiments, Z2is -CH2-. In some embodiments, Ra, Rb, Rcand Rdare each H. In some embodiments, Rais H and Rbis F. In some embodiments, Raand Rbare each F. In some embodiments, Rcis H. In some embodiments, Rcis F. In some embodiments, Rdis H. In some embodiments, Rdis F. In some embodiments, W is selected from –P=O(OH)2, –P=S(OH)2, –P=O(SH)(OH), – P=S(SH)(OH), and –COOH, or a salt thereof. In some embodiments, W is –P=O(OH)2, or a salt thereof. In some embodiments, W is COOH, or a salt thereof. In some embodiments, Raand Rbare each F, and W is –P=O(OH)2, or a salt thereof. In some embodiments Raand Rbare each H, and W is –P=O(OH)2, or a salt thereof. In some embodiments Rais F, Rbis H, and W is –P=O(OH)2, or a salt thereof. In some embodiments, Z2is linked to the anomeric position of the pyranose ring with an alpha- configuration. In such cases, the M6PR binding moiety (X) of Formula IV-1 to IV-3 can be referred to as Formula IV-A1 to IV-A3, respectively. In some embodiments of Formula IV-A1 to IV-A3, Z2is S. In some embodiments of formula (IV-A1) to (IV-A3), Z2is O. In some embodiments of Formula IV-A1 to IV-A3, Z2is -CH2-. In some embodiments of Formula IV-A1 to IV-A3, Z2is -CF2-. In some embodiments of Formula IV-A1 to IV-A3, W is selected from –P=O(OH)2, –P=S(OH)2, –P=O(SH)(OH), –P=S(SH)(OH), and –COOH, or a salt thereof. In some embodiments of Formula IV-A1 to IV-A3, W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-A1 to IV-A3, W is COOH, or a salt thereof. In some embodiments of Formula IV-A1 Raand Rbare each F, and W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-A1 Raand Rbare each H, and W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-A1 Rais F, Rbis H, and W is –P=O(OH)2, or a salt thereof. In some embodiments, Z2is linked to the anomeric position of the pyranose ring with a beta- configuration. The inventors demonstrated that a compound including a M6PR binding moiety having a β–glycoside configuration can have at least equivalent binding and / or cellular uptake activity as compared to a conjugate having the corresponding α-glycoside configuration. In some embodiments, such M6PR binding moieties having a β–glycoside configuration can provide increased stability as compared to a reference compound having a β–glycoside configuration. Accordingly, in some embodiments, the M6PR binding moiety (X) is described by one of Formula IV-B1 to IV-B3: IV-B1 IV-B2 IV-B3 wherein Ra, Rb, Rcand Rdare independently H or F. In some embodiments of Formula IV-B1 to IV-B3, Z2is S. In some embodiments of Formula IV-B1 to IV-B3, Z2is O. In some embodiments of Formula IV-B1 to IV-B3, Z2is -CH2-. In some embodiments of Formula IV-B1 to IV-B3, Z2is -CF2-. In some embodiments of Formula IV-B1 to IV-B3, W is selected from –P=O(OH)2, –P=S(OH)2, –P=O(SH)(OH), –P=S(SH)(OH), and –COOH, or a salt thereof. In some embodiments of Formula IV-B1 to IV-B3, W is selected from –P=O(OH)2, –P=S(OH)2, –P=O(SH)(OH), –P=S(SH)(OH), and –COOH, or a salt thereof. In some embodiments of Formula IV-B1 to IV-B3, W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-B1 to IV-B3, W is COOH, or a salt thereof. In some embodiments of Formula IV-B1 Raand Rbare each F, and W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-B1 Raand Rbare each H, and W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-B1 Rais F, Rbis H, and W is –P=O(OH)2, or a salt thereof. It has been demonstrated that a conjugate including M6PR binding moiety having a β–S- glycoside configuration can have at least equivalent or superior binding and / or cellular uptake activity as compared to a conjugate having the corresponding α–S-glycoside configuration, or to a conjugate having an α–O-glycoside configuration. Accordingly, in some embodiments of Formula IV-B1 to IV-B3, the M6PR binding moiety (X) is described by one of Formula IV-BS1 to IV-BS3: (IV-BS1) (IV-BS1) (IV-BS1) wherein Ra, Rb, Rcand Rdare independently H or F. In some embodiments of Formula IV-BS1 to IV-BS3, Ra, Rb, Rcand Rdare each H. In some embodiments of Formula IV-BS1 Rais H and Rbis F. In some embodiments of Formula IV-BS1 Raand Rbare each F. In some embodiments of Formula IV-BS2 Rcis H. In some embodiments of Formula IV-BS2 Rcis F. In some embodiments of Formula IV-BS3 Rdis H. In some embodiments of Formula IV-BS3 Rdis F. In some embodiments of Formula IV-BS1 to IV-BS3, Z2is S. In some embodiments of Formula IV-BS1 to IV-BS3, Z2is O. In some embodiments of Formula IV-BS1 to IV-BS3, Z2is -CH2-. In some embodiments of Formula IV-BS1 to IV-BS3, Z2is -CF2-. In some embodiments of Formula IV-BS1 and IV-BS3, W is selected from –P=O(OH)2, – P=S(OH)2, –P=O(SH)(OH), –P=S(SH)(OH), and –COOH, or a salt thereof. In some embodiments of Formula IV-BS1 and IV-BS3, W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV- BS1 and IV-BS3, W is COOH, or a salt thereof. In some embodiments of Formula IV-BS1 Raand Rbare each F, and W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-BS1 Raand Rbare each H, and W is –P=O(OH)2, or a salt thereof. In some embodiments of Formula IV-BS1 Rais F, Rbis H, and W is –P=O(OH)2, or a salt thereof. In some embodiments, the mannose ring or analog thereof of the M6PR binding moiety can be incorporated into the compounds of this disclosure by attachment of a linking moiety to the Z2group attached at the anomeric or 1-position of the sugar ring. In some embodiments, the M6PR binding moiety is incorporated into the compounds of this disclosure by attachment of a linker to the Z3group attached to the cyclic group A. It is understood that in the compounds of Formula III, the cyclic group attached to Z2can be considered part of the M6PR binding moiety (X) and provide for a desirable binding property to the M6PR. Cyclic group A The A cyclic group of Formula III-XIII can be a monocyclic or bicyclic group. A bicyclic group of interest can be a fused bicyclic group or a bicyclic group containing two monocyclic linked via a covalent bond. The A cyclic group of Formula III-XIII can be optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle (e.g., saturated heterocycle), or optionally substituted cycloalkyl. The A cyclic group of Formula III-XIII can be a monocyclic aryl or monocyclic heteroaryl group. In some embodiments of Formula III-XIII, A is a 5-membered monocyclic heteroaryl group. In some embodiments of Formula III-XIII, A is a 6-membered monocyclic aryl or heteroaryl group. In some embodiments of Formula III-XIII, A can be a multicyclic aryl or multicyclic heteroaryl group, such as a bicyclic aryl or bicyclic heteroaryl group. In some embodiments of Formula III-XIII, A is a fused bicyclic group. In some embodiments of Formula III-XIII, A is a bicyclic group comprising two aryl and / or heteroaryl monocyclic rings connected via a covalent bond. In some embodiments of Formula III-XIII, A is a bicyclic aryl or bicyclic heteroaryl group having two 6-membered rings. In some embodiments of Formula III-XIII, A is a bicyclic aryl or bicyclic heteroaryl group having one 6-membered ring that is connected via a covalent bond or fused to a 5-membered ring. In some embodiments of Formula III-XIII, A is selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted quinoline, optionally substituted triazole and optionally substituted phenylene- triazole. In some embodiments of Formula III-XIII, A is not phenyl (also referred to as phenylene in the context of formula (III), e.g., 1,4-phenylene). In some embodiments of Formula III-XIII, A is substituted with at least one OH substituent. In some embodiments of Formula III-XIII, A is substituted with 1, 2, or more OH groups. In some embodiments of Formula III-XIII, A is substituted with at least one optionally substituted (C1-C6)alkyl. In some embodiments of Formula III-XIII, A is optionally substituted 1,4-phenylene, optionally substituted 1,3-phenylene, or optionally substituted 2,5-pyridylene. In some embodiments of Formula III-XIII, A is selected from: wherein: R11to R14is independently selected from H, halogen, OH, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, COOH, NO2, CN, NH2, -N(R25)2, -OCOR25, -COOR25, -CONHR25, and -NHCOR25; and R25is independently selected from H, and optionally substituted (C1-C6)alkyl. In some embodiments of Formula III-XIII, A is optionally substituted fused bicyclic aryl or optionally substituted fused bicyclic heteroaryl. In some embodiments of Formula III-XIII, A is optionally substituted naphthalene or optionally substituted quinoline. In some embodiments of Formula III-XIII, A is selected from: , wherein: R11and R13to R14is independently selected from H, halogen, OH, optionally substituted (C1- C6)alkyl, optionally substituted (C1-C6)alkoxy, COOH, NO2, CN, NH2, -N(R25)2, -OCOR25, -COOR25, - CONHR25, and -NHCOR25; s is 0 to 3; and each R25is independently selected from H, and optionally substituted (C1-C6)alkyl. In some embodiments of Formula III-XIII, A is selected from: In some embodiments of Formula III-XIII, A is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl of following formula: or a salt thereof, wherein: Cy is independently monocyclic aryl or monocyclic heteroaryl; R11to R15is independently selected from H, halogen, OH, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, COOH, NO2, CN, NH2, -N(R25)2, -OCOR25, -COOR25, -CONHR25, and -NHCOR25; s is 0 to 4; and each R25is independently selected from H, and optionally substituted (C1-C6)alkyl. In some embodiments, when Cy is optionally substituted phenyl, then A is optionally substituted biphenyl of the formula: . In some embodiments of Formula III-XIII, A is selected from: In some embodiments, when Cy is triazole, then A is selected from: . In some embodiments, at least one of R11to R15is OH (e.g., at least two are OH). In some embodiments, R11to R15are each H. Linking Moiety Z3The linking moiety Z3can be any convenient linking moiety that connects the linker L to the cyclic ring A. In some embodiments, Z3is has a backbone of 3 atoms or less. In some embodiments, Z3is selected from a covalent bond, -O-, -NR23-, -NR23CO-, -CONR23-, - NR23CO2-, -OCONR23, -NR23C(=X1)NR23-, -CR24=N-, -CR24=N-X2, -N(R23)SO2- and -SO2N(R23)-; wherein X1and X2are selected from O, S and NR23; and R23and R24are independently selected from H, C(1-3)-alkyl (e.g., methyl) and substituted C(1-3)-alkyl. In some embodiments, Z3is a covalent bond connecting A to L. In some embodiments, Z3is optionally substituted amido, urea or thiourea.In some embodiments, wherein:X1is O or S; t is 0 or 1; and each R23is independently selected from H, C(1-3)-alkyl (e.g., methyl or ethyl) and substituted C(1-3)-alkyl. In some embodiments of Z3, X1is O. In some embodiments of Z3, X1is S. In some embodiments of Z3, t is 0 and X1is O, such that Z3is amido. In some embodiments of Z3, t is 1 such that Z3is urea or thiourea. In some embodiments, Z3is -N(R23)SO2- or -SO2N(R23)-. In some embodiments, Z3is -NHSO2- or -SO2NH-. In some embodiments, Z3is -N(R23)CO- or -CON(R23)-. In some embodiments, Z3is -NHCO- or -CONH-. In some embodiments, Z3is -NHC(=X1)NH-, wherein X1is O or S. In some embodiments, X1is O (i.e., Z3is -NHC(=O)NH-). In some embodiments, X1is S. In some embodiments, Z3is optionally substituted triazole. When Z3is optionally substituted triazole, it can be synthetically derived from click chemistry conjugation of an azido containing precursor and an alkyne containing precursor of the compound. In some embodiments, Z3is selected in combination with cyclic group A and / or linking moiety Z1to provide desirable M6PR binding and internalization properties for X. In some embodiments of Formula III-XIII, -A-Z3- is selected from: In some embodiments, -A-Z3- is .

