Lysosome-targeting chimeras and methods of use

Abstract

The present disclosure describes lysosome-targeting chimeras having at least one target-binding moiety capable of specifically binding a cell surface molecule or an extracellular molecule; and at least one thiol-responsive moiety. Methods of making and using the lysosome-targeting chimeras are also provided.

Description

[0001] Attorney Docket No.11555-008WO1 LYSOSOME-TARGETING CHIMERAS AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to United States Provisional Application No. 63 / 550,832, filed February 7, 2024, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. GM-136395 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD This disclosure relates to compounds and compositions for targeted degradation of molecules and uses thereof. BACKGROUND Targeted protein degraders have attracted significant attention for the past few years due to their potential advantages in efficacy over traditional inhibitors. While extracellular and membrane proteins make up over 40% of the human proteome, there is still a deficiency in effective therapeutic degraders for such targets. Existing degraders lack precise control, resulting in varied outcomes. Further, the complex synthetic processes for current degraders and limited target availability emphasize the need for more targeted protein degradation strategies. Lysosomal target chimeras are an efficient method for targeted protein degradation. Such systems make use of the lysosome degradation pathway by recruiting proteins with the help of lysosome-shuttling receptors located at the cell surface. There is a clear need for additional approaches for targeted protein degradation, particularly those that target extracellular or membrane proteins. This disclosure addresses this as well as other needs. Attorney Docket No.11555-008WO1 SUMMARY The present disclosure provides compounds, compositions, and methods of making and using said compounds and compositions. More particularly, the present disclosure provides lysosome-targeting chimeras capable of interacting with one or more thiols on the surface of a cell. This interaction facilitates the uptake of the protein of interest and cases degradation of the same through the lysosomal pathway. The disclosure herein provides a robust system that relies on the abundant thiols that may be overexpressed in cells of interest, such as cancer cells. In one aspect, a lysosome-targeting chimera is provided. In some aspects, the lysosome- targeting chimera comprises at least one target-binding moiety capable of specifically binding a cell surface molecule or an extracellular molecule. In some aspects, the lysosome-targeting chimera comprises at least one thiol-responsive moiety. In another aspect, a method is provided for degrading a cell surface molecule or an extracellular molecule. In some aspects, the method comprises contacting the cell surface molecule or the extracellular molecule with a lysosome-targeting chimera described herein. In some aspects, contacting the cell surface molecule or the extracellular molecule occurs under conditions where the lysosome-targeting chimera shuttles the cell surface molecule or the extracellular molecule to a lysosome for degradation. In another aspect, a pharmaceutical composition is provided comprising a lysosome-targeting chimera described herein and a pharmaceutically acceptable carrier or excipient. In another aspect, a method is provided for treating a disease or disorder associated with a cell surface molecule or extracellular molecule in a subject in need thereof. In some aspects, the method comprises administering to the subject a therapeutically effective amount of a lysosome-targeting chimera described herein. The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description, the drawings, and the claims. DESCRIPTION OF DRAWINGS FIGs. 1A-1I depict and provide data regarding PD-L1 degradation mediated by Atz- P10 PolyTAC as a representative PolyTAC as described in the examples. (FIG. 1A) Schematic Attorney Docket No.11555-008WO1 representation of plug-and-degrade PolyTAC platform. (FIGs. 1B and 1C) Western blot analysis of total PD-L1 levels in MDA-MB-231 cells with the treatment of Atz at 1 µM or varying concentrations of Atz-P10 PolyTAC for 24 h. n = 3 biologically independent experiments. (FIGs. 1D and 1E) Relative surface expression of PD-L1 determined by live- cell flow cytometry following the treatment of 1 µM of Atz, Atz-P10 for 24 h. (FIG. 1F) Visualization of PD-L1 degradation in MDA-MB-231 cells by confocal microscopy with the treatment of Atz or Atz-P10 at 1 µM for 24 h. Scale bar: 20 µm. (FIG. 1G) Schematic representation of PDS-containing polymers (P10), antibody (Atz), antibody with appended polymer with no PDS units (Atz-P0), antibody with one PDS unit per linker (Atz-PDS), and Atz-P10. (FIGs.1H and 1I) Western blot analysis of total PD-L1 levels in MDA-MB-231 cells after the treatment with 1 µM of P10, Atz, Atz-P0, Atz-PDS, and Atz-P10 for 24 h, suggesting the multivalent interactions behind PolyTACs for extracellular targeted protein degradation. n = 3 biologically independent experiments. The statistical significance was assessed using one-way ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. FIGs. 2A-2F provide data regarding the mechanism of targeted protein degradation of membrane proteins by representative PolyTACs as described in the examples. (FIGs.2A and 2B) Western blot analysis of total PD-L1 levels in MDA-MB-231 cells after the pretreatment for 1 h with either 100 nM bafilomycin or 5 µM MG-132 followed by 24 h of treatment with 1 µM of Atz, Atz-P10 PolyTAC degrades PD-L1 in a lysosome-dependent manner. n = 3 biologically independent experiments. The statistical significance was assessed using two- way ANOVA, ****P < 0.0001. (FIGs.2C and 2D) Western blot analysis of total PD-L1 levels in MDA-MB-231 cells after the pretreatment of 1 µM of Atz for 1 h in MDA-MB-231 cells followed by 24 h of treatment with 1 µM of Atz-P10 PolyTAC shows the decreased degradation due to the masking of surface PD-L1 by Atz. n = 3 biologically independent experiments. The statistical significance was assessed using one-way ANOVA, ****P < 0.0001 (FIGs. 2E and 2F) MDA-MB-231 cells pre-treated with the thiol inhibitor N- ethylmaleimide (NEM) blocked the PD-L1 degradation capability of Atz-P10 showing the thiol mediated degradation of PolyTAC. n = 3 biologically independent experiments. The statistical significance was assessed using one-way ANOVA, *P < 0.05, **P < 0.01. FIGs. 3A-3G depict and provide data regarding the degradation of other therapeutically relevant cell surface proteins by representative PolyTACs as described in the examples. (FIG. 3A) Schematic of the PolyTACs for targeting different cell surface proteins for lysosomal degradation. (FIGs.3B and 3C) Trop2 levels were significantly reduced after a 24 h treatment Attorney Docket No.11555-008WO1 of SK-BR3 cells with 1 µM of Sac-P10PolyTAC compared to Sac alone. n = 3 biologically independent experiments. The statistical significance was assessed using one-way ANOVA, ****P < 0.0001 (FIGs. 3D and 3E) EGFR levels were reduced to half after a 48 h treatment of MDA-MB-231 cells with 1 µM of Cet-P10PolyTAC compared to Cet alone. n = 3 biologically independent experiments. The statistical significance was assessed using one- way ANOVA, **P < 0.01 (FIGs. 3F and 3G) The consecutive degradation of PD-L1 and Trop2 in MDA-MB-231 cells after the treatment of 1 µM of both Atz-P10 PolyTAC and Sac- P10PolyTAC for 24 h. n = 3 biologically independent experiments. The statistical significance was