[0012] In some embodiments of Formula III-XIII, Z2is O. In some embodiments of Formula III-XIII, Z2is S. In some embodiments of Formula III-XIII, Z2is -NR21-. In some embodiments of Formula III-XIII, Z2is -C(R22)2-, wherein each R22is independently selected from H, halogen (e.g., F) and optionally substituted (C1-C6)alkyl. In some embodiments, Z2is - CH2-. In some embodiments, Z2is -CHF-. In some embodiments, Z2is -CF2-. In some embodiments, ; wherein: Z21is O, S, or -C(R22)2-; R16is OH or CH3; and w is 0 to 4 (e.g., w is 0, 1, or 2). In some embodiments, Z21is S or O. In some embodiments, Z21is -CH2-. In some embodiments, Z21is -CHF-. In some embodiments, Z21is -CF2-. In some embodiments, R16is OH and w is 1. In some embodiments, R16is CH3and w is 1. In some embodiments, w is 0. In some embodiments, -Z2-A-Z3- is selected from , . Prodrugs Aspects of this disclosure include prodrugs of any of the ASGPR ligand moieties described herein that are incorporated into the linker compounds and conjugates of this disclosure. The term “prodrug” refers to an agent which is converted into the drug in vivo by some physiological or chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Prodrugs forms of any of the ASGPR ligand moieties described herein can be useful because, for example, can lead to particular therapeutic benefits as a consequence of an extension of the half-life of the resulting compound or conjugate in the body or a reduction in the active dose required. Prodrugs can also be useful in some situations, as they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmacological compositions over the parent drug. A prodrug derivative of a ASGPR ligand moiety generally includes a labile promoiety substituent at a suitable site of the moiety. The promoiety refers to the group that is removed by enzymatic or chemical reactions, when a prodrug is converted to the drug in vivo. In some embodiments, the promoiety is a group, such as an optionally substituted alkanoyl, attached via an ester linkage to a hydroxyl group of the moiety. In some embodiments, a prodrug derivative of one or more of the hydroxyl groups of the sugar ring of the ASGPR ligand moiety may be incorporated into the compounds. For example, an ester promoiety can be incorporated at one or more of the hydroxyl groups at the 3 and / or 4 positions of the core sugar ring (e.g., as described in Formula (II)). In some embodiments, the hydroxyl groups at the 3 and 4 positions of the core sugar ring are cyclically linked to form a promoiety (e.g., as described herein). In some embodiments, the promoiety is the part of an ester group attached to a hydroxyl of X, such as -C(O)CH3, -C(O)CH(CH3)2, -C(O)C(CH3)3, or -CH2OC(O)C(CH3)3. In some embodiments, the promoiety is -CH2OC(O)C(CH3)3. In some embodiments, a promoiety cyclically links two adjacent hydroxyl groups via a carbonate linkage, i.e., a cyclic carbonate. Linker The terms “linker,” “linking moiety,” and “linking group” are used interchangeably and refer to a linking moiety or multiple (e.g., 1-20) linker components that covalently connects two or more moieties or compounds, such as ligands and other moieties of interest. In some cases, the linker is divalent and connects two moieties. In some embodiments, the linker is a branched linking group that is trivalent or of a higher multivalency. In some cases, the linker that connects the two or more moieties has a linear or branched backbone of 500 atoms or less (such as 400 atoms or less, 300 atoms or less, 200 atoms or less, 100 atoms or less, 80 atoms or less, 60 atoms or less, 50 atoms or less, 40 atoms or less, 30 atoms or less, or even 20 atoms or less) in length, e.g., as measured between the two or more moieties. A linker may be a covalent bond that connects two groups or a linear or branched chain of between 1 and 500 atoms in length, for example of about 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 100, 150, 200, 300, 400 or 500 atoms in length, where the linker may be linear, branched, cyclic or a single atom. In some embodiments, one, two, three, four, five or more, ten or more, or even more carbon atoms of a linker backbone may be optionally substituted with heteroatoms, e.g., sulfur, nitrogen, or oxygen heteroatom. In certain instances, when the linker includes a PEG group, every third atom of that segment of the linker backbone is substituted with an oxygen. The bonds between backbone atoms may be saturated or unsaturated, usually not more than one, two, or three unsaturated bonds will be present in a linker backbone. The linker may include one or more substituent groups, for example an alkyl, aryl, or alkenyl group. A linker may include, without limitations, one or more of the following: oligo(ethylene glycol), ether, thioether, disulfide, amide, carbonate, carbamate, tertiary amine, alkyl which may be straight or branched, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t- butyl), and the like. The linker backbone may include a cyclic group, for example, an aryl, a heterocycle, a cycloalkyl group or a heterocycle group, where 2 or more atoms, e.g., 2, 3, or 4 atoms, of the cyclic group are included in the backbone. In some embodiments, a “linker” or “linking moiety” is derived from a molecule with two reactive termini, one for conjugation to a moiety of interest (Y), e.g., a biomolecule (e.g., an antibody) and the other for conjugation to a moiety (noted as X) that binds to a ASGPR cell surface receptor. When Y is a polypeptide, the polypeptide conjugation reactive terminus of the linker is in some cases a site that is capable of conjugation to the polypeptide through a cysteine thiol or lysine amine group on the polypeptide, and so is can be a thiol-reactive group such as a maleimide or a dibromomaleimide, or as defined herein, or an amine-reactive group such as an active ester (e.g., perfluorophenyl ester or tetrafluorophenyl ester), or as defined herein. In some embodiments of the formula described herein, the linker (i.e., L1-L6) comprises one or more straight or branched-chain carbon moieties and / or polyether (e.g., ethylene glycol) moieties (e.g., repeating units of -CH2CH2O-), and combinations thereof. In some embodiments, these linkers optionally have amide linkages, urea or thiourea linkages, carbamate linkages, ester linkages, amino linkages, ether linkages, thioether linkages, sulfhydryl linkages, heteroaryl linkages, or other hetero functional linkages. In some embodiments, the linker comprises one or more carbon atoms, nitrogen atoms, sulfur atoms, oxygen atoms, and combinations thereof. In some embodiments, the linker comprises one or more of an ether bond, thioether bond, amine bond, amide bond, carbon-carbon bond, carbon-nitrogen bond, carbon- oxygen bond, carbon-sulfur bond, and combinations thereof. In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure. In some embodiments, the linker comprises one or more heteroaryl cyclic structures, e.g., a triazole, such as a 1,2,3-traizole. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 4 to 500 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 4 to 50 consecutive atoms. In some embodiments, linker separates X and Y by a chain of 6 to 50 consecutive atoms, by a chain of 11 to 50 consecutive atoms, by a chain of 16 to 50 consecutive atoms, by a chain of 21 to 50 consecutive atoms, by a chain of 26 to 50 consecutive atoms, by a chain of 31 to 50 consecutive atoms, by a chain of 36 to 50 consecutive atoms, by a chain of 41 to 50 consecutive atoms, or by a chain of 46 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 6 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 11 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 16 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 21 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 26 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 31 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 36 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) separates X and Y by a chain of 41 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1- L6) separates X and Y by a chain of 46 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) is a chain of 5 to 500 consecutive atoms separating X and Y and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In some embodiments, the linker (i.e., L1-L6) is a chain of 7 to 500 consecutive atoms separating X and Y and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In some embodiments, the linker (i.e., L1-L6) is a chain of 10 to 500 consecutive atoms separating X and Y and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In some embodiments, the linker (i.e., L1-L6) is a chain of 15 to 400 consecutive atoms separating X and Y and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or heteroatom linked to X. In some embodiments, the linker (i.e., L1-L6) is a chain of 16 to 400 consecutive atoms separating X and Y (or Z) and which comprises an optionally substituted arylene linked to X, optionally substituted heteroarylene linked to X, optionally substituted alkylene linked to X, or a heteroatom linked to X. In some embodiments, L is of Formula XII: wherein each L1to L5is independently a linker component which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 0, 1, or 2; ** represents the point of attachment of L1to X via Z1; and *** represents the point of attachment to Y; wherein: when n is 1, a is 1, and c is 0; and when n is >1, a is 1, and c is 1. It is understood that the linker may be considered as connecting directly to a Z1group of a ASGPR ligand moiety (X) (e.g., as described herein). In some embodiments, the linker may be considered as connecting directly to the Z1group. Alternatively, the -Z1-L1- group (e.g., as described herein) can be considered part of a linking moiety that connects L to Y. The disclosure is meant to include all such configurations of ASGPR ligand moiety (X) and linker (L). In some embodiments of Formula XII, L1includes a linear backbone of 6 to 40 consecutive atoms, such as 10 to 40, 10 to 30, 16 to 30, or 20 to 30 consecutive atoms. In some embodiments of Formula XII, the linking moiety L1includes a linear backbone of each L1comprises a linear backbone of 6 to 20 consecutive atoms, such as 6 to 16 consecutive atoms, such as 8, 9, 10, 11, 12, 13, 14, 15 or 16 consecutive atoms. In some embodiments, the linker of Formula XII includes one or repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In some embodiments, the linker of Formula XII includes 1 to 10 ethylene glycol moieties, such as 1, 2, 3, 4, 5 or 6 ethylene glycol moieties. In some embodiments, the linker of Formula XII includes one or more triazole (e.g., 1,2,3- triazole) containing linker components. It is understood that the triazole may be derived from an azido- alkyne click chemistry and thus have two possible orientations depending on the method of synthesis: In some embodiments, the triazole containing linker component is: wherein w1 and u1 are independently 0 to 12, such as 0, 1, 2, 3, 4, 5 or 6. In some embodiments of the linker of Formula XII, d is 1 and the linker component L4is selected from one of Formula L2A-L2D: wherein: each Z2and Z3is independently absent or selected from -NHCO-, -CONH-, -CO-, -O-, -NH-, and -NCH3-; x is 1 to 12 (e.g., 1 to 6, or 1 to 3); and y is 0 to 12 (e.g., 1 to 6, or 1 to 3). In some embodiments of any one of Formula L2A-L2D, Z2is -NHCO-. In some embodiments of any one of Formula L2A-L2D, Z2is -CONH-. In some embodiments of any one of Formula L2A- L2D, Z2is -CO-. In some embodiments of any one of Formula L2A-L2D, Z2is -O-. In some embodiments of any one of Formula L2A-L2D, Z2is -NH-. In some embodiments of any one of Formula L2A-L2D, Z2is -NCH3-. In some embodiments of any one of Formula L2A-L2D, Z2is absent. In some embodiments of any one of Formula L2A-L2D, Z3is -NHCO-. In some embodiments of any one of Formula L2A-L2D, Z3is -CONH-. In some embodiments of any one of Formula L2A- L2D, Z3is -CO-. In some embodiments of any one of Formula L2A-L2D, Z3is -O-. In some embodiments of any one of Formula L2A-L2D, Z3is -NH-. In some embodiments of any one of Formula L2A-L2D, Z3is - NCH3-. In some embodiments of any one of Formula L2A-L2D, Z3is absent. In some embodiments of Formula L2A, Z2is -O-, y is 0, and the linker comprises a linker component Formula L2Ai: In some embodiments of Formula L2B, Z2is -O- or -CO-, and the linker comprises a linker component of Formula L2Bi or L2Bii: In some embodiments of Formula L2C, Z2is -O-, -C(O)-, -NHC(O)-, or -NH-, and the linker comprises a linker component of Formula L2Ci, L2Cii, L2Ciii, or L2Civ: .In some embodiments, of any one of Formula L2A- L2Civ, x is 1 to 6. In some embodiments, x is 1 to 3. In some embodiments, x is 1. In some cases, x is 2. In some embodiments, x is 3. In some embodiments of Formula L2D, Z2is absent and the linker comprises a linker component of Formula L2Di: In some embodiments of any one of Formula L2A-L2Di, y is 0 to 6. In some embodiments, y is 0 to 3. In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments of Formula XII, d is 1 and the linker component L4is selected from: In some embodiments of Formula XII, d is 1 and the linker component L4is Formula XIV: wherein: r is 1 or 2; and when n is 2, r is 1, when n is 3, r is 2. In some embodiments of the linker of formula (XI), b is 1 and the linker component L2is Formula Xva or XVb: wherein: r is 1 or 2; and when n is 2, r is 1, when n is 3, r is 2. In some embodiments L2is of Formula XIIIa or XIIIb and L2includes two 2 or more amino acid residues (e.g., 3 or more, or 4 or more amino acid residues, linear or dendrimer). In some embodiments, L2includes 4 or more amino acid residues that are branched linker components selected from Lys, Orn, Asp, Glu, Ser, and Cys (e.g., where the sidechain, amino and carboxylic acid are each linked to an adjacent moiety). In some embodiments, Formula XVI includes a linear backbone of 6 to 40 consecutive atoms, such as 10 to 40, 10 to 30, or 20 to 30 consecutive atoms. In some embodiments, Formula XVI includes repeating ethylene glycol moieties (e.g., - CH2CH2O- or -OCH2CH2-). In some embodiments, Formula XVI includes 2 to 20 ethylene glycol moieties, such as 2 to 15, 2 to 10, 3 to 20, 3 to 15, 3 to 10, 4 to 15, 5 to 15 or 5 to 10 ethylene glycol moieties. In some instances, Formula XVI includes 2 or more ethylene glycol moieties, such as 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, or even more ethylene glycol moieties. In some embodiments, Formula XVI includes one or more triazole linker components. In some instances, the linker includes one or more 1,2,3-triazole linker components. In some embodiments, the one or more 1,2,3-triazoel moieties is selected from one of the following structures: , wherein w1, u1 and q1 are independently 1 to 25 (e.g., 1 to 12, such as 1 to 6). In some embodiments, the linker component L3includes C10-C20-alkylene (e.g., C12-alkylene), or -(OCH2CH2)p-, where p is 1 to 25, such as 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25 or 20 to 24. In some embodiments, the linker (i.e., L1-L6) comprises Formula XVII: wherein: a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); f is 1 to 6 (e.g., 1, 2, or 3); and Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation group (e.g., as described herein) of a linker precursor to a compatible group on Y. In some embodiments of the Formula XVII, Z or the terminal L6is a residual moiety resulting from the covalent linkage (e.g., via a thioether bond) of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Y. In some embodiments, the thiol-reactive chemoselective ligation group includes maleimide, bromomaleimide, haloacetamide, vinyl sulfone, or thiolactone. In some embodiments, the thiol-reactive group is selected from one of the following structures: , wherein: u is 1 to 11 (e.g., 1 to 5); v is 1 to 11 (e.g., 1 to 5); and X is H or Br. In some embodiments of formula XVII, Z is a residual moiety resulting from the covalent linkage (e.g., via an amide bond) of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y. In some embodiments, the amine-reactive chemoselective ligation group includes an active ester (e.g., N-hydroxysuccinimidyl (NHS) ester, sulfo-NHS ester, pentafluorophenyl (PFP) ester, tetrafluorophenyl (TFP) ester, or the like). In some embodiments, the linker (i.e., L1-L6) comprises one of Formula XVIIIa-XVIIIc: wherein: a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1, 2, or 3). In some embodiments, the linker (i.e., L1-L6) comprises LA: wherein: Z4is selected from -NHC(O)NH-, -NHC(O)-, -C(O)NH-, -O-, -NH-; a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1, 2, or 3). In some embodiments of LA, Z4is -NHC(O)NH-. In some cases, Z4is -NHC(O)-. In some cases, Z4is -C(O)NH-. In some cases, Z4is -O-. In some cases, Z4is -NH-. In some embodiments of LA, a is 1-4; b is 1-4; c is 1-3; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 4; b is 1; c is 2; d is 2; e is 5; and f is 2. In some embodiments, Z4is -NHC(O)NH- and a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, Z4is -NHC(O)- and a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1- 6; and f is 1-3. In some embodiments, the linker (i.e., L1-L6) comprises LB: wherein: a is 0 to 12 (e.g., 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1, 2, or 3); c is 1 to 6 (e.g., 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1, 2, or 3). In some embodiments of LB, a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 4; b is 1; c is 2; r is 1; d is 2; e is 5; and f is 2. In some embodiments, a is 2; b is 1; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, a is 4; b is 1; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, a is 1; b is 2; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments, a is 0; b is 3; c is 2; r is 1; d is 2; e is 3; and f is 2. In some embodiments of LB, a is 1-4; b is 1-4; c is 1-3; r is 2; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 2; b is 1; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, a is 4; b is 1; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, a is 1; b is 2; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, a is 0; b is 3; c is 2; r is 2; d is 2; e is 3; and f is 2. In some embodiments, the linker (i.e., L1-L6) comprises LC: wherein: a is 0 to 12 (e.g., 1 to 6, 2 to 6, or 2, or 3); b is 1 to 6 (e.g., 1 to 4, such as 1, 2, or 3); c is 1 to 6 (e.g., 1 to 3, such as 1, 2, or 3); r is 1 or 2; d is 1 to 6 (e.g., 1 to 3, such as 1, 2, or 3); e is b is 1 to 6 (e.g., 1, 2, or 3); and f is 1 to 6 (e.g., 1 to 3, such as 1, 2, or 3). In some embodiments of Lc, a is 1-4; b is 1-4; c is 1-3; r is 1; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 2; b is 4; c is 2; r is 1; d is 2; e is 5; and f is 2. In some embodiments of Lc, a is 1-4; b is 1-4; c is 1-3; r is 2; d is 1-3; e is 1-6; and f is 1-3. In some embodiments, a is 2; b is 4; c is 2; r is 2; d is 2; e is 5; and f is 2. In some embodiments, the -Z1-L1- includes a group selected from: ; wherein R24and R25are each independently selected from H, optionally substituted C(1-6)alkyl, optionally substituted fluoroalkyl, and halogen; and each R21is independently selected from H, optionally substituted (C1-C6)alkyl, and optionally substituted alkanoyl. In some embodiments, R21is H. In some embodiments, R24is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, R25is C(1-3)-alkyl, or C(1-3)-fluoroalkyl. In some cases, the fluoroalkyl is CF3. In some embodiments, the linker includes a polypeptide scaffold where some or all of the sidechain groups of the amino acid residues of such a polypeptide scaffold have been modified to attach a X binding moiety (e.g., as described herein). It is understood that X binding moieties (e.g., as described herein) can be conjugated to amino acid residues, such as Asp, Lys, Orn, Glu, and Ser, of a polypeptide containing linker via a convenient conjugation chemistry. In some embodiments, the linker contains a polylysine polypeptide. In some embodiments, the linker contains a polyornithine polypeptide. In some embodiments, the linker contains a polyserine polypeptide. In some embodiments, the linker contains a polyaspartate polypeptide. The polypeptide backbone of such a linker can be a randomly polymerized polymer having an average length, or a polymer of defined length prepared e.g., in a controlled stepwise fashion. In some cases, the polypeptide linker has a length of 10-100 amino acid residues, such as 20-90, or 20-50 amino acid residues. In some embodiments, the N-terminal or C-terminal of the polypeptide linker is modified to include a linking moiety to an additional X binding moiety (e.g., as described herein). In some embodiments, the N-terminal or C-terminal of the polypeptide linker segment is modified with one or more linking moieties or linker components (e.g., as described herein) suitable for attachment Y including a polypeptide that specifically binds target autoantibody. In some embodiments of the linker of the Formulas described herein comprises one or more linker components, such as L1, L2, L3, L4, L5, L6, etc. In some embodiments, the residual moiety (Z) from a chemoselective ligation group can be considered a linker component. Various exemplary linker components are described herein. In some embodiments, the linker of the Formulas described herein is of Formula L-II: wherein: n is 1, 2, or 3; each L1to L6is independently a linker component which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** represents the point of attachment of X via Z1to L1; and *** represents the point of attachment to Y, optionally via Z. In some embodiments, each L1to L5independently comprises one or more linker components independently selected from -C1-20-alkylene-, -NHC(O)-C1-6-alkylene-, -C(O)NH-C1-6-alkylene-, -NHC1-6-alkylene-, -NHC(O)NH-C1-6-alkylene-, -NHC(S)NH-C1-6-alkylene-, -C1-6-alkylene-NHC(O)-, -C1-6-alkylene-C(O)NH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHC(O)NH-, -C1-6-alkylene-NHC(S)NH-, -O(CH2)p-, -(OCH2CH2)p-, -NHC(O)-, -C(O)NH-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and -NCH3-; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; L6is a linker component comprising one or more -C1-20-alkylene-, -NR16C(O)-C1-6-alkylene-, -C(O)NR16-C1-6-alkylene-, -NR16-C1-6-alkylene-, -NR16C(O)NR16-C1-6-alkylene-, -NR16C(S)NR16-C1-6-alkylene-, -C1-6-alkylene-NR16C(O)-, -C1-6-alkylene-C(O)NR16-, -C1-6-alkylene-NR16-, -C1-6-alkylene-NR16C(O)N R16-, -C1-6-alkylene-NR16C(S)NR16-, -O(CH2)p-, -(OCH2CH2)p-, -NR16C(O)-, -C(O)NR16-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, or -NR16-; and each R16is independently -H, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted monocyclic heteroaryl or monocyclic heteroaryl. In some embodiments, each linker component L1to L5is independently selected from -C1-20- alkylene-, -NHC(O)-C1-6-alkylene-, -C(O)NH-C1-6-alkylene-, -NH-C1-6-alkylene-, -NHC(O)NH-C1-6- alkylene-, -NHC(S)NH-C1-6-alkylene-, -C1-6-alkylene-NHC(O)-, -C1-6-alkylene-C( )NH-, -C1-6-alkylene- NH-, -C1-6-alkylene-NHC(O)NH-, -C1-6-alkylene-NHC(S)NH-, -O(CH2)p-, -(OCH2CH2)p-, -NHC(O)-, - C(O)NH-, -NHS(O)2-, -S(O)2NH-, -C(O)-, -S(O)2-, -O-, -S-, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and -NCH3-; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently1 to 50; and