assessed using two-way ANOVA, ***P < 0.001, ****P < 0.0001. FIGs. 4A-4H depict and provide data regarding how representative PolyTACs enable intracellular uptake of soluble extracellular proteins as described in the examples. (FIG.4A) Schematic of PolyTAC concept for targeting soluble extracellular proteins for lysosomal degradation. (FIG. 4B) Flow cytometry results showing the enhanced uptake of rabbit IgG when treated with Goat anti-rabbit IgG-P10 for 6 h in MDA-MB-231 cells, Rabbit IgG alone shows similar uptake as that with the treatment of Goat anti-rabbit IgG. n = 3 biologically independent experiments. (FIG. 4C) flow cytometry bar graphs showing significant uptake of VEGF–647 in MDA-MB-231 cells following 6 h of treatment with Beva-P10 compared to treatment with Beva alone and VEGF alone. Beva control showed no difference compared to treatment with VEGF–647 alone. n = 3 biologically independent experiments. (FIG. 4D) Flow cytometry results demonstrating a significant uptake of Streptavidin (NA-647) in MDA- MB-231 cells treated for 6 h with Biotin-P10 compared with NA-647 alone or NA-647+ Biotin-P0. n = 3 biologically independent experiments. (FIG.4E) CLSM images showing the enhanced uptake of rabbit IgG when treated with Goat anti-rabbit IgG-P10 for 6 h in MDA- MB-231 cells compared to the treatment with either Rabbit IgG alone or Rabbit IgG with Goat anti-rabbit IgG. n = 3 biologically independent experiments. Scale bar; 20 µm. FIG.4F) Time-dependent IgG uptake using flow cytometry shows the highest increment in cellular internalization relative to IgG alone by 6 folds in 6 h and steady state in 48 h. n = 3 biologically independent experiments. (FIG. 4G) the flow cytometry data shows that the levels of IgG uptake depend on the equivalence of PolyTAC. IgG uptake steadily increases from 0.1 equivalence of α-rabbit IgG-P10 and reaches a plateau at 2 equivalences. n = 3 biologically independent experiments. (FIG.4H) Pre-blocking the exofacial thiols of MDA- MB-231 cells with the thiol inhibitor NEM resulted in a fivefold decrease in IgG uptake with Goat anti-rabbit IgG-P10compared to the control without NEM. n = 3 biologically Attorney Docket No.11555-008WO1 independent experiments. The statistical significance was assessed using one-way ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. FIG.5 depicts the synthesis of P0 and P10 via reversible addition-fragmentation chain transfer polymerization as described in the examples. FIGs. 6A-6B depict and provide data regarding: (FIG.6A) General steps for the preparation of representative PolyTACs as described in the examples. Antibodies were functionalized with TCO-PEG4-NHS. TCO-labeled antibodies were then reacted with tetrazine-conjugated polymer via click reaction. (FIG. 6B) Native gel electrophoresis followed by Coomassie staining was used to monitor the conversion of Atz to Atz-TCO and Atz-P10. FIGs. 7A-7D provide data regarding the approach followed to identify the number of polymers per antibody of representative PolyTACs as described in the examples. (FIG. 7A) Calibration curve of Atz solution determined by BCS assay. (FIG.7B) Absorption spectra of Atz and Atz-Cy5-P10.(FIG. 7C) Calibration curve of Cy5- P10solution determined by fluorescence intensity (Ex / Em = 640 nm / 670 nm). (FIG.7D) Fluorescence spectrum of Atz- Cy5-P10. FIGs. 8A-8B provide data regarding the surface thiol levels on MDA-MB-231 cells as described in the examples. (FIG.8A) Flow cytometry histograms of MDA-MB-231 without staining or with staining by PE or PE-Mal. (FIG.8B) Qualitative evaluation of exofacial thiols on MDA-MB-231 cell membrane determined by mean fluorescence intensity (MFI). FIGs. 9A-9B provide data regarding concentration-dependent PD-L1 degradation with Atz- P10after 48 h of treatment in the MDA-MB-231 cell line as described in the examples. FIGs.10A-10B provides data regarding how PD-L1 expression decreases over time in MDA- MB-231 with treatment of Atz-P10 determined by western blot as described in the examples. MDA-MB-231 cells incubated with Atz, Atz-P10at 1µM for 1, 6, 12, and 48 h. PD-L1 levels were normalized to untreated cells at each time point. FIGs. 11A-11B provide data regarding how expression of PD-L1 is insignificantly affected by the treatment of Atz and P10 as described in the examples. (FIG. 11A) In addition to treatment with Atz or P10separately, cells were treated with either a 15-minute premix of Atz and P10 (Atz+P10_premix) or simultaneous co-treatment of Atz and P10 (Atz+P10_separate) for 24 hours. Both treatments showed insignificant difference in PD-L1 degradation compared to Atz alone. (FIG.11B) Treatment of MDA-MB-231 cells with Atz, Atz-P10for 1 Attorney Docket No.11555-008WO1 h, following by being washed and kept for 23 hours. In comparison, degradation was found to be more prominent in continuous treatment rather than in washed treatment. Lesser degradation was found for washed cases due to possible regeneration of proteins. FIGs.12A-12B provide data regarding inhibition studies for endocytosis as described in the examples. Western blot analysis of PD-L1 expression after the treatment with Atz-P10 (1 µM) (FIG. 12A) following the pretreatment with different endocytosis inhibitors for 30 min, and (FIG.12B) at 37 ºC and 4 ºC. FIG.13 provides data regarding Trop-2 degradation in MDA-MB-231. Western blot analysis of Trop2 level after the treatment of 1 µM Sacituzumab or Sacituzumab-P10 for 24h. FIG. 14 provides data regarding the colocalization of secreted proteins with lysosome after the treatment with representative PolyTACs as described in the examples. Live cell imaging of MDA-MB-231 cells treated with rabbit-IgG alone, goat anti-rabbit IgG, premixed rabbit- IgG-647 with goat anti-rabbit IgG-P10 for 6 hours. Scale bar: 20 µm. FIG. 15 depicts the synthesis of biotin-based degraders for streptavidin via reversible addition-fragmentation chain transfer polymerization. FIG. 16 provides data regarding the colocalization of secreted proteins with lysosome after the treatment with representative PolyTACs as described in the examples. Live cell imaging of MDA-MB-231 cells that were incubated with Streptavidin along with either NA-647 alone or NA-647 plus Biotin-P0 or Biotin-P10 for 24 h. Scale bar: 20 µm. FIGs.17A-17C provide data regarding inhibition studies for endocytosis for secreted proteins as described in the examples. Flow cytometry analysis of total surface expression of IgG after the treatment (FIG. 17A) at 37 ºC and 4 ºC and with different (FIG. 17B) clathrin-mediated endocytosis, and (FIG.17C) caveolae-mediated endocytosis. FIGs. 18A-18D provide data regarding HER2 degradation in SK-BR-3 and MCF-10A cells with trastuzumab-P10. No HER2 degradation was found in MCF-10A, whereas a high potency was observed in SK-BR-3 cells. Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known aspects. Many modifications and other aspects Attorney Docket No.11555-008WO1 disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, benefiting from the teachings presented in the descriptions herein and the associated drawings. Therefore, it is understood that the disclosures are not limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. As apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or any other order that is logically possible. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not explicitly state in the claims or descriptions that the steps are to be limited to a particular order, it is in no way intended that an order be inferred in any respect. This holds for any possible non-express basis for interpretation, including logic concerning an arrangement of steps or operational flow, meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. All publications mentioned herein are incorporated by reference to disclose and describe the methods or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure before the filing date of the present application. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. It is also to be understood that the terminology herein describes particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such Attorney Docket No.11555-008WO1 as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Before describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions As used herein, “comprising” is interpreted as specifying the presence of the stated features, integers, steps, or components but does not preclude the presence or addition of one or more features, integers, steps, components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, “consisting essentially of” is intended to include examples encompassed by the term “consisting of.” As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context dictates otherwise. Ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. Further, the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. There are many values disclosed herein, and each value is also disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value and to “about” another particular value. Similarly, when values are expressed as approximations, using the antecedent “about,” the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed. When a range is expressed, a further aspect includes from the one particular value and to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, Attorney Docket No.11555-008WO1 e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘less than x,’ ‘less than y.’ and ‘less than z.’ Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y,’ and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y,’ and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’.” Such a range format is used for convenience and brevity and, thus, should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5% but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate, larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. Where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless expressly stated otherwise. As used herein, the term “therapeutically effective amount” refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but Attorney Docket No.11555-008WO1 generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration. Consequently, single-dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The individual physician can adjust the dosage in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. However, a patient may insist on a lower or tolerable dose for medical reasons, psychological reasons, or virtually any other reason. A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound or pharmaceutical composition, changing the disclosed compound or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more doses daily for one or Attorney Docket No.11555-008WO1 several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. As used herein, “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur. The description includes instances where said event or circumstance occurs and those where it does not. As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). “Subject” can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof. As used herein, “treating” and “treatment” generally refer to obtaining a desired pharmacological or physiological effect. The effect can be but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition such as a cancer. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term “treatment” as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term “treatment,” as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in which the disorder is to be prevented. As used herein, the term “treating” can include inhibiting the disease, disorder, or condition, e.g., impeding its progress, and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration. Attorney Docket No.11555-008WO1 As used herein, “therapeutic” can refer to treating, healing, or ameliorating a disease, disorder, condition, or side effect or decreasing the rate of advancement of a disease, disorder, condition, or side effect. As used herein, the term or phrase “effective,” “effective amount,” or “conditions effective to” refers to such amount or condition that is capable of performing the function or property for which an effective amount or condition is expressed. As will be pointed out below, the exact amount or particular condition required will vary from one aspect to another, depending on recognized variables such as the materials employed and the processing conditions observed. Thus, it is not always possible to specify an exact “effective amount” or “condition effective to.” However, it should be understood that an appropriate effective amount can be readily determined by one of the ordinary skills in art, using only routine experimentation. Although the operations of a representative aspects of the disclosed method may be described in a particular sequential order for convenient presentation, it should be understood that disclosed aspects can encompass an order of operations other than the particular sequential order disclosed. For example, operations described sequentially may, in some cases, be rearranged or performed concurrently. Further, descriptions and disclosures provided in association with one particular aspect are not limited to that aspect and may be applied to any aspect disclosed. The terms “coupled” and “associated” generally mean electrically, electromagnetically, and / or physically (e.g., mechanically or chemically) coupled or linked and do not exclude the presence of intermediate elements between the coupled or associated items. It will be understood that when an element is referred to as being "connected" or "coupled" to another element, it can be directly connected or coupled to the other element, or intervening elements can be present. In contrast, when an element is referred to as being "directly connected" or "directly coupled" to another element, there are no intervening elements present. Other words used to describe the relationship between elements or layers should be interpreted in a like fashion (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," "on" versus "directly on"). It will be understood that although the terms "first," "second," etc., can be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another Attorney Docket No.11555-008WO1 element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of example aspects. Spatially relative terms, such as "beneath," "below," "lower," "above," "upper," “upward,” “downward,” “top,” “bottom,” and the like, can be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if the device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be oriented "above" the other elements or features. Thus, the term "below" can encompass both an orientation of above and below. The device can be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein are interpreted accordingly. Terms such as “proximal,” “distal,” “ radially outward,” “radially inward,” “outer,” “inner,” and “side” describe the orientation and / or location of portions of the components or elements within a consistent but arbitrary frame of reference which is made clear by reference to the text and the associated drawings describing the components or elements under discussion. Such terminology can include the words specifically mentioned above, derivatives