[0013] . In some embodiments of the linker of the Formulas described herein, the linker comprises one or more (1 to 20, 1-10, or 1-6) linker components (e.g., L1to L6) wherein each independently comprises one or more linker components independently selected from -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH- C1-6-alkylene-, -NHC1-6-alkylene-, -NHCONH-C1-6-alkylene-, - NHCSNH-C1-6-alkylene-, -C1-6-alkylene- NHCO-, -C1-6-alkylene-CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCONH-, -C1-6-alkylene- NHCSNH-, -O(CH2)p-, -(OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3- linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (naturally or non- naturally occurring amino acid residue), -NH-, and -NCH3-, wherein each p is independently1 to 50. In some embodiments of the linker of the Formulas described herein, any of the linker components (e.g., L1-L6) comprises repeating ethylene glycol moieties (e.g., -CH2CH2O- or -OCH2CH2-). In some embodiments of the linker of the Formulas described herein, any of the linker components (e.g., L1-L6) comprises 1 to 25 ethylene glycol moieties, such as 3 to 25, 5 to 25, 7 to 25, 10 to 25, 15 to 25, 17 to 25, 20 to 25, or 22 to 25 ethylene glycol moieties. In some embodiments, the linker comprises 3 or more ethylene glycol moieties, such as 5 or more, 7 or more, 10 or more, 15 or more, 20 or more, or even more ethylene glycol moieties. In some embodiments of the linker of the Formulas described herein, any of the linker components (e.g., L1-L6) comprises one or more triazole linker components. In some instances, the linker comprises one or more 1,2,3-triazole linker components. In some embodiments, the one or more 1,2,3-triazole moieties is selected from one of the following structures: , , wherein w1, u1 and q1 are independently 1 to 25 (e.g., 1 to 12, such as 1 to 6). In some embodiments of the linker of the Formulas described herein, n is 1, such that b is 0, and the linker is of the Formula L-IIa: wherein L1and L3are each independently a linker component (e.g., as described herein), wherein L1to L3together provide a linear linker between X and Y; a is 1; c is 0 or 1; ** represents the point of attachment to L1of X via Z1; and *** represents the point of attachment to Y. In some embodiments, the linear linker has a backbone of 20 or more consecutive atoms covalently linking X to Y via Z1, such as a backbone of 25 or more consecutive atoms, or 30 or more consecutive atoms, and in some cases, up to 100 consecutive atoms. In some embodiments of formula (IIa), the linear linker separates X and Y (or Z1) by a chain of 20 to 50 consecutive atoms. In some embodiments, the linear linker separates X and Y (or Z1) by a chain of 21 to 50 consecutive atoms, by a chain of 22 to 50 consecutive atoms, by a chain of 23 to 50 consecutive atoms, by a chain of 24 to 50 consecutive atoms, by a chain of 25 to 50 consecutive atoms, by a chain of 26 to 50 consecutive atoms, by a chain of 27 to 50 consecutive atoms, by a chain of 28 to 50 consecutive atoms, or by a chain of 29 to 50 consecutive atoms. In some embodiments of formula (IIa), the linear linker separates X and Y (or Z1) by a chain of 30 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y (or Z1) by a chain of 31 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y (or Z1) by a chain of 32 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y (or Z1) by a chain of 33 to 60 consecutive atoms. In some embodiments, the linear linker separates X and Y (or Z1) by a chain of 34 to 60 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y (or Z1) by a chain of 35 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y (or Z1) by a chain of 36 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y (or Z1) by a chain of 41 to 50 consecutive atoms. In some embodiments, the linker (i.e., L1-L6) comprises separates X and Y (or Z1) by a chain of 46 to 50 consecutive atoms. In some embodiments, n is 2 or more, such that any one or more of L1- L6together provide a branched linker between X and Y. In some embodiments of the linker of the Formulas described herein, n is 1, such that b is 0, and the linker is of the Formula L-IIb: wherein n is 1, 2, or 3; each L1and L3are independently a linker component (e.g., as described herein) each L2is independently a branched linker component; a is 1, 2, or 3; b is 1, 2, or 3; c is 1, 2, or 3; ** represents the point of attachment to X via Z1; and *** represents the point of attachment to Y, optionally via Z. In some embodiments, n is 2 or more, and L2is selected from: , ,wherein each x and y are independently 1 to 10. In some embodiments, L1-L2comprises a backbone of 14 or more consecutive atoms between X and the branching atom, such as 14 to 50, 14 to 40, 14 to 35 or 14 to 30 consecutive atoms between X and the branching atom. In some embodiments, L3comprises a backbone of 10 to 80 consecutive atoms, such as 12 to 70, 12 to 60, or 12 to 50 consecutive atoms. In some embodiments, wherein L3comprises a linker component selected from (C10-C20-alkylene (e.g., C12-alkylene), or -(OCH2CH2)p-, where p is 1 to 25, such as 3 to 25, 5 to 24, 7 to 25, 10 to 25, 15 to 25 or 20 to 24. In some embodiments, L1to L5each independently comprise one or more linker components independently selected from -C1-20-alkylene-, -NHCO-C1-6-alkylene-, -CONH-C1-6-alkylene-, -NH C1-6- alkylene-, -NHCONH-C1-6-alkylene-, - NHCSNH-C1-6-alkylene-, -C1-6-alkylene-NHCO-, -C1-6-alkylene- CONH-, -C1-6-alkylene-NH-, -C1-6-alkylene-NHCONH-, -C1-6-alkylene-NHCSNH-, -O(CH2)p-, - (OCH2CH2)p-, -NHCO-, -CONH-, -NHSO2-, -SO2NH-, -CO-, -SO2-, -O-, -S-, monocyclic heteroaryl (e.g., 1,2,3-triazole), monocyclic aryl (e.g., phenyl, e.g., 1,4-linked phenyl or 1,3-linked phenyl), monocyclic heterocycle (e.g., pyrrolidine-2,5-dione, piperazine or piperidine ring as described herein), amino acid residue (naturally or non- naturally occurring amino acid residue), -NH-, and -NCH3-, wherein each p is independently 1 to 50. In some embodiments, -(L1)a- comprises an optionally substituted alkyl or ethylene glycol linker component. In some embodiments, L1comprises an optionally substituted -C1-6-alkylene-. In some embodiments, L1comprises an ethylene glycol linker component. In some embodiments, each L1is independently selected from -C1-6-alkylene-, -(CH2CH2O)t-, -C1-6-alkylene-NR4CO-, -C1-6-alkyleneCONH-, or OCH2, wherein t is 1 to 20; and each R4is independently selected from H, and optionally substituted (C1-C6)alkyl. In some embodiments, each L1is -C1-6-alkylene-, such as -C1-3-alkylene-. In some embodiments, each L1is -(CH2CH2O)t-, where t is 1 to 20, such as 1 to 15, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. In some embodiments, each L1is --C1-6-alkylene-NR4CO-. In some embodiments, each L1is -C1-6-alkyleneCONH-. In some embodiments, each L1is or OCH2. , - wherein R13is selected from H, halogen, OH, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)alkoxy, COOH, NO2, CN, NH2, -N(R21)2, -OCOR21, -COOR21, -CONHR21, and -NHCOR21; and each r independently 0 to 20, and any of the L1moieties are optionally further substituted. In some embodiments, one linker component (e.g., L2) is -OCH2-. In certain other embodiments, L2is (OCH2CH2)q-, and q is 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2. In some embodiments, q is 2 to 8, such as 2 to 6 , 4 to 6, or 2 to 4. In some embodiments, one linker component (e.g. L3) is absent or is independently selected from -C1-6-alkylene-, -(CH2CH2O)t-, -C1-6-alkylene-NHCO-, -C1-6-alkyleneCONH-,or OCH2, wherein t is 1 to 20. In some embodiments, L3is absent. In some embodiments, one linker component (e.g., L3) comprises -C1-6-alkylene-. In some embodiments, one linker component (e.g. L3) comprises - (CH2CH2O)t-, where t is 1 to 20, such as 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3. In some embodiments, one linker component (e.g., L3) comprises -C1-6-alkylene-NHCO-. In some embodiments, one linker component (e.g., L3) comprises -C1-6-alkyleneCONH-. In some embodiments, one linker component (e.g., L3) comprises OCH2. In some embodiments of the Formulas described herein, the linker comprises one or more branched linker component. In some embodiments of the Formulas described herein, the linker comprises one or more branched linker component selected from: , wherein each x and y are each independently 1 to 10, such as 1-6, 1-3, e.g., 1 or 2. In In some embodiments, each x is 1, 2 or 3, e.g., 2. In some embodiments, one linker component (e.g. L4, L5, or L6) comprises one or more of: an amino acid residue (e.g., Asp, Lys, Orn, Glu), an amino acid analogue, N-substituted amido (-N(-)C(=O)- ), tertiary amino, polyol (e.g., O-substituted glycerol), and the like. Analogs of an amino acid, include but not limited to, unnatural amino acids, as well as other modifications known in the art. The amino acid includes L-amino acids, D-amino acids, or both, and may contain any of a variety of amino acid modifications or analogs known in the art. In some embodiments, the linker includes a polypeptide scaffold where some or all of the sidechain groups of the amino acid residues have been modified to attach a X binding moiety (e.g., as described herein). It is understood that X binding moieties (e.g., as described herein) can be conjugated to amino acid residues, such as Asp, Lys, Orn, Glu, and Ser, of a polypeptide containing linker via a convenient conjugation chemistry. In some embodiments, the linker contains a polylysine polypeptide. In some embodiments, the linker contains a polyornithine polypeptide. In some embodiments, the linker contains a polyserine polypeptide. In some embodiments, the linker contains a polyaspartate polypeptide. The polypeptide can be a randomly polymerized polymer having an average length, or a polymer of defined length prepared e.g., in a controlled stepwise fashion. In some cases, the polypeptide linker segment has a length of 10-100 amino acid residues, such as 20-90, or 20-50 amino acid residues. In some embodiments, the N-terminal or C-terminal of the polypeptide linker segment is modified to include a linking unit to an additional M6PR binding moiety (e.g., as described herein). In some embodiments, the N-terminal or C-terminal of the polypeptide linker segment is modified with one or more linking units (e.g., as described herein) suitable for attachment to a Y moiety of interest. In some embodiments, a is 1. In some embodiments, at least one of b, c, d, and e is not 0. In some embodiments, b is 1 or 2. In some embodiments, c is 1 or 2. In some embodiments, e is 1 or 2. In some embodiments, b, d, and e are independently 1 or 2. In some embodiments, a, b, d, and e are each 1, and c is 0. In some embodiments, the linker comprises 20 to 100 consecutive atoms, such as 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40 or 20 to 30 consecutive atoms. In some embodiments, the linker comprises 25 to 100 consecutive atoms, such as 30 to 100, 35 to 100, 40 to 100, 45 to 100, 50 to 100, 55 to 100, 60 to 100, 65 to 100, 70 to 100, 75 to 100, 80 to 100, 85 to 100, 90 to 100, or 95 to 100 consecutive atoms. In some embodiments, the linker comprises 25 or more consecutive atoms, such as 26 or more, 27 or more, 28 or more, 29 or more or 30 or more consecutive atoms. In some embodiments, the linker comprises 30 or more consecutive atoms, such as 31 or more, 32 or more, 33 or more, 34 or more, 35 or more, 36 or more, 37, or more, 38 or more, 39 or more, 40 or even more consecutive atoms. In some embodiments, the linker is a branched linker or linker component as shown in Table 1.