thereof, and words of similar import. Similarly, the terms “first,” “second,” and other such numerical terms referring to structures neither imply a sequence nor order unless clearly indicated by the context. As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs. Still further, the term “substantially” can, in some aspects, refer to at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount. As used herein, the term “substantially,” in, for example, the context “substantially identical” or “substantially similar,” refers to a method or a system, or a component that is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least Attorney Docket No.11555-008WO1 about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% by similar to the method, system, or the component it is compared to. Chemical Definitions Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each is specifically described unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration. The compounds provided herein may either be enantiomerically pure or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of ordinary skill in the art will recognize that administering a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administering the compound in its (S) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein may contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers unless stated to the contrary, all such possible isomers are contemplated, as well as mixtures of such isomers. Compounds described herein may also present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated. A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group. Attorney Docket No.11555-008WO1 The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or group are replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and / or can be formulated into a form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react, or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art. Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, AxO-(C0-C6alkyl)-, AxS-(C0-C6 alkyl)-, (AxAyN)-(C0-C6 alkyl)-, AzC(O)-(C0-C6 alkyl)-, AzC(N)-(C0-C6 alkyl)-, and AzS(O)-(C0-C6alkyl)-, and AzS(O)2-(C0-C6alkyl)-, wherein Axand Ayare independently selected at each occurrence from Aa, AzC(O)-, AzC(N)-, AzS(O)-, and AzS(O)2-, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein Azis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6-membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -OAa, -SAa, and -NAaAb, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein Aaand Abare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6-membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3alkyl)-, (5- to 10-membered Attorney Docket No.11555-008WO1 monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, each of which may be optionally substituted by one or more B groups as allowed by valency; and wherein B is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6alkyl)-, ApO-, ApS-, ApAqN-, AoC(O)-, AoC(O)-O-, AoC(O)-NAq-, AoS(O)2-, AoS(O)2-O-, and AoS(O)2-NAq-, wherein Aois independently selected at each occurrence from Ap, halo, ApO-, and ApAqN-, and wherein Apand Aqare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)- (C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-. The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person in the context in which said functional groups are recited.As used herein, the symbol “ ” (which hereinafter can be referred to as “a point ofattachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For example, “ ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non- depicted chemical entity can be specified by inference. For example, the compound CH3-R3,wherein R3 is H or “ ” infers that when R3 is “XY”, the point of attachment bond isthe same bond as the bond by which R3is depicted as being bonded to CH3. “Halo” or “halogen” independently indicates any fluoro, chloro, bromo or iodo. The term “nitro,” as used herein, is represented by the formula —NO2. The term “cyano,” as used herein, is represented by the formula —CN Attorney Docket No.11555-008WO1 The term “azido,” as used herein, is represented by the formula –N3. The term “oxo,” as used herein, is represented by the formula =O. “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain aspects, the alkyl is C1-C2, C1-C3, or C1-C6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges as used herein indicate an alkyl group with the length of each member of the range described as an independent species. For example, C1-C6alkyl, as used herein, indicates an alkyl group having 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 C1-C4alkyl, as used herein, indicates an alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C0-Cnalkyl is used herein in conjunction with another group, for example (C3-C7cycloalkyl)C0-C4alkyl, or -C0-C4(C3- C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms, such as -O-C0-C4alkyl(C3- C7cycloalkyl). Examples of alkyl include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n- hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In some aspects, the alkyl group is optionally substituted as described herein. “Haloalkyl” refers to an alkyl group that is substituted with one or more halo groups, e.g., fluoro, chloro, bromo, iodo, or combinations thereof. “Cycloalkyl” is a saturated or partially unsaturated mono- or multicyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some aspects, the cycloalkyl group is optionally substituted as described herein. “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2-C4alkenyl and C2- C6alkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group, with each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, Attorney Docket No.11555-008WO1 ethenyl and propenyl. In one aspect, the alkenyl group is optionally substituted as described herein. “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-C6alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkynyl group, with 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 one aspect, the alkynyl group is optionally substituted as described herein. “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one aspect, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include the fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si, and S, to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one aspect, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one aspect, the aryl group is optionally substituted as described herein. The term “heterocycle” refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions. Examples of saturated heterocycle groups, including saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, Attorney Docket No.11555-008WO1 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-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical, and the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms. In one aspect, the heterocycle group is optionally substituted as described herein. “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring that contains from 1 to 4, or in some aspects 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one aspect, the only heteroatom is nitrogen. In one aspect, the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms. In some aspects, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring which contains from 1 to 4 heteroatoms selected from N, O, S, B, or P is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is an aromatic ring. When the total number of S and O atoms in the heteroaryl ring exceeds 1, these heteroatoms are not adjacent to one another within the ring. In one aspect, the total number of S and O atoms in the heteroaryl ring is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl ring is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, Attorney Docket No.11555-008WO1 isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. In one aspect, the heteroaryl group is optionally substituted as described herein. A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts which are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)1-4- COOH, and the like, or using a different acid that produced the same counterion. Suitable counterions found in pharmaceutically acceptable salts described herein include, but are not limited to, cations such as calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, potassium, procaine, sodium, triethylamine, and zinc, and anions such as acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, Attorney Docket No.11555-008WO1 camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, and tosylate. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, PA., p.1418 (1985). As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compound. Representative derivatives include but are not limited to, salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound. As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high- performance liquid chromatography (HPLC) and mass spectrometry (MS), gas- chromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Both traditional and modern methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers, such as Sigma- Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March's Attorney Docket No.11555-008WO1 Advanced Organic Chemistry, (John Wiley and Sons, 8thEdition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3rdedition, 2017). The present disclosure also includes compounds 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. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,11C,13C,15N,17O,18O,18F,31P, 32P,35S,36Cl, and125I, respectively. In one aspect, isotopically labeled compounds can be used in metabolic studies (with14C), reaction kinetic studies (with, for example,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive 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 herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H), may optionally be used anywhere in described structures that achieve the desired result. Alternatively, or in addition, isotopes of carbon, e.g.,13C and14C, may be used. In one aspect, the isotopic substitution is replacing hydrogen with deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in the allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect). 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 certain aspects, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some aspects, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, enrichment at any point is above natural abundance and, in an aspect, is enough to alter a detectable property of the compounds as a drug in a human. Attorney Docket No.11555-008WO1 The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one aspect, the disclosure includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, or d6-DMSO. A solvate can be in a liquid or solid form. A “prodrug,” as used herein, means a compound which, when administered to a host in vivo, is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described compounds herein. Prodrugs can be used to achieve any desired effect, including to enhance the properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo. Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others. In certain aspects, the prodrug renders the parent compound more lipophilic. In certain aspects, a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner. For example, non- limiting aspects include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compounds that have at least two functional groups that can link the parent compound with another prodrug moiety and are typically biodegradable in vivo. In some aspects, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound. Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on Attorney Docket No.11555-008WO1 the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a hydroxylated prodrug moiety to form a phosphate ester; a hydroxyl on the parent drug and a phosphonate on the prodrug to form a phosphonate ester; a hydroxyl on the parent drug and a phosphoric acid prodrug moiety to form a phosphate ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24alkyl) to form an ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-S-(C2-24 alkyl) to form a thioester; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24alkyl) to form an ether; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an thioether; and a carboxylic acid, oxime, hydrazide, hydrazine, amine or hydroxyl on the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including but not limited to polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyanhydride, polyester, polyamide, or a peptide. In some aspects, a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug. The amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties. The amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid. Lysosome-Targeting Chimeras In one aspect, the present disclosure provides lysosome-targeting chimeras. In some aspects, the lysosome-targeting chimera includes at least one target-binding moiety. In some aspects, the at least one target-binding moiety is capable of specifically binding to a cell surface molecule or an extracellular molecule. In some aspects, the lysosome-targeting chimera includes at least one thiol-responsive moiety. In some aspects, the lysosome-targeting chimera includes a compound of Formula I Attorney Docket No.11555-008WO1 B-L-T (I) wherein: B comprises the target-binding moiety; L is selected from a bond and a linker moiety; and T comprises the thiol-responsive moiety. In some aspects, the lysosome-targeting chimera enhances degradation of the cell surface molecule or extracellular molecule relative to degradation of the cell surface molecule or extracellular molecule in the presence of the target-binding moiety alone. In some aspects, the lysosome-targeting chimera enhances degradation of the cell surface molecule or extracellular molecule relative to degradation of the cell surface molecule or extracellular molecule in the presence of the target-binding moiety or the thiol-responsive moiety alone. By “enhances degradation” in this context means the cell surface molecule or extracellular molecule is degradation in the presence of the lysosome-targeting chimera and is not degraded in the presence of the target-binding moiety alone, or the presence of the target-binding moiety or the thiol-responsive moiety alone, under the same conditions; or the cell surface molecule or extracellular molecule is degraded in the presence of the lysosome-targeting chimera to a greater extent than the cell surface molecule or extracellular molecule is degraded in the presence of the target-binding moiety alone, or the presence of the target- binding moiety or the thiol-responsive moiety alone, under the same conditions. When the cell surface molecule or extracellular molecule is degraded in the presence of the lysosome- targeting chimera to a greater extent than the cell surface molecule or extracellular molecule is degraded in the presence of the target-binding moiety alone, or the presence of the target- binding moiety or the thiol-responsive moiety alone, under the same conditions, the degradation may be 1.2 fold or greater, 1.4 fold or greater, 1.6 fold or greater, 1.8 fold or greater, 2 fold or greater, 2.5 fold or greater, 3 fold or greater, 