[0014]

[0015] A chemoselective ligation group is a group having a reactive functionality or function group capable of conjugation to a compatible group of a second moiety. For example, chemoselective ligation groups (or a precursor thereof) may be one of a pair of groups associated with a conjugation chemistry such as azido-alkyne click chemistry, copper free click chemistry, Staudinger ligation, tetrazine ligation, hydrazine-iso-Pictet-Spengler (HIPS) ligation, cysteine-reactive ligation chemistry (e.g., thiol-maleimide, thiol-haloacetamide or alkyne hydrothiolation), amine-active ester coupling, tyrosine specific conjugation chemistry (e.g., e-Y-CLICK), methionine specific conjugation chemistry (e.g., oxaziridine-based or ReACT chemistry), reductive amination, dialkyl squarate chemistry, etc. Chemoselective ligation groups that may be utilized in linking two moieties, include, but are not limited to, amino (e.g., a N-terminal amino or a lysine sidechain group of a polypeptide), azido, aryl azide, alkynyl (e.g., ethynyl or cyclooctyne or derivative), active ester (e.g., N-hydroxysuccinimide (NHS) ester, sulfo-NHS ester or PFP ester or thioester), haloacetamide (e.g., iodoacetamide or bromoacetamide), chloroacetyl, bromoacetyl, hydrazide, maleimide, vinyl sulfone, 2-sulfonyl pyridine, cyano-alkyne, thiol (e.g., a cysteine residue), disulfide or protected thiol, isocyanate, isothiocyanate, aldehyde, ketone, alkoxyamine, hydrazide, aminooxy, phosphine, HIPS hydrazinyl-indolyl group, or aza- HIPS hydrazinyl-pyrrolo-pyridinyl group, tetrazine, cyclooctene, squarate, and the like. In some instances, chemoselective ligation group is capable of spontaneous conjugation to a compatible chemical group when the two groups come into contact under suitable conditions (e.g., copper free Click chemistry conditions). In some instances, the chemoselective ligation group is capable of conjugation to a compatible chemical group when the two groups come into contact in the presence of a catalyst or other reagent (e.g., copper catalyzed Click chemistry conditions). In some embodiments, the chemoselective ligation group is a photoactive ligation group. For example, upon irradiation with ultraviolet light, a diazirine group can form reactive carbenes, which can insert into C-H, N-H, and O-H bonds of a second moiety. In some instances, the terminal linker component (e.g., the terminal L6) is a precursor of the reactive functionality or function group capable of conjugation to a compatible group of a second moiety. For example, a carboxylic acid is a precursor of an active ester chemoselective ligation group. In some embodiments, the terminal linker component (e.g., the terminal L6) is a reactive moiety capable forming a covalent bond to a polypeptide (e.g., with an amino acid sidechain of a polypeptide having a compatible reactive group). The reactive moiety can be referred to as a chemoselective ligation group. In some embodiments, the terminal linker component (e.g., the terminal L1, L3or L6) is a thio- reactive chemoselective ligation group (e.g., as described in Table 2). In some cases, Y can produce a residual moiety Z resulting from the covalent linkage of a thiol-reactive chemoselective ligation group to one or more cysteine residue(s) of Y. In some embodiments, the terminal linker component (e.g., the terminal L1, L3or L6) is a Cys- reactive chemoselective ligation group (e.g., a maleimide derivative as described herein). In some cases, the Cys-reactive chemoselective ligation group includes a maleimide group. In some embodiments, the chemoselective ligation group includes a maleimide group, e.g., mal-1 to mal-7. In some embodiments, the terminal linker component (e.g., the terminal L1, L3or L6) is an amino- reactive chemoselective ligation group. In some cases, the terminal linker component (e.g., the terminal L1, L3or L6) can produce a residual moiety Z resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y. In some embodiments, the terminal linker component (e.g., the terminal L1, L3or L6) is a Lys- reactive chemoselective ligation group. In some embodiments the Lys-reactive chemoselective ligation group is a PFP ester. Exemplary chemoselective ligation groups, and synthetic precursors thereof, which may be adapted for use in the compounds of this disclosure are shown in Table 2. In Table 2, the can represent a point of attachment to a linking moiety or linker component (or a linked X moiety). Table 3 shows exemplary residual moieties, wherein the “***” indicates the point of attachment of Y. Exemplary ASGPR-binding Compounds with Chemoselective Ligation Group for preparing conjugates This disclosure includes conjugates, e.g., Formula I, which can be prepared from a precursor ligand-linker compound including: (1) one or more particular ligand binding moiety (X) as described herein; (2) a linker comprising one or more linker components or linker constructs as described herein, and (3) a chemoselective ligation group as described herein, such as any one of the groups of Table 2. Table 3 illustrates various monovalent ASGPR ligand-linker compounds for use in preparing conjugates of the disclosure. The following Tables illustrate several exemplary ASGPR ligand-linker compounds (or ASGPR binding compounds) of this disclosure that include a chemoselective ligation group, or a precursor thereof. It is understood that this disclosure includes conjugates of each of the exemplary compounds of Tables 4-7 to Y, wherein the chemoselective ligation group reacts with an amino acid on Y. The chemoselective ligation group of such compounds can be utilized to connect to another Y moiety of interest (e.g., as described below). It is understood that any of these compounds can also be prepared de novo to include an alternative Y moiety of interest (e.g., as described below) rather than the chemoselective ligation group. In some embodiments, such compounds are referred to as a conjugate, e.g., a biomolecule conjugate that specifically binds a target protein.

[0016]

[0017]

[0018]

[0019]

[0020]

[0021] The present disclosure is meant to encompass any single stereoisomer, or mixture thereof, of any one of the compounds described herein. In some embodiments, X comprises an enantiomer of a D- N- acetylgalactosamine (GalNAc), or an analog or derivative of GalNAc. Table 8 illustrates exemplary trivalent ASGPR binding intermediate compounds of this disclosure including X.

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030] Table 9 illustrates exemplary ASGPR binding intermediate compounds of which comprise a bicyclic X (such as, e.g., a promoiety on X).

[0031] Table 10 illustrates exemplary ASGPR binding intermediate compounds which comprise a chemoselective ligation group for use in preparing the conjugates described herein.

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] In some embodiments, provided is a conjugate of Formula:

[0045] , ,

[0046] , wherein Y is an antibody or antigen-binding fragment as disclosed herein. In some embodiments, Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In some embodiments, provided is a conjugate of Formula IC: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180. In some embodiments, provided is a conjugate of Formula IC:

[0047] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, provided is a conjugate of Formula IC: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181. In some embodiments, provided is a conjugate of Formula IC: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In some embodiments, provided is a conjugate of Formula IE:

[0048] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180. In some embodiments, provided is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, provided is a conjugate of Formula IE: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181. This conjugate may also be referred to as P-421—2301. In some embodiments, provided is a conjugate of Formula IE:

[0049] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. In some embodiments, provided is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180. In some embodiments, provided is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, provided is a conjugate of Formula IF:

[0050] wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181. In some embodiments, provided is a conjugate of Formula IF: wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO: 156. Exemplary CI-M6PR-binding Compounds with a Chemoselective Ligation Group for Preparing Conjugates Exemplary M6PR binding moieties, X, which can be utilized in the preparation of conjugates of this disclosure are shown in Table 11.

[0051] Exemplary synthons or synthetic precursors which can be utilized in the preparation of compounds of this disclosure to incorporate a desired M6PR binding moiety of interest are shown in Table 12. It is understood that alternative synthons, including homologs and analogs of the ones shown in Table 12 are possible depending on the M6PR binding moiety and linker that is selected. It is understood that the synthons of Table 12 can include structural precursors of linking moiety Z3, and a structural element that becomes part of the linker (L) in the compounds and conjugates of this disclosure. It is understood that based on the exemplary synthetic precursors of Table 12, synthons corresponding to any of the M6PR binding moieties can be utilized to prepare compounds of this disclosure.

[0052] Other M6PR binding moieties of interest and synthons or synthetic precursors thereof, are shown in Table 13. X101-X103 show compounds having a phosphate ester or thiophosphate ester head group. X109-X110 show exemplary compounds of formula (V). Antibodies and Antigen-Binding Fragments The conjugates of this disclosure comprise an antibody or fragment thereof (i.e., antigen-binding fragment moiety), Y, that exhibits pH-dependent binding characteristics towards IgE. In some embodiments, the antibody or antigen-binding fragment moiety (Y) as used herein is a mutant form of omalizumab or ligelizumab. These mutants include mutants wherein one or more amino acids of the parent omalizumab or ligelizumab sequences have been changed to a histidine. Certain mutant antibodies and antibody fragments described herein which exhibit pH-dependent binding characteristics towards IgE have weaker binding to IgE at acidic pH than at a neutral pH. Certain mutant antibodies and antibody fragments described herein which exhibit pH-dependent binding characteristics towards IgE have faster dissociation rates with IgE at acidic pH than at a neutral pH. Anti-IgE Antibodies Immunoglobulin E (IgE) is the last of the five human immunoglobulins to be discovered and is associated with several of allergic diseases and reactions including allergic rhinitis, atopic dermatitis, asthma, urticaria, food allergies, and anaphylaxis. Omalizumab and ligelizumab are two humanized anti- IgE antibodies that were developed for various therapeutic uses. Omalizumab was first approved in the U.S. and Europe for the treatment of asthma, and has since been approved for use to treat urticaria and food allergy. However, neither omalizumab nor ligelizumab exhibit pH-dependent binding properties. On the other hand, antibodies or fragments thereof described herein show superior pH-dependent IgE binding properties. One application of such antibodies is using in LYTACs (lysosome-targeting chimeras) for targeted protein degradation, where a high acidic:neutral KD or koff may be desired. Mutant antibodies described herein may also have favorable physical properties as measured by, for example, transition melting temperature, aggregation temperature, size exclusion chromatography, hydrophilic interaction chromatography, cross-interaction chromatography, and poly-specificity. The present invention provides anti-IgE antibodies with pH-dependent binding characteristics, wherein such antibodies possess one or more amino acid differences as compared to a parental anti-IgE antibody. As used herein, a “parental” anti-IgE antibody is an anti- IgE antibody which does not exhibit pH-dependent binding characteristics or which exhibits only intermediate pH-dependent binding characteristics (e.g., wherein the binding affinity of the parental antibody to IgE at neutral pH is no more than 3 times greater than the binding affinity of the antibody to IgE at acidic pH; or wherein the parental antibody binds IgE with a t1 / 2 at acidic pH that is no more than 3 times shorter than the t1 / 2for the antibody binding to IgE at neutral pH). In some cases, a “parental” anti- IgE antibody may be an anti- IgE antibody that exhibits enhanced binding to IgE at acidic pH as compared to neutral pH. In some embodiments, a “parental” anti- IgE antibody is an antibody which is obtained by standard antibody production / isolation methods (e.g., mouse immunization, phage display, etc.) without any amino acid modifications artificially introduced in the complementarity determining regions (CDRs). In some embodiments, a parental anti-IgE antibody is omalizumab or ligelizumab. Mutant antibodies described herein show superior pH-dependent IgE binding properties. For example, an antibody according to one embodiment, comprising VH comprising an amino acid sequence of SEQ ID NO.159; and VL comprising an amino acid sequence of SEQ ID NO.181, was shown to have a KD ratio (acidic pH 6.0: neutral pH 7.4) of about 45.5 as measured by biolayer interferometry (BLI), and a koff ratio (acidic pH 6.0: neutral pH 7.4) of about 3.2 as measured by BLI. Similarly, an antibody according to one embodiment, comprising VH comprising an amino acid sequence of SEQ ID NO.166; and VL comprising an amino acid sequence of SEQ ID NO.181, was shown to have KD ratio (acidic pH 6.0: neutral pH 7.4) of about 52.9 as measured by BLI, and a koff ratio (acidic pH 6.0: neutral pH 7.4) of about 4.2 as measured by BLI. In accordance with one embodiment of the present disclosure, therefore, provided is an isolated antibody or fragment thereof which has specificity to a human IgE protein and binds to one or more amino acid residues selected from the human IgE protein. The human IgE protein, as known in the art, includes 428 amino acid residues, as shown in SEQ ID NO: 209 in the table below. In the present disclosure, “immunoglobulin E”, “human immunoglobulin E”, “IgE”, or human “IgE” may refer to this human IgE protein having an amino acid sequence of SEQ ID NO: 209. Table A. Amino Acid Sequence of hIgE Sequence: In accordance with one embodiment of the present disclosure, provided is an isolated antibody or fragment thereof that bind human IgE at a higher KD(lower affinity) at an acidic pH than at a neutral pH. For example, the isolated antibody or fragment thereof. In certain embodiments, such isolated antibody or fragment thereof includes one or more amino acid substitutions with histidine from a regular anti-IgE antibodies or fragments thereof (“parental antibody”; e.g., omalizumab, ligelizumab, etc.). For example, the isolated antibody or fragment thereof may have histidine at least one of the following positions: 31, 33, 52, 53, 54, 55, 64, 73, 95, 99, 100b, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 31, 33, 34, 35, 50, 51, 52, 53, 54, 66, 91, 92, 93, 94, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may have histidine at least two, three, or four of the following positions: 31, 33, 52, 53, 54, 55, 64, 73, 95, 99, 100b, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 31, 33, 34, 35, 50, 51, 52, 53, 54, 66, 91, 92, 93, 94, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may comprise histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 64, 73, 95, 99, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 49, 51, 52, 53, 54, 66, 91, 92, 93, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may comprise histidine at two, three, four or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 64, 73, 95, 99, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 49, 51, 52, 53, 54, 66, 91, 92, 93, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may further comprise histidine at one or more amino acid positions selected from the group consisting of: 33, 55 and 100b of a heavy chain variable region (VH) and 31, 94 and 50 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may comprise histidine at one or more amino acid positions selected from the group consisting of: 31, 100e, of a heavy chain variable region (VH) and 29, 49, 51, 53, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may have histidine at least one of the following positions: 31, 33, 100b of a heavy chain variable region (VH) and 29, 31, 49, 50, 51, 53, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may have histidine at least two, three, four, five, six, or more of the following positions: 31, 33, 100b of a heavy chain variable region (VH) and 29, 31, 49, 50, 51, 53, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the isolated antibody or fragment thereof may have histidine at one or more amino acid positions selected from the group consisting of: 31 and 100e of a heavy chain variable region (VH) and 29, 49, 51, 53, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. The antibody or fragment thereof may further comprising histidine at one or more amino acid positions selected from the group consisting of: 33 and 100b of a heavy chain variable region (VH) and 31 and 50 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, VH does not comprise amino acid sequence of SEQ ID NO: 263, 264, 265, 266, 273, 274, 275, or 276 or VL does not comprise amino acid sequence of SEQ ID NO: 267, 268, 269, 270, 271, 272, 277, 278, 279, or 280. For example, the isolated antibody or fragment thereof binds to IgE exhibits a KD ratio (acidic pH (i.e., pH 6.0): neutral pH (i.e., pH 7.4)) of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60 or greater. In other words, the isolated antibody or fragment thereof binds to IgE at a KD which is about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 times or more of KD at a neutral pH (i.e., pH 7.4). In some embodiments, the isolated antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH (i.e., pH 6.0) than at a neutral pH (i.e., pH 7.4) with a KD (acidic pH / neutral pH) ratio greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 10, 20, 30, 40, 50, or 60. In accordance with one embodiment of the present disclosure, The isolated antibody or fragment thereof of claim 1, wherein the antibody binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH. For example, the isolated antibody or fragment thereof binds to IgE exhibits a koff ratio (acidic pH (i.e., pH 6.0): neutral pH (i.e., pH 7.4)) of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or greater. In other words, the isolated antibody or fragment thereof binds to IgE at a koff which is about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 times or more of koffat a neutral pH (i.e., pH 7.4). In some embodiments, the isolated antibody or fragment thereof binds IgE at a higher koff(higher dissociation) at an acidic pH (i.e., pH 6.0) than at a neutral pH (i.e., pH 7.4) with a koff(acidic pH / neutral pH) ratio greater than about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. In certain embodiments, such isolated antibody or fragment thereof includes one or more amino acid substitutions with histidine from a parental anti-IgE antibodies or a fragment thereof. Mutant of Parental Antibody 1 In accordance with one embodiment of the present disclosure, a reference anti-IgE antibody (“Parental Antibody 1”) comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3 as described in tables below. In some embodiments, the Parent Antibody 1 is omalizumab, or a variant or fragment thereof. Table B. CDR Sequences of Parental Antibody 1: Table C. VH / VLSequences of Parental Antibody 1: In accordance with one embodiment of the present disclosure, provided is a mutant of Parental Antibody 1or fragment thereof, which bind human IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH. The mutant antibody or fragment thereof may have one or more amino acid substitutions to histidine. In some embodiments, the mutant antibody or fragment thereof may have substitution to histidine in positions selected from the group consisting of: 31, 35, 52, 53, 54, 55, 65, 74, 95, 99, 100b, 100d, 100e, 101 of a heavy chain variable region (VH) and 25, 29, 30, 33, 34, 35, 51, 52, 53, 54, 55, 57, 70, 91, 92, 93, 94, 95, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the mutant antibody or fragment thereof may have substitution to histidine in position 65 or 100b of a heavy chain variable region (VH) and 35, 53, 57 of a light chain variable region (VL), according to Kabat numbering. For example, an isolated antibody or fragment thereof comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein: the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211 or 216, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 211 or 216; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 212 or 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 213, 218, 219, 220, or 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 214, 222, 223, or 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215 or 225, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 215 or 225. Table D. CDR Sequences of an Example pH-dependent anti-IgE antibody In some embodiment, an isolated antibody or fragment thereof comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein: the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211 or 216; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215 or 225. In some embodiment, an isolated antibody or fragment thereof comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein: the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 213 or 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214 or 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 212; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 221; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 224; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiment, the CDRH1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 211; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 217; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 210; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 214; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 215. In some embodiments, the isolated antibody or fragment thereof may comprise: (a) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 214, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 215; (b) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 224, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 215; (c) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO:217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 224, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 215; or (d) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO:217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 224, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 214. In some embodiments, an isolated antibody or fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO:1, or a variant of any of the foregoing amino acid sequences in which one or more amino acids is substituted with a histidine residue, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID Nos: 51, or a variant of any of the foregoing amino acid sequences in which one or more amino acids is substituted with a histidine residue. Table E. VH / VLSequences of an Example pH-dependent anti-IgE antibody In some embodiments, the heavy chain variable region (VH) and / or the light chain variable region (VL) includes one or more amino acid substitutions to histidine in a non-CDR framework region. In one aspect, the present disclosure provides anti-IgE antibodies or fragments thereof which exhibit pH- dependent binding characteristics, and which comprise a heavy chain variable region (VH) having amino acid sequence of SEQ ID NO: 1 or 46, and a light chain variable region (VL) having amino acid sequence of SEQ ID NO: 51, 63, 67, 71, 89-92, In some embodiments, a VH / VL amino acid sequence pair comprises the amino acid sequence pair of any one of SEQ ID Nos: 1 / 89, 1 / 90, 1 / 91, 1 / 92, 46 / 63, 46 / 67, 46 / 71, 46 / 89, 46 / 90, 46 / 91, 46 / 92. In one aspect, the present disclosure provides anti-IgE antibodies or fragments thereof which exhibit pH-dependent binding characteristics, and which comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VHcomprises SEQ ID NO: 1 or a variant of SEQ ID NO: 1 having at least 90% sequence identity with SEQ ID NO: 1, and VLcomprises SEQ ID NO: 51 or a variant of SEQ ID NO: 51 having at least 90% sequence identity with SEQ ID NO: 51. The variant of SEQ ID NO: 1 for VHmay comprise one or more amino acid substitutions selected from the group consisting of K64H, D73H, and W100bH. The variant of SEQ ID NO: 1 for VH may comprise one or more amino acid substitutions of W100bH. The variant of SEQ ID NO: 51 for VLmay comprise one or more amino acid substitutions selected from the group consisting of D27cH, G29H, D30H, S31H, Y49H, A50H, A51H, Y53H, G66H, and S91H. The variant of SEQ ID NO: 51 for VL may comprise one or more amino acid substitutions selected from the group consisting of D27cH, G29H, S31H, Y49H, and Y53H. The variant of SEQ ID NO: 51 for VL may comprise one or more amino acid substitutions selected from the group consisting of S31H, Y49H, and Y53H. In some embodiments, an isolated antibody or fragment thereof, which binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH, may comprise a CDRH1 comprising the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 210; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 211 or 216, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 211 or 216; a CDRH3 comprising the amino acid sequence of SEQ ID NO: 212 or 217, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 212 or 217; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 213, 218, 219, 220, or 221; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 214, 222, 223, or 224; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 215 or 225, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 215 or 225, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 64 and 73 of a heavy chain variable region (VH) and 27c, 29, 30, 49, 50, 51, 53, 66, and 91of a light chain variable region (VL), according to Kabat numbering. In some embodiments, the antibody or fragment thereof may further comprise histidine at one or more amino acid positions selected from the group consisting of: 100b of a heavy chain variable region (VH) and 31 of a light chain variable region (VL), according to Kabat numbering. Mutant of Parental Antibody 2 In accordance with one embodiment of the present disclosure, a reference anti-IgE antibody (“Parental Antibody 2”) comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3 as described in tables below. In some embodiments, the Parent Antibody 2 is ligelizumab, or a variant or fragment thereof. Table F. CDR Sequences of Parental Antibody 2: Table G. VH / VL Sequences of Parental Antibody 2: In accordance with one embodiment of the present disclosure, provided is a mutant of Parental Antibody 2 or fragment thereof, which bind human IgE at a higher KD(lower affinity) at an acidic pH than at a neutral pH. The mutant antibody or fragment thereof may have one or more amino acid substitutions to histidine. In some embodiments, the mutant antibody or fragment thereof may have one or more substitutions to histidine. For example, an isolated antibody or fragment thereof comprises a heavy chain variable region (VH) comprising a CDRH1, a CDRH2, and a CDRH3, and a light chain variable region (VL) comprising a CDRL1, a CDRL2 and a CDRL3, wherein: the CDRH1 comprises the amino acid sequence of SEQ ID NO: 226, 232, 233, 234, or 235, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 226, 232, 233, 234, or 235; the CDRH2 comprises the amino acid sequence of SEQ ID NO: 227, 236, 237, 238, or 239, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 227, 236, 237, 238, or 239; the CDRH3 comprises the amino acid sequence of SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282; the CDRL1 comprises the amino acid sequence of SEQ ID NO: 229, 246, or 247, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 229, 246, or 247; the CDRL2 comprises the amino acid sequence of SEQ ID NO: 230, 248, 249, 250, 251, or 281, an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 230, 248, 249, 250, 251, or 281; and the CDRL3 comprises the amino acid sequence of SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257. In some embodiments, the antibody or fragment thereof may comprise: (a) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256; (b) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 247, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 281, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231; (c) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 282, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257; (d) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 243, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257; (e) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 245, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 249, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231; (f) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 249, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231; (g) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256; or (h) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 243, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 247, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 281, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 282, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 243, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 245, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 249, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 249, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256. In one embodiment, the antibody or fragment thereof comprises a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 243, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256. Table H. CDR Sequences of an Example pH-dependent anti-IgE antibody In some embodiments, an isolated antibody or fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 96, 158, 161, 162, 164, 165, 166, 167, 168, or a variant of any of the foregoing amino acid sequences in which one or more amino acids is substituted with a histidine residue, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID Nos: 130, 142, 143, 156, 157, 175, 176, 179, 180, 181, 185, or a variant of any of the foregoing amino acid sequences in which one or more amino acids is substituted with a histidine residue. Table I. VH / VL Sequences of an Example pH-dependent anti-IgE antibody