3.5 fold or greater, 4 fold or greater, 4.5 fold or greater, 5 fold or greater, 5.5 fold or greater, 6 fold or greater, 6.5 fold or greater, 7 fold or greater, 7.5 fold or greater, 8 fold or greater, 8.5 fold or greater, 9 fold or greater, 9.5 fold or greater, or 10 fold or greater in the presence of the lysosome-targeting chimera. Target-Binding Moieties Attorney Docket No.11555-008WO1 In some aspects, the lysosome-targeting chimeras of the present disclosure include a target- binding moiety capable of specifically binding a cell surface molecule or an extracellular molecule. In some aspects, the target-binding moiety is selected from a polypeptide, a ligand (e.g., a ligand for the cell surface molecule or extracellular molecule), an aptamer, a nanoparticle, and a small molecule. In some aspects, when the target-binding moiety is a polypeptide, the moiety is an antibody. The terms “antibody” and “immunoglobulin” include antibodies and immunoglobulins of any isotope (e.g., IgG (e.g., IgG1, IgG2, IgG3, or IgG4), IgE, IgD, IgA, IgM, etc.), whole antibodies (e.g., antibodies composed of a tetramer which in term is composed of two dimers of a heavy and light chain polypeptide); single chain antibodies; fragments of antibodies (e.g., fragments of whole or single chain antibodies) which retain specific binding to the cell surface molecule or extracellular molecule, including, but not limited to, Fv, single chain Fv (scFv), Fab, F(ab’)2, Fab’, (scFv’)2, diabodies, and nanobodies; single domain antibodies (VHH); chimeric antibodies; monoclonal antibodies; fully human antibodies; humanized antibodies (e.g., humanized whole antibodies, humanized antibody fragments, etc.); and fusion proteins including an antigen-binding portion of an antibody and a non-antibody protein or fragment thereof. The antibody may be detectably labeled, e.g., with an in vivo imaging agent or the like. The antibody may be further conjugated to other moieties, such as polyethylene glycol (PEG). Fusion to an antibody Fc region (or a fragment thereof), conjugated to PEG, etc., may find use, e.g., for increasing the serum half-life of the chimeras upon administration to the subject. In some aspects, the target-binding moiety is a ligand for one or more cell surface molecules or extracellular molecules. As used herein, a “ligand” is a substance that forms a complex with a biomolecule to serve a biological purpose. The ligand may be a substance that forms a complex with a cell surface molecule or an extracellular molecule. In some aspects, the ligand is modified in such a way that complex formation with the cell surface molecule or extracellular molecule occurs, but the normal biological result of such complex formation does not occur. In some aspects, the target-binding moiety is an aptamer. By “aptamer” is meant a nucleic acid (e.g., an oligo nucleotide) that has a specific binding affinity for one or more cell surface molecules or extracellular molecules. Aptamers exhibit certain desirable properties, such as ease of selection and synthesis, high binding affinity and specificity, low immunogenicity, and versatile synthetic accessibility. Attorney Docket No.11555-008WO1 In some aspects, the target-binding moiety is a small molecule. By “small molecule” is meant a compound having a molecule weight of 1000 atomic mass units (amu) or less. In some aspects, the small molecule is 750 amu or less, 500 amu or less, 400 amu or less, 300 amu or less, or 200 amu or less. In some aspects, the small molecule is not made up of repeating molecular units, such as present in a polymer. In some aspects, the target-binding moiety binds to a cell surface molecule. By “cell surface molecule” is meant a molecule associated with a cell membrane, e.g., a cell membrane- tethering domain or a transmembrane domain. The cell surface molecule may be any cell surface molecule that is desired for targeted degradation via the endosomal / lysosomal pathway. In some aspects, the cell surface molecule is associated with a disease or disorder, for example, a disease or disorder described herein. In some aspects, the cell surface molecule is a cell surface receptor. Cell surface receptors of interest include, but are not limited to, cell adhesion receptors, stem cell receptors, immune cell receptors, growth factor receptors, cytokine receptors, hormone receptors, receptor tyrosine kinases, a receptor in the epidermal growth factor receptor (EGFR) family (e.g., HER2 (human epidermal growth factor receptor 2), etc.), a receptor in the fibroblast growth factor receptor (FGFR) family, a receptor in the vascular endothelial growth factor receptor (VEGFR) family, a receptor in the platelet-derived growth factor receptor (PDGFR) family, a receptor in the rearranged during transfection RET) receptor family, a receptor in the Eph receptor family, a receptor in the discoidin domain receptor (DDR) family, and a mucin protein (e.g., MUC1). In some aspects, the cell surface molecule is CD71 (transferrin receptor). In some aspects, the cell surface receptor is an immune cell receptor selected from a T cell receptor, a B cell receptor, a natural killer (NK) cell receptor, a macrophage receptor, a monocyte receptor, a neutrophil receptor, a dendritic cell receptor, a mast cell receptor, a basophil receptor, and an eosinophil receptor. In some aspects, the cell surface molecule is FcRn. In some aspects, the target-binding moiety binds a cell surface molecule, which mediates its effect not through a specific molecule interaction (and therefore is not susceptible to blocking) but rather through bulk biophysical or aggregate effects. A non-limiting example of such a cell surface molecule is a mucin. Examples of mucins include but are not limited to, MUC1, MUC16, MUC5AC, MUC4, CD43, CD45, GPIb, and the like. In some aspects, the target-binding moiety specifically binds one or more cell adhesion receptors. In some aspects, the cell adhesion receptor is an integrin, such as αvβ1 integrin, αvβ3 integrin, αvβ6 integrin, or α5β1 integrin. Attorney Docket No.11555-008WO1 In some aspects, the target-binding moiety specifically binds a cell surface molecule on a cell associated with a disease or disorder, for example, a disease or disorder described herein. In some aspects, the target-binding moiety specifically binds a cell surface molecule present on a cancer cell. By “cancer cell” is meant a cell exhibiting a neoplastic cellular phenotype, which may be characterized by one or more of, for example, abnormal cell growth, abnormal cellular proliferation, loss of density-dependent growth inhibition, anchorage-independent growth potential, ability to promote tumor growth or development in an immunocompromised non-human animal model, or any appropriate indicator of cellular transformation. “Cancer cell” may be used interchangeably herein with “tumor cell,” “malignant cell,” or “cancerous cell,” and encompasses cancer cells of a solid tumor, a semi- solid tumor, a hematological malignancy (e.g., a leukemia cell, a lymphoma cell, a myeloma cell, etc.), a primary tumor, a metastatic tumor, and the like. In some aspects, the cell surface molecule present on the cancer cell is a tumor-associated antigen or a tumor-specific antigen. In some aspects, the target-binding moiety specifically binds a cell surface molecule present on an immune cell. In some aspects, the cell surface molecule is present on an immune cell selected from a T cell, a B cell, a natural killer (NK) cell, a macrophage, a monocyte, a neutrophil, a dendritic cell, a mast cell, a basophil, and an eosinophil. In some aspects, the cell surface molecule present on an immune cell is an inhibitory immune receptor. As used herein, an “inhibitory immune receptor” is a receptor present on an immune cell that negatively regulates an immune response. Examples of inhibitory immune receptors which may be bound according to the present disclosure include inhibitory immune receptors of the Ig superfamily, including, but not limited to, CD200R, CD300a (IRp60; mouse MAIR-I), CD300f (IREM-1); CEACAM1 (CD66a), FcyRIIb, ILT-2 (LIR-1; LILRB1; CD85j), ILT-3 (LIR-5; CD85k; LILRB4), ILT-4 (LIR-2; LILRB2), ILT-5 (LIR-3; LILRB3; mouse PIR-B), LAIR-1, PECAM-1 (CD31), PILR-α (FDF03), SIRL-1, and SIRP-α. Further examples of inhibitory immune receptors that may be bound according to the present disclosure include sialic acid-binding Ig-like lectin (Siglec) receptors, e.g., Siglec 7, Siglec 9, and the like. Additional examples of inhibitory immune receptors that may be bound according to the present disclosure include C-type lectins, including, but not limited to, CLEC4A (DCIR), Ly49Q, and MICL. Details regarding inhibitory immune receptors may be found, e.g., in Steevels et al. (2011) Eur. J. Immunol. 