[0053] In one aspect, the present disclosure provides anti-IgE antibodies or fragments thereof which exhibit pH-dependent binding characteristics, and which comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH / VLamino acid sequence pair comprises the amino acid sequence pair of any one of SEQ ID Nos: 96 / 175, 96 / 176, 96 / 180, 96 / 185, 158 / 143, 158 / 156, 158 / 179, 159 / 181, 161 / 136, 161 / 181, 162 / 143, 162 / 156, 164 / 130, 165 / 142, 165 / 157, 166 / 157, 166 / 181, 167 / 143.167 / 157, or 168 / 130. In some embodiments, VH / VLamino acid sequence pair comprises: 96 / 180, 96 / 185, 161 / 181, 165 / 157, or 167 / 143. In one aspect, the present disclosure provides anti-IgE antibodies or fragments thereof which exhibit pH-dependent binding characteristics, and which comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VHcomprises SEQ ID NO: 96 or a variant of SEQ ID NO: 96 having at least 90% sequence identity with SEQ ID NO: 96, and VLcomprises SEQ ID NO: 130 or a variant of SEQ ID NO: 130 having at least 90% sequence identity with SEQ ID NO: 130. The variant of SEQ ID NO: 96 for VH may comprise one or more amino acid substitutions selected from the group consisting of W31H, E35H, D52H, G53H, T54H, F55H, F95H, S99H, D100dH, Y100eH, and D101H. The variant of SEQ ID NO: 130 for VL may comprise one or more amino acid substitutions selected from the group consisting of A25H, I29H, A51H, S52H, S54H, S91H, W92H, S93H, W94H, T96H, and T97H. In some embodiments, either VHor VLcomprise at least one amino acid substitutions selected from the group consisting of W31H (VH), Y100eH (VH), I29H (VL), A51H (VL), T96H (VL), and T97H (VL). In some embodiments, an isolated antibody or fragment thereof, which binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH, may comprise a CDRH1 comprising the amino acid sequence of SEQ ID NO: 226, 232, 233, 234, or 235, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 226, 232, 233, 234, or 235; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 227, 236, 237, 238, or 239, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 227, 236, 237, 238, or 239; a CDRH3 comprising the amino acid sequence of SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 229, 246, or 247, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 229, 246, or 247; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 230, 248, 249, 250, 251, or 281, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 230, 248, 249, 250, 251, or 281; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 55, 95, 99, 100d, and 100e, 101 of a heavy chain variable region (VH) and 25, 29, 51, 52, 54, 53, 91, 92, 93, 94, 96, and 97 of a light chain variable region (VL), according to Kabat numbering. The antibody or fragment thereof of claim 26, further comprising histidine at one or more amino acid positions selected from the group consisting of: 33, 58, 100b, 100c of a heavy chain variable region (VH) and 31 of a light chain variable region (VL), according to Kabat numbering. It will also be understood by one of ordinary skill in the art that antibodies as disclosed herein may be modified such that they vary in amino acid sequence from the naturally occurring binding polypeptide from which they were derived. For example, a polypeptide or amino acid sequence derived from a designated protein may be similar, e.g., have a certain percent identity to the starting sequence, e.g., it may be 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the starting sequence. In certain embodiments, the antibody comprises an amino acid sequence or one or more moieties not normally associated with an antibody. Exemplary modifications are described in more detail below. For example, an antibody of the disclosure may comprise a flexible linker sequence, or may be modified to add a functional moiety (e.g., PEG, a drug, a toxin, or a label). Antibodies, variants, or derivatives thereof of the disclosure include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from binding to the epitope. For example, but not by way of limitation, the antibodies can be modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the antibodies may contain one or more non-classical amino acids. In some embodiments, the antibodies may be conjugated to therapeutic agents, prodrugs, peptides, proteins, enzymes, viruses, lipids, biological response modifiers, pharmaceutical agents, or PEG. The antibodies may be conjugated or fused to a therapeutic agent, which may include detectable labels such as radioactive labels, an immunomodulator, a hormone, an enzyme, an oligonucleotide, a photoactive therapeutic or diagnostic agent, a cytotoxic agent, which may be a drug or a toxin, an ultrasound enhancing agent, a non-radioactive label, a combination thereof and other such agents known in the art. The antibodies can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antigen-binding polypeptide is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. The antibodies can also be detectably labeled using fluorescence emitting metals such as152Eu, or others of the lanthanide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA). Techniques for conjugating various moieties to an antibody are well known, see, e.g., Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp.243-56 (Alan R. Liss, Inc. (1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2ndEd.), Robinson et al., (eds.), Marcel Dekker, Inc., pp.623- 53 (1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies ‘84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), Academic Press pp.303-16 (1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev. (52:119-58 (1982)). Polynucleotides Encoding the Antibodies and Methods of Preparing the Antibodies: The antibody, antibody fragment, or antigen-binding fragment for use in the conjugates disclosed herein, can be prepared using isolated polynucleotides or nucleic acid molecules encoding the antibodies, variants or derivatives thereof of the disclosure. The polynucleotides of the present disclosure may encode the entire heavy and light chain variable regions of the antigen-binding polypeptides, variants or derivatives thereof on the same polynucleotide molecule or on separate polynucleotide molecules. Additionally, the polynucleotides of the present disclosure may encode portions of the heavy and light chain variable regions of the antigen-binding polypeptides, variants or derivatives thereof on the same polynucleotide molecule or on separate polynucleotide molecules. Methods of making antibodies are well known in the art and described herein. In certain embodiments, both the variable and constant regions of the antigen-binding polypeptides of the present disclosure are fully human. Fully human antibodies can be made using techniques described in the art and as described herein. For example, fully human antibodies against a specific antigen can be prepared by administering the antigen to a transgenic animal which has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled. Exemplary techniques that can be used to make such antibodies are described in U.S. patents: 6,150,584; 6,458,592; 6,420,140 which are incorporated by reference in their entireties. Preparation of the Conjugates In some embodiments, the conjugation of the one or more (Xn-L)- groups (e.g., m is 1, 2, or 3) to a Y results in the generation of a residual moiety resulting from the covalent linkage of a chemoselective ligation group to a compatible group of Y. For example, conjugates of this disclosure can be prepared using the building blocks described herein as exemplified in Scheme 1. In Scheme 1, conjugates of Formula I: are represented by Formula III: or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 1 to 3; m is 1 to 10; X and Y are each independently as defined herein; each L1to L6is independently a linker component which together provide a linear or branched linker between Z1and Y; and a, b, c, d, and e are each independently 1, 2, 3, 4, or 5. Scheme I is intended to be exemplary and in no way is intended to limit the scope of the disclosure. However, as can be appreciated by one of skill in the art, the compounds of this disclosure have various L moieties which may be constructed by coupling X to one or more first portions of the linker L (e.g., an -L1- moiety) via Z1to provide exemplary target binding moiety, or X, building blocks. In Scheme 1, RM1and RM2are each independently reactive functional groups for coupling reactions (e.g., alkyne, -N3, -C(O)OH, -NH2, etc.); and Y’ is a chemoselective ligation group capable of conjugating to an amino acid residue(s) of Y. Scheme I Methods for the steps and exemplary reagents and starting materials (i.e., compounds of Formula 1-1, 1-2, 1-3) are described throughout or can be derived from the art. In certain embodiments of the conjugate of Formula III, R6is Z, where Z is a residual moiety resulting from the covalent linkage of a chemoselective ligation moiety (e.g., Tables 2-7). In certain embodiments of the conjugate of Formula III, R6is Z, where Z is a residual moiety resulting from the covalent linkage of a thiol reactive chemoselective ligation group to one or more cysteine residue(s) of Y. In certain other embodiments of the conjugate of Formula III, R6is Z, where Z is a residual moiety resulting from the covalent linkage of an amine-reactive chemoselective ligation group to one or more lysine residue(s) of Y. In certain embodiments, the conjugates with their linker structures described herein have weaker binding affinity to cell surface receptors. Without being bound to any particular mechanism or theory, such weaker binding affinity may be corrected to longer half-life of the conjugates, and may be useful for tuning (e.g., modifying) the pharmacokinetic properties of the conjugates described herein. In certain embodiments, such weaker binding conjugates still have sufficiently robust uptake. Conjugates of a polypeptide, e.g., an antibody (Ab) and compound (Xn-L-Y) may be made using a variety of bifunctional protein coupling agents such as 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, sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate). The present disclosure further contemplates that the conjugates described herein may be prepared using any suitable methods as disclosed in the art (see, e.g., Bioconjugate Techniques (Hermanson ed., 2d ed. 2008)). In certain embodiments of the conjugates described herein, L is bonded through an amide bond to a lysine residue of the polypeptide. In certain embodiments of the conjugates described herein, L is bonded through a thioether bond to a cysteine residue of the polypeptide. In certain embodiments of the conjugates described herein, L is bonded through an amide bond to a lysine residue of Ab. In certain embodiments of the conjugates described herein, L is bonded through a thioether bond to a cysteine residue of Ab. In certain embodiments of the conjugates described herein, L is bonded through two thioether bonds to two cysteine residues of Ab, wherein the two cysteine residues are from an opened cysteine-cysteine disulfide bond in Ab. In certain embodiments, the opened cysteine-cysteine disulfide bond is an interchain disulfide bond. In certain embodiments of the conjugates described herein, when L is bonded through an amide bond to a lysine residue of a polypeptide (e.g., an antibody), m is an integer from 1 to 80. In certain embodiments of the conjugates described herein, when L is bonded through a thioether bond to a cysteine residue of P, m is an integer from 1 to 8. In certain embodiments, conjugation to the polypeptide, or the antibody Ab may be via site- specific conjugation. Site-specific conjugation may, for example, result in homogeneous loading and minimization of conjugate subpopulations with potentially altered antigen-binding or pharmacokinetics. In certain embodiments, for example, conjugation may comprise engineering of cysteine substitutions at positions on the polypeptide or antibody, e.g., on the heavy and / or light chains of an antibody that provide reactive thiol groups and do not disrupt polypeptide or antibody folding and assembly or alter polypeptide or antigen binding (see, e.g., Junutula et al., J. Immunol. Meth.2008; 332: 41-52; and Junutula et al., Nature Biotechnol.2008; 26: 925-32; see also WO2006 / 034488 (herein incorporated by reference in its entirety)). In another non-limiting approach, selenocysteine is cotranslationally inserted into a polypeptide or antibody sequence by recoding the stop codon UGA from termination to selenocysteine insertion, allowing site specific covalent conjugation at the nucleophilic selenol group of selenocysteine in the presence of the other natural amino acids (see, e.g., Hofer et al., Proc. Natl. Acad. Sci. USA 2008; 105: 12451-56; and Hofer et al., Biochemistry 2009; 48(50): 12047-57). Yet other non-limiting techniques that allow for site-specific conjugation to polypeptides or antibodies include engineering of non-natural amino acids, including, e.g., p-acetylphenylalanine (p-acetyl-Phe), p-azidomethyl-N- phenylalanine (p-azidomethyl-Phe), and azidolysine (azido-Lys) at specific linkage sites, and can further include engineering unique functional tags, including, e.g., LPXTG, LLQGA, sialic acid, and GlcNac, for enzyme mediated conjugation. See Jackson, Org. Process Res. Dev.2016; 20: 852-866; and Tsuchikama and An, Protein Cell 2018; 9(1):33-46, the contents of each of which is incorporated by reference in its entirety. See also US 2019 / 0060481 A1 & US 2016 / 0060354 A1, the contents of each of which is incorporated by reference in its entirety. All such methodologies are contemplated for use in connection with making the conjugates described herein. Loading of the compounds of formula (I) to the polypeptides (e.g., antibodies) described herein is represented by “m” in formula (III), and is the average number of units of “Xn-L-” or “Xn-” per conjugate molecule. As used herein, the term “DAR” refers to the average value of “m” or the loading of the conjugate. The number of “X” moieties (e.g., folate moieties) per each unit of “Xn-L-” or “Xn-” is represented by “n” in formula (III). As used herein, the term “valency” or “valencies” refers to the number of “X” moieties per unit (“n”). It will be understood that loading, or DAR, is not necessarily equivalent to the number of “X” moieties per conjugate molecule. By means of example, where there is one “X” moiety per unit (n = 1; valency is “1”), and one “Xn-L-” unit per conjugate (m = 1), there will be 1 x 1 = 1 “X” moiety per conjugate. However, where there are two “X” moieties per unit (n = 2; valency is “2”), and four “Xn-L-” units per conjugate (m = 4), there will be 2 x 4 = 8 “X” moieties per conjugate. Accordingly, for the conjugates described herein, the total number of “X” moieties per conjugate molecule will be n x m. As used herein, the term “total valency” or “total valencies” refers to the total number of “X” moieties per conjugate molecule (n x m; total valency). DAR (loading) may range from 1 to 80 units per conjugate. The conjugates provided herein may include collections of polypeptides, antibodies or antigen binding fragments conjugated with a range of units, e.g., from 1 to 80. The average number of units per polypeptide or antibody in preparations of the conjugate from conjugation reactions may be characterized by conventional means such as mass spectroscopy. The quantitative distribution of DAR (loading) in terms of m may also be determined. In some instances, separation, purification, and characterization of homogeneous conjugate where m is a certain value may be achieved by means such as electrophoresis. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 80. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 70. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 60. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 50. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 40. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 35. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 30. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 25. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 20. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 18. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 15. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 12. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 10. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 9. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 8. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 7. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 6. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 5. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 4. In certain embodiments, the DAR for a conjugate provided herein ranges from 1 to 3. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 12. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 10. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 9. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 8. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 7. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 6. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 5. In certain embodiments, the DAR for a conjugate provided herein ranges from 2 to 4. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 12. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 10. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 9. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 8. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 7. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 6. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 5. In certain embodiments, the DAR for a conjugate provided herein ranges from 3 to 4. In certain embodiments, the DAR for a conjugate provided herein is about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, or more. In some embodiments, the DAR for a conjugate provided herein is about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, or about 3.9. In some embodiments, the DAR for a conjugate provided herein is about 2.2. In some embodiments, the DAR for a conjugate provided herein ranges from 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, or 2 to 13. In some embodiments, the DAR for a conjugate provided herein ranges from 3 to 20, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, or 3 to 13. In some embodiments, the DAR for a conjugate provided herein is about 1. In some embodiments, the DAR for a conjugate provided herein is about 2. In some embodiments, the DAR for a conjugate provided herein is about 3. In some embodiments, the DAR for a conjugate provided herein is about 4. In some embodiments, the DAR for a conjugate provided herein is about 3.8. In some embodiments, the DAR for a conjugate provided herein is about 5. In some embodiments, the DAR for a conjugate provided herein is about 6. In some embodiments, the DAR for a conjugate provided herein is about 7. In some embodiments, the DAR for a conjugate provided herein is about 8. In some embodiments, the DAR for a conjugate provided herein is about 9. In some embodiments, the DAR for a conjugate provided herein is about 10. In some embodiments, the DAR for a conjugate provided herein is about 11. In some embodiments, the DAR for a conjugate provided herein is about 12. In some embodiments, the DAR for a conjugate provided herein is about 13. In some embodiments, the DAR for a conjugate provided herein is about 14. In some embodiments, the DAR for a conjugate provided herein is about 15. In some embodiments, the DAR for a conjugate provided herein is about 16. In some embodiments, the DAR for a conjugate provided herein is about 17. In some embodiments, the DAR for a conjugate provided herein is about 18. In some embodiments, the DAR for a conjugate provided herein is about 19. In some embodiments, the DAR for a conjugate provided herein is about 20. In some embodiments, the DAR for a conjugate provided herein is about 25. In some embodiments, the DAR for a conjugate provided herein is about 30. In some embodiments, the DAR for a conjugate provided herein is about 35. In some embodiments, the DAR for a conjugate provided herein is about 40. In some embodiments, the DAR for a conjugate provided herein is about 50. In some embodiments, the DAR for a conjugate provided herein is about 60. In some embodiments, the DAR for a conjugate provided herein is about 70. In some embodiments, the DAR for a conjugate provided herein is about 80. In certain embodiments, fewer than the theoretical maximum of units are conjugated to the polypeptide, e.g., antibody, during a conjugation reaction. A polypeptide may contain, for example, lysine residues that do not react with the compound or linker reagent. Generally, for example, antibodies do not contain many free and reactive cysteine thiol groups which may be linked to a drug unit; indeed most cysteine thiol residues in antibodies 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 or cysteine. In some embodiments, the compound is conjugated via a lysine residue on the antibody. In some embodiments, the linker unit or a drug unit is conjugated via a cysteine residue on the antibody. In certain embodiments, the amino acid that attaches to a unit is in the heavy chain of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the light chain of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the hinge region of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the Fc region of an antibody. In certain embodiments, the amino acid that attaches to a unit is in the constant region (e.g., CH1, CH2, or CH3 of a heavy chain, or CH1 of a light chain) of an antibody. In yet other embodiments, the amino acid that attaches to a unit or a drug unit is in the VH framework regions of an antibody. In yet other embodiments, the amino acid that attaches to unit is in the VL framework regions of an antibody. The DAR (loading) of a conjugate may be controlled in different ways, e.g., by: (i) limiting the molar excess of compound or conjugation reagent relative to polypeptide, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the polypeptide, such that the number and position of cysteine residues is modified for control of the number and / or position of linker- drug attachments (such as for thiomabs prepared as disclosed in WO2006 / 034488 (herein incorporated by reference in its entirety)). It is to be understood that the preparation of the conjugates described herein may result in a mixture of conjugates with a distribution of one or more units attached to a polypeptide, for example, an antibody. Individual conjugate molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g., hydrophobic interaction chromatography, including such methods known in the art. In certain embodiments, a homogeneous conjugate with a single DAR (loading) value may be isolated from the conjugation mixture by electrophoresis or chromatography. In certain embodiments of the conjugate of formula (III) m is 1 to 20, such as 2 to 10, 2 to 8, or 2 to 6. In certain cases, m is 10 or less. In certain cases, m is 2 to 8. In certain cases, m is 2 to 6. In certain cases, m is an average loading of about 4. It is to be understood that the preparation of the conjugates described herein may result in a mixture of conjugates with a distribution of one or more units attached to a polypeptide, for example, an antibody. Individual conjugate molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g., hydrophobic interaction chromatography, including such methods known in the art. In certain embodiments, a homogeneous conjugate with a single DAR (loading) value may be isolated from the conjugation mixture by electrophoresis or chromatography. Pharmaceutical Compositions In another embodiment, provided herein are pharmaceutical compositions including one or more bifunctional molecules (e.g., conjugates) disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of the conjugates provided herein, and optionally one or more additional prophylactic or therapeutic agents, in a pharmaceutically acceptable carrier. Pharmaceutical carriers suitable for administration of the conjugates provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. The conjugates described herein can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. In some embodiments, the conjugate is formulated into one or more suitable pharmaceutical preparations, such as solutions, suspensions, powders, sustained release formulations or elixirs in sterile solutions or suspensions for parenteral administration, or as transdermal patch preparation and dry powder inhalers. In compositions provided herein, a conjugate described herein may be mixed with a suitable pharmaceutical carrier. The concentration of the conjugate in the compositions can, for example, be effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates a condition or disorder described herein or a symptom thereof. In some embodiments, the pharmaceutical compositions provided herein are formulated for single dosage administration. To formulate a composition, the weight fraction of conjugate is dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated. Concentrations of the conjugate in a pharmaceutical composition provided herein will depend on, e.g., the physicochemical characteristics of the conjugate, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. Pharmaceutical compositions described herein are provided for administration to a subject, for example, humans or animals (e.g., mammals) in unit dosage forms, such as sterile parenteral (e.g., intravenous) solutions or suspensions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof. Pharmaceutical compositions are also provided for administration to humans and animals in unit dosage form, including oral or nasal solutions or suspensions and oil-water emulsions containing suitable quantities of a conjugate or pharmaceutically acceptable derivatives thereof. The conjugate is, In some embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refers to physically discrete units suitable for human or animal (e.g., mammal) subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of a conjugate sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit-dose forms include ampoules and syringes and individually packaged capsules. Unit-dose forms can be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit- dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of capsules or bottles. Hence, in specific aspects, multiple dose form is a multiple of unit-doses which are not segregated in packaging. In some embodiments, the conjugates herein are in a liquid pharmaceutical formulation. Liquid pharmaceutically administrable formulations can, for example, be prepared by dissolving, dispersing, or otherwise mixing a conjugate and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, and the like, to thereby form a solution or suspension. In some embodiments, a pharmaceutical composition provided herein to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, and pH buffering agents and the like. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see, e.g., Remington: The Science and Practice of Pharmacy (2012) 22nded., Pharmaceutical Press, Philadelphia, PA Dosage forms or compositions containing antibody in the range of 0.005% to 100% with the balance made up from non-toxic carrier can be prepared. Parenteral administration, In some embodiments, is characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. Other routes of administration may include, enteric administration, intracerebral administration, nasal administration, intraarterial administration, intracardiac administration, intraosseous infusion, intrathecal administration, and intraperitoneal administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions can be either aqueous or nonaqueous. If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thicke...