41(3):575-587. In some aspects, the cell surface molecule present on an immune cell is a ligand of an inhibitory immune receptor. In some aspects, the cell surface molecule present on an immune cell is an immune checkpoint Attorney Docket No.11555-008WO1 molecule. Non-limiting examples of immune checkpoint molecules that may be bound include PD-1, PD-L1, CTLA4, TIM3, LAG3, TIGIT, and a member of the B7 family. In some aspects, the target-binding moiety binds to a cell surface molecule selected from PSMA, FcRn, PD-L1, PD1, CTLA4, CD41 (integrin alpha-IIb), CD52, BAFF, FGFR2, CD 30 (TNFR2F8), CD3, EpCAM, EGFR, IGF-1 receptor (CD221), HER2, CD22, CD19, CD20, CD79a, Trop-2, Nectin-4, BCMA, Folate receptor alpha, LAG-3, tissue factor, IFNAR1, G protein-coupled receptor 5D, gp100, cMET, Factor IXa, and Factor X. In some aspects, the target-binding moiety comprises an antibody selected from atezolizumab, avelumab, sugemalimab, cosibelimab, durvalumab, avelumab, cemiplimab, camrelizumab, serplulimab, penpulimab, sintilimab, toripalimab, retifanlimab, dostarlimab, pembrolizumab, nivolumab, tremelimumab, ipilimumab, abciximab, alemtuzumab, belimumab, bemarituzumab, brentuximab, catumaxomab, cetuximab, necitumumab, panitumumab, cixutumumab, trastuzumab, margetuximab, pertuzumab, inotuzumab, moxetumomab, loncastuximab, rituximab, ibritomomab, tositimomab, ofatumumab, ublituximab, ocrelizumab, obinutuzumab, polatuzumab, sacituzumab, enfortumab, belantamab, , mirvetuximab, relatlimab, tisotumab, anifrolumab, odronextamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, teclistamab, tebentafusp, amivantamab, emicizumab, and blinatumomab. In some aspects, the target-binding moiety binds to an extracellular molecule. By “extracellular molecule” is meant a soluble molecule external to the cell membranes of any cell in the vicinity of the soluble molecule. The extracellular molecule may be any extracellular molecule that is desired for targeted degradation via the endosomal / lysosomal pathway. In some aspects, the extracellular molecule is a ligand for a cell surface receptor. Cell surface receptor ligands of interest include but are not limited to, growth factors (e.g., epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and the like), cytokines (e.g., an interleukin, an interferon, a tumor necrosis factor (TNF), a transforming growth factor β (TGF-β), including any particular subtypes of such cytokines), hormones, and the like. In some aspects, the extracellular molecule is apolipoprotein E4 (ApoE4). In some aspects, the extracellular molecule is an antibody, e.g., an antibody that specifically binds a cell surface molecule or different extracellular molecule. In some aspects, the antibody is an autoantibody. Non-limiting examples of autoantibodies include rheumatoid factor (RF), antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA), anti-double stranded DNA (anti-dsDNA), anticentromere antibodies (ACA), antihistone Attorney Docket No.11555-008WO1 antibodies, cyclic citrullinated peptide antibodies (CCP), extracellular nuclear antigen antibodies (e.g., anti-SS-A (Ro) and anti-SS-B (La), anti-RNP, anti-Jo-1, anti-Sm, Scl-70), cardiolipin antibodies, beta-2 glycoprotein 1 antibodies, antiphospholipid antibodies (APA), lupus anticoagulants (LA), diabetes-related autoantibodies, anti-tissue transglutaminase (anti- tTG), anti-gliadin antibodies (AGA), intrinsic factor antibodies, parietal cell antibodies, thyroid autoantibodies (e.g., anti-TPO, TSH receptor antibodies), smooth muscle antibodies 9SMA), antimitochondrial antibodies (AMA), liver kidney microsome type 1 antibodies (anti-LKM-1), anti-glomerular basement membrane (GBM), acetycholine receptor (AChR) antibodies, etc. In some aspects, the extracellular molecule is a secreted protein that accumulates in disease (e.g., α-synuclein), a cholesterol carrier (e.g., ApoB), an infectious disease toxin (e.g., AB toxins, ESAT-6), an infectious particle (e.g., a whole virus, a whole bacterium, etc.), a clotting factor (e.g., Factor IX), the target of any government (e.g., FDA) approved antibody that binds to an extracellular molecule (e.g., TNFα), any chemokine or cytokine (e.g., mediators of sepsis or chronic inflammation such as IL-1), a proteinaceous hormone (e.g., insulin, ACTH, etc.), a proteinaceous mediator of a mood disorder, a proteinaceous mediator of energy homeostasis (e.g., leptin, ghrelin, etc.), a proteinaceous allergen present in the bloodstream or an antibody against such an allergen (e.g., for peanut allergies), a proteinaceous toxin (e.g., snake venom hyaluronidase, etc.), etc. In some aspects, the target-binding moiety binds an extracellular molecule selected from TNF-α, VEGF-A, PCSK9, IL-13, IL-23p19, Ang-2, and IL-17A,F. In some aspects, the target-binding moiety comprises an antibody selected from adalimumab, infliximab, bevacizumab, alirocumab, rozanolixizumab, mirikizumab, faricimab, bimekizumab, and tralokinumab. In some aspects, the cell surface molecule or extracellular molecule is a mutated protein. In some aspects, a lysosome-targeting chimera as described herein causes shuttling of the mutated protein into the lysosome, promoting its loading onto a major histocompatibility complex (MCH, e.g., MHC I or MHC II), and thereby promoting recognition of the mutated protein by the immune system. In this context, the lysosome-targeting chimera finds use in generating antibodies specific to a mutated and unwanted protein. By “specifically binds” is meant that the target-binding moiety binds to its target with greater affinity, avidity, more readily, and / or with greater duration than they bind to other substances, Attorney Docket No.11555-008WO1 e.g., in a sample. In some aspects, the target-binding moiety binds to its target with an affinity of Ka(that is, an equilibrium association constant of a particular binding interaction with units of 1 / M) of, for example, greater than or equal to about 105M-1. In some aspects, the target- binding moiety binds to its target with a Kagreater than or equal to 106M-1, 107M-1, 108M-1, 109M-1, 1010M-1, 1011M-1, 1012M-1, or 1013M-1. “High affinity” binding refers to a binding with a Kaof at least 107M-1, at least 108M-1, at least 109M-1, at least 1010M-1, at least 1011M-1, at least 1012M-1, at least 1013M-1, or greater. Alternatively, affinity may be defined as an equilibrium dissociation constant (KD) of a particular binding interaction with units of M (e.g., 10-5M to 10-13M, or less). In some aspects, specific binding means the target-binding