Claims

1. WHAT IS CLAIMED IS:

1. A conjugate that comprises a ligand moiety, X, conjugated to a target-binding moiety, Y, via a linker, L; wherein the ligand moiety, X, binds a lysosomal targeting molecule extracellularly; the target-binding moiety, Y, which binds IgE extracellularly; the target-binding moiety, Y, dissociates from the IgE intraendosomally; and the conjugate is externalized from a cell; further wherein the target-binding moiety comprises an antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 64, 73, 95, 99, 100d, 100e, and 101 of a heavy chain variable region (VH) and 25, 27c, 29, 30, 49, 51, 52, 53, 54, 66, 91, 92, 93, 96, and 97 of a light chain variable region (VL), according to Kabat numbering.

2. The conjugate of claim 1, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 33, 55 and 100b of a heavy chain variable region (VH) and 31, 94 and 50 of a light chain variable region (VL), according to Kabat numbering.

3. The conjugate of claim 1 or 2, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 100e, of a heavy chain variable region (VH) and 29, 49, 51, 53, 96, and 97 of a light chain variable region (VL), according to Kabat numbering.

4. The conjugate of any one of claims 1-3, wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 20.

5. The conjugate of any one of claims 1-4, wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 50.

6. The conjugate of any one of claims 1-5, wherein the antibody or fragment thereof binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH.

7. The conjugate of any one of claims 1-6, wherein the antibody or fragment thereof binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH with a koff(acidic pH / neutral pH) ratio greater than 2.

8. The conjugate of any one of claims 1-7, wherein the antibody or fragment thereof binds IgE with a higher dissociation rate (koff) at an acidic pH than at a neutral pH with a koff(acidic pH / neutral pH) ratio greater than 3.

9. The conjugate of claim 1, wherein the antibody or fragment thereof binds IgE at a higher KD(lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 210; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 211 or 216, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 211 or 216; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 212 or 217; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 213, 218, 219, 220, or 221; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 214, 222, 223, or 224; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 215 or 225, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 215 or 225, wherein each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 does not comprise SEQ ID NO: 210, 211, 212, 213, 214, and 215, respectively.

10. The conjugate of claim 9 wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 1.

1.

11. The conjugate of claim 9 or 10, wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 1.

5.

12. The conjugate of any one of claims 9-11, wherein the antibody or fragment thereof comprises a heavy chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of K64, D73, and W100b, according to Kabat numbering.

13. The conjugate of any one of claims 9-12, wherein the antibody or fragment thereof comprises a light chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of D27c, G29, D30, S31, Y49, A50, A51, Y53, G66, and S91, according to Kabat numbering.

14. The conjugate of any one of claims 9-13, wherein the at least one amino acid of the antibody or fragment thereof is replaced with a histidine is selected from S31, Y49 and Y53, according to Kabat numbering.

15. The conjugate of any one of claims 9-14, wherein the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1, 46 or an amino acid sequence having at least 90% amino acid sequence identity to SEQ ID NO: 1 or 46, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 51, 63, 67, 71, 89, 90, 91, 92 oran amino acid sequence having at least 90% amino acid sequence identity to SEQ ID NO: 51, 63, 67, 71, 89, 90, 91, 92.

16. The conjugate of any one of claims 9-15, wherein the antibody or fragment thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence of SEQ ID NO: 1 or 46, and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 51, 63, 67, 71, 89, 90, 91, or 92.

17. The conjugate of any one of claims 9-16, wherein the antibody or fragment thereof comprises a VH / VL amino acid sequence pair comprises the amino acid sequence pair of any one of SEQ ID Nos: 1 / 89, 1 / 90, 1 / 91, 1 / 92, 46 / 63, 46 / 67, 46 / 71, 46 / 89, 46 / 90, 46 / 91, 46 / 92.

18. The conjugate of claim 17, wherein the antibody or fragment thereof comprises: (a) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221 a CDRH2 comprising an amino acid sequence of SEQ ID NO: 214, and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 215; (b) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221 a CDRH2 comprising an amino acid sequence of SEQ ID NO: 224, and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 215; (c) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO:217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 224, and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 215; or (d) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 210, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 211, a CDRH3 comprising an amino acid sequence of SEQ ID NO:217, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 221, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 224, and a CDRH3 comprising an amino acid sequence of SEQ ID NO: 214.

19. The conjugate of claim 1, wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 226, 232, 233, 234, or 235, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 226, 232, 233, 234, or 235; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 227, 236, 237, 238, or 239, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 227, 236, 237, 238, or 239; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 229, 246, or 247, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 229, 246, or 247; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 230, 248, 249, 250, 251, or 281, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 230, 248, 249, 250, 251, or 281; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, wherein each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 does not comprise SEQ ID NO: 226, 227, 228, 229, 230, and 231, respectively.

20. The conjugate of claim 19, wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH with a KD (acidic pH / neutral pH) ratio greater than 20.

21. The conjugate of claim 19 or 20, wherein the antibody or fragment thereof comprises a heavy chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of W31, E35, D52, G53, T54, F55, F95, S99, D100d, Y100e, and D101.

22. The conjugate of any one of claims 19-21, wherein the antibody or fragment thereof comprises a light chain having at least one amino acid substitution with a histidine at positions selected from the group consisting of A25, I29, A51, S52, S54, S91, W92, S93, W94, T96, and T97.

23. The conjugate of any one of claims 19-22, wherein the antibody or fragment thereof comprises at least one amino acid substitution with a histidine at positions selected from the group consisting of W31 (heavy chain), Y100e (heavy chain), I29 (light chain), A51 (light chain), T96 (light chain), and T97 (light chain).

24. The conjugate of any one of claims 19-23, wherein the antibody or fragment thereof comprises: (a) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229,a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 256; (b) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 228, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 247, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 281, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 231; (c) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 282, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 248, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257; (d) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 235, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 243, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 230, and a CDRL3 comprising an amino acid sequence of SEQ ID NO: 257; or (e) a CDRH1 comprising an amino acid sequence of SEQ ID NO: 233, a CDRH2 comprising an amino acid sequence of SEQ ID NO: 227, a CDRH3 comprising an amino acid sequence of SEQ ID NO: 245, a CDRL1 comprising an amino acid sequence of SEQ ID NO: 229, a CDRL2 comprising an amino acid sequence of SEQ ID NO: 249, and a CDRL3 comprising an amino acid sequence of SEQ ID NO:

231.

25. The conjugate of claim 18, wherein the antibody or fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH / VLamino acid sequence pair comprises the amino acid sequence pair of any one of SEQ ID NOs: 96 / 175, 96 / 176, 96 / 180, 96 / 185, 158 / 143, 158 / 156, 158 / 179, 159 / 181, 161 / 136, 161 / 181, 162 / 143, 162 / 156, 164 / 130, 165 / 142, 165 / 157, 166 / 157, 166 / 181, 167 / 143.167 / 157, or 168 / 130.

26. An conjugate thereof, wherein the antibody or fragment thereof binds IgE at a higher KD(lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 210, or an amino acid sequence having one or two amino acid substitution from SEQ IDNO: 210; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 211 or 216, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 211 or 216; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 212 or 217, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 212 or 217; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 213, 218, 219, 220, or 221, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 213, 218, 219, 220, or 221; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 214, 222, 223, or 224, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 214, 222, 223, or 224; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 215 or 225, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 215 or 225, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 64 and 73 of a heavy chain variable region (VH) and 27c, 29, 30, 49, 50, 51, 53, 66, and 91of a light chain variable region (VL), according to Kabat numbering.

27. The conjugate of claim 26, wherein the antibody or fragment thereof further comprises histidine at one or more amino acid positions selected from the group consisting of: 100b of a heavy chain variable region (VH) and 31 of a light chain variable region (VL), according to Kabat numbering.

28. The conjugate of claim 1, wherein the antibody or fragment thereof binds IgE at a higher KD (lower affinity) at an acidic pH than at a neutral pH and comprises a CDRH1 comprises the amino acid sequence of SEQ ID NO: 226, 232, 233, 234, or 235, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 226, 232, 233, 234, or 235; a CDRH2 comprises the amino acid sequence of SEQ ID NO: 227, 236, 237, 238, or 239, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 227, 236, 237, 238, or 239; a CDRH3 comprises the amino acid sequence of SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 228.240, 241, 242, 243, 244, 245, or 282; a CDRL1 comprises the amino acid sequence of SEQ ID NO: 229, 246, or 247, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 229, 246, or 247; a CDRL2 comprises the amino acid sequence of SEQ ID NO: 230, 248, 249, 250, 251, or 281, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 230, 248, 249, 250, 251, or 281; and a CDRL3 comprises the amino acid sequence of SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, or an amino acid sequence having one or two amino acid substitution from SEQ ID NO: 231, 252, 253, 254, 255, 256, or 257, wherein the antibody or fragment thereof comprises histidine at one or more amino acid positions selected from the group consisting of: 31, 35, 52, 53, 54, 55, 95, 99, 100d, 100e, 101 of a heavy chain variable region (VH) and 25, 29, 51, 52, 54, 91, 92, 93, 94, 96, and 97 of a light chain variable region (VL), according to Kabat numbering.

29. The conjugate of claim 26, wherein the antibody or fragment thereof further comprises histidine at one or more amino acid positions selected from the group consisting of: 33, 58, 100b, 100c of a heavy chain variable region (VH) and 50 of a light chain variable region (VL), according to Kabat numbering.

30. The conjugate of any preceding claim, wherein the conjugate is of Formula I:or a prodrug thereof, or a or a pharmaceutically acceptable salt thereof, wherein: n is 1 to 500; m is 1 to 20; each X is independently the ligand moiety; and Y is the target-binding moiety.

31. The conjugate of any preceding claim, wherein the lysosomal targeting molecule is a cell surface receptor that provides for internalization of the conjugate.

32. The conjugate of any preceding claim, wherein the lysosomal targeting molecule is selected from asialoglycoprotein receptor (ASGPR), cation independent mannose-6-phosphate receptor (CI-M6PR also referred to herein as M6PR), folate receptor, LDLR, CD63, sortilin, IFITM3, molecules in the endosome / lysosome pathway, LIMP-1, and LIMP-2.

33. The conjugate of any preceding claim, wherein X is a moiety that binds ASGPR or M6PR.

34. The conjugate of any preceding claim, wherein X is a moiety that binds ASGPR.

35. The conjugate of claim 34, wherein the conjugate is of Formula I:or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 1 to 500; m is 1 to 20; L is a linker; and X is an asialoglycoprotein receptor (ASGPR) binding moiety of Formula A-I:wherein: R1is selected from -Z1-*, -H, -OH, optionally substituted (C1-C6)alkyl, -OCH3,-OCH2CH=CH, optionally substituted -S-(C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -S-aryl, and optionally substituted -S-heteroaryl; R2is selected from -Z1-*, -NHCOCH3, -NHCOCF3, -NHCOCH2CF3, -OH, -NHR, and optionally substituted triazole; R6is selected from -Z1-*, -OH, -OR, optionally substituted (C1-C6)alkyl, -OC(O)R, -C(O)NHR, -NRxxRyy, optionally substituted aryl, optionally substituted heteroaryl, -NHCOR, and -NRCOR; each R is independently optionally substituted (C1-C6)alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rxxand Ryyare independently H, optionally substituted (C1-C6)alkyl, or Rxxand Ryycan cyclize to form an optionally substituted heterocyclyl; wherein one of R1, R2, and R6is -Z1-*; R3and R4are each independently H, or a promoiety, or R3and R4are cyclically linked to form a promoiety; R11is H or a bridging moiety that connects the 5-position carbon to the 1-position carbon of the ring; Z1is a linking moiety selected from -Z11-, -Z11-A1-*, -A2-, -NR21CO-*, - CONR21-*, -NR21SO2*-, -SO2NR21-*, -NR21C(=O)NR21-, and -NR21C(=S)NR21-; where “ * ” represents a point of connection of Z1to the linker (L); -Z11- is -O-, -S-, -N(R21)-, or -C(R22)2; -A1- and -A2- are optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R21is independently selected from H, optionally substituted (C1-C6)alkyl, -COR, and optionally substituted heteroaryl; and each R22is independently selected from H, halogen, and optionally substituted (C1-C6)alkyl.

36. The conjugate of claim 35, wherein -L-Y comprises:,37. The conjugate of claim 35 or 36, wherein X is represented by Formula A-II:.

38. The conjugate of any one of claims 35-37, wherein R1is –Z1–*, –H, –NHCOCH3, or (C1-C6)alkyl.

39. The conjugate of any one of claims 34-38, wherein R3and R4are each –H.

40. The conjugate of claim 33, wherein X is a moiety that binds to M6PR.

41. The conjugate of claim 40, wherein X is of Formula IV:wherein: W is a non-hydrolyzable hydrophilic head group; Z1is selected from optionally substituted (C1-C3)alkylene and optionally substituted ethenylene; Z2is selected from S, NR21and C(R22)2, wherein each R21is independently selected from H, and optionally substituted (C1-C6)alkyl, and each R22is independently selected from H, halogen and optionally substituted (C1-C6)alkyl; each A is independently an optionally substituted aryl or heteroaryl linking moiety; and each Z3is independently a linking moiety.

42. The conjugate of claim 41, wherein Z2is S.

43. The conjugate of claim 41 or 42, wherein W is phosphonate, thiophosphonate, carboxylic or malonic acid, or a salt thereof.

44. The conjugate of any one of claims 41-43, wherein X is:wherein Ra, Rb, Rcand Rdare independently H or F.

45. The conjugate of any one of claims 41-44, wherein X is:wherein Ra, Rb, Rcand Rdare independently H or F.

46. The conjugate of any one of claims 41-45, wherein A is optionally substituted aryl or optionally substituted heteroaryl, preferably A is independently selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted biphenyl, optionally substituted naphthalene, optionally substituted triazole and optionally substituted phenylene-triazole.

47. The conjugate of any preceding claim, wherein L comprises of 10 to 60 consecutive branched or linear chain atoms.

48. The conjugate of any preceding claim, wherein L is of formula (IIb’):wherein: n is 1, 2, or 3; each L1to L6is independently a linker component which together provide a linear or branched linker between Z1and Y; a, b, c, d, and e are each independently 1, 2, 3, 4, or 5; ** represents the point of attachment to L1of X via Z1; and *** represents the point of attachment to Y.

49. The conjugate of claim 48, wherein each L1to L5independently comprises one or more linker components independently selected from –C1-20-alkylene–, –NHC(O)-C1-6-alkylene–, –C(O)NH-C1-6- alkylene–, –NH-C1-6-alkylene–, –NHC(O)NH-C1-6-alkylene–, –NHC(S)NH-C1-6-alkylene–, –C1-6-alkylene–NHC(O)-, –C1-6-alkylene–C(O)NH-, –C1-6-alkylene–NH-, –C1-6-alkylene–NHC(O)NH-, –C1-6-alkylene–NHC(S)NH-, -O(CH2)p–, –(OCH2CH2)p–, –NHC(O)–, –C(O)NH–, –NHS(O)2–, –S(O)2NH–, –C(O)–, –S(O)2–, –O–, –S–, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, –NH–, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently 1 to 50; L6is a linking group comprising one or more linker components independently selected from –C1-20-alkylene–, –NR16C(O)-C1-6-alkylene–, –C(O)NR16-C1-6-alkylene–, –NR16-C1-6-alkylene–, –NR16C(O)NR16-C1-6-alkylene–, –NR16C(S)NR16-C1-6-alkylene–, –C1-6-alkylene–NR16C(O)-, –C1-6-alkylene–C(O)NR16-, –C1-6-alkylene–NR16-, –C1-6-alkylene–NR16C(O)N R16-, –C1-6-alkylene– NR16C(S)NR16-, -O(CH2)p–, –(OCH2CH2)p–, –NR16C(O)–, –C(O)NR16–, –NHS(O)2–, –S(O)2NH–, –C(O)–, –S(O)2–, –O–, –S–, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, amino acid residue, or –NR16–; andeach R16is independently –H, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted monocyclic heteroaryl or monocyclic heteroaryl.

50. The conjugate of claim 48, wherein each L1to L5is independently selected from –C1-20-alkylene–, –NHC(O)-C1-6-alkylene–, –C(O)NH-C1-6-alkylene–, –NH-C1-6-alkylene–, –NHC(O)NH-C1-6-alkylene–, –NHC(S)NH-C1-6-alkylene–, –C1-6-alkylene–NHC(O)-, –C1-6-alkylene–C(O)NH-, –C1-6-alkylene–NH-, –C1-6-alkylene–NHC(O)NH-, –C1-6-alkylene–NHC(S)NH-, -O(CH2)p–, –(OCH2CH2)p–, –NHC(O)–, –C(O)NH–, –NHS(O)2–, –S(O)2NH–, –C(O)–, –S(O)2–, –O–, –S–, monocyclic heteroaryl, monocyclic aryl, monocyclic heterocycle, monocyclic carbocycle, amino acid residue, -NH-, and –NMe–; wherein each L1to L5is independently optionally substituted with one to five halo; each p is independently 1 to 50; and ,51. A method of degrading a target molecule in a subject in need thereof, comprising administering an effective amount of a conjugate of any preceding claim to the subject.

52. The method of claim 51, wherein at least 90% of the target is degraded at four days following the administration.

53. The method of claim 51, wherein at least 90% of the target is degraded at seven days following the administration.

54. The method of claim 51, wherein the extracellular concentration of the target is substantially maintained for a time period of at least four days, at an amount of at least 90% less than the initial extracellular concentration of the target prior to administering an effective amount of the conjugate.

55. The method of claim 51, wherein the time period is seven days or more.

56. The method of any one of claims 51-55, wherein a super-stoichiometric target:conjugate ratio is degraded.

57. The method of claim 56, wherein the ratio is at least about 5.

58. The method of any one of claims 51-57, wherein the target-binding moiety, Y, has a higher binding affinity for the target molecule extracellularly than intraendosomally.

59. The method of any one of claims 51-58, wherein the target is IgE.

60. A method of degrading a target molecule in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate that comprises: a means for binding a lysosomal targeting molecule extracellularly; a means for binding a target molecule extracellularly; a means for dissociating from the target molecule intraendosomally; and wherein the conjugate is externalized from a cell.

61. The method of claim 60, wherein the means for binding a lysosomal targeting molecule, remains bound to the lysosomal targeting molecule intraendosomally.

62. The method of claim 60 or 61, wherein the means for binding a target molecule also binds FcRn intraendosomally; and optionally wherein the conjugate dissociates from the lysosomal targeting molecule intraendosomally.

63. A conjugate of Formula IA:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO:

156.

64. A conjugate of Formula IB:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO:

156.

65. A compound of Formula IC:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

66. A conjugate of Formula ID:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156;(d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

67. A conjugate of Formula IE:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

68. A conjugate of Formula IF:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:(a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO:

156.

69. A conjugate of Formula IG:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

70. A compound of Formula IH:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

71. A conjugate of Formula IJ:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180; (b) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 143; (c) VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO: 156;(d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

72. A conjugate of Formula IK:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

73. A conjugate of Formula IL:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO: 180;(b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

74. A conjugate of Formula IM:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (a) VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO: 180; (b) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 143; (c) VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO: 156; (d) VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO: 181; or (e) VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO:

156.

75. The conjugate of any one of claims 62-73, wherein Y is an antibody or fragment thereof comprising: a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 161; and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

181.

76. A conjugate of Formula IC:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO:

180.

77. A conjugate of Formula IC:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO:

143.

78. A conjugate of Formula IC:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 161 and VLcomprises the amino acid sequence of SEQ ID NO:

181.

79. A conjugate of Formula IC:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 162 and VL comprises the amino acid sequence of SEQ ID NO:

156.

80. A conjugate of Formula IE:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 96 and VL comprises the amino acid sequence of SEQ ID NO:

180.

81. A conjugate of Formula IE:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VL comprises the amino acid sequence of SEQ ID NO:

143.

82. A conjugate of Formula IE:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO:

181.

83. A conjugate of Formula IE:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156.

84. A conjugate of Formula IF:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 96 and VLcomprises the amino acid sequence of SEQ ID NO:

180.

85. A conjugate of Formula IF:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 158 and VLcomprises the amino acid sequence of SEQ ID NO:

143.

86. A conjugate of Formula IF:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VH comprises the amino acid sequence of SEQ ID NO: 161 and VL comprises the amino acid sequence of SEQ ID NO:

181.

87. A conjugate of Formula IF:wherein Y is an antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein VHcomprises the amino acid sequence of SEQ ID NO: 162 and VLcomprises the amino acid sequence of SEQ ID NO: 156.

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