moiety binds to its target with a KDof less than or equal to about 10-5M, less than or equal to about 10-6M, less than or equal to about 10-9M, 10-10M, 10-11 M, or 10-12M or less. The binding affinity of the target-binding moiety to its target can be readily determined using conventional techniques, e.g., by competitive ELISA (enzyme-linked immunosorbent assay), equilibrium dialysis, by using surface plasmon resonance (SPR) technology, radioimmunoassay, or the like. Thiol-Responsive Moieties In some aspects, the lysosome-targeting chimeras of the present disclosure include a thiol- responsive moiety. In some aspects, the thiol-responsive moiety is capable of binding to one or more thiol groups on a surface of a cell. In some aspects, the thiol-responsive moiety includes a polymer. Any suitable polymer capable of binding to one or more thiol groups on a surface of a cell may be used as the thiol- responsive moiety. In some aspects, the polymer may comprise a synthetic polymer. In other aspects, the polymer may comprise a natural polymer, including a modified natural polymer. In some aspects, the polymer comprises a random copolymer. In other aspects, the polymer comprises a block copolymer. Suitable polymers for use as the thiol-responsive moiety may be prepared according to any suitable methods, such as reversible addition-fragmentation chain transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), free radical polymerization, group transfer polymerization, ring-opening polymerization, and ring-opening metathesis polymerization (ROMP). In some aspects, the polymer is formed via RAFT polymerization. In some aspects, the thiol-responsive moiety comprises a polymer having one or more thiol- reactive groups (e.g., sulfide or disulfide) within a main chain of the polymer. In some aspects, Attorney Docket No.11555-008WO1 the thiol-responsive moiety may comprise a polydisulfide, for example, poly(lipoic acid). In some aspects, the thiol-responsive moiety comprises a polymer having one or more structural units selected from: or combinations Raand Rbare independently selected at each occurrence from hydrogen, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, thiol, or combinations thereof, each of which may be optionally substituted as described herein and as allowed by valency. In other aspects, the thiol-responsive moiety comprises a polymer having a main chain and one or more side chains comprising one or more thiol-reactive groups. In some aspects, the thiol-responsive moiety may comprise a polymer having a main chain comprising a polymethacrylate, a polyacrylate, a polyester, a polyamide, a polycarbonate, a polycarbamate, a polyurethane, a polynorbornene, a poly(oxanorbornene), a polycaprolactone, a polylactide, a polylactide-co-glycolide, a polyoxazoline, a polypeptide, or combinations thereof, having one or more one or more side chains having one or more thiol-reactive groups. In some aspects, the thiol-responsive moiety may comprise a polymer having a main chain comprising a polymethacrylate, a polyacrylate, a polyester, a polyamide, a polycarbonate, a polycarbamate, a polyurethane, a polynorbornene, a poly(oxanorbornene), a polycaprolactone, a polylactide, a polylactide-co-glycolide, a polyoxazoline, a polypeptide, or combinations thereof, and further comprising one or more additional structural units having one or more one or more side chains having one or more thiol-reactive groups. In some aspects, the main chain comprises one or more structural units selected from: , Attorney Docket No.11555-008WO1 , In some aspects, the thiol-responsive moiety comprises one or more thiol-reactive groups selected from a thiol, disulfide (including linear or cyclic disulfides), a maleimide or derivatives thereof (such as a dibromomaleimide), an alkene, an alkyne, a bis-sulfone, a selenide, or a diselenide. In some aspects, the thiol-responsive moiety may comprise one or more thiol-reactive groups derived from a compound selected from the following:

[0002] Attorney Docket No.11555-008WO1 R N N N OO O OO group N O R R R R R R In some aspects, the thiol-responsive moiety comprises one or more R groups having the structure: wherein: Attorney Docket No.11555-008WO1 R1is selected from an aliphatic group, an oligo(alkylene) glycol, and a poly(alkylene) glycol, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) Z groups as allowed by valency; R2is selected from an aliphatic group, an oligo(alkylene) glycol, a poly(alkylene) glycol, a therapeutic agent (such as a chemotherapeutic or radiotherapeutic agent), a label (such as a radiolabel or a fluorophore), a nanomaterial (such as a nanodot), or a proteolysis-targeting chimera (PROTAC), each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) Z groups as allowed by valency; Z is independently selected at each occurrence from halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C6cycloalkyl)(C0-C3alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, RxO-(C0-C3 alkyl)-, RxS-(C0-C3 alkyl)-, (RxRyN)-(C0-C3 alkyl)-, RxO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(O)-(C0-C3alkyl)-, RxO- S(O)2-(C0-C3 alkyl)-, (RxRyN) S(O)2-(C0-C3 alkyl)-, RzC(O)-O-(C0-C3 alkyl)-, RzC(O)- (RxN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RzC(O)-(C0- C6 alkyl)-, RzS(O)-(C0-C3 alkyl)-, and RzS(O)2-(C0-C3 alkyl)-, each of which may be optionally substituted by one or more (for example, 1, 2, 3, or 4) Y groups as allowed by valency; Rxand Ryare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORx, -SRx, and -NRxRy, each of which may be optionally substituted with one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, Attorney Docket No.11555-008WO1 hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, and thiol. In some aspects, R1is selected from –(CH2)i- and –(CH2CH2O)j-, wherein each of i and j is independently an integer from 1 to about 16. In some aspects, the thiol-responsive moiety includes a polymer having structural units of ; wherein R is as defined herein; R3, R3’, R4, and R4’are independently selected from hydrogen, halogen, a C1-C12 aliphatic group, a C1-C12 alkoxy; R5and R5’are independently selected from hydrogen, halogen, and a C1-C12aliphatic group; L1and L2are independently a linking group (for example, selected , wherein R7is hydrogen or C1-C6 alkyl); and (for example, an oligo(alkylene) glycol or a poly(alkylene) glycol). In some aspects, each of R3, R3’, R4, and R4’are hydrogen. In some aspects, each or R5and R5’are methyl. Attorney Docket No.11555-008WO1 In some aspects, In some aspects, each of L1and L2 , wherein R7is as defined herein. Moieties In some aspects, the lysosome-targeting chimeras described herein include conjugates. In some aspects, the lysosome-targeting chimeras include the target-binding moiety conjugated to the thiol-responsive moiety. Methods of making such conjugates are also provided, including conjugating the target-binging moiety to the thiol-responsive moiety. In some aspects, the methods include site-specifically conjugating the target-binding moiety to the thiol-responsive moiety. For example, when the target-binding moiety includes a peptide, the conjugating may include site-specifically conjugating the thiol-responsive moiety to a pre- selected amino acid of the target-binding moiety. In some aspects, the pre-selected amino acid is at the N-terminus or C-terminus of the target-binding moiety. In other aspects, the pre- selected amino acid is internal to the target-binding moiety, i.e., between the N-terminal and C-terminal amino acids of the target-binding moiety. In some aspects, the pre-selected amino acid is a non-natural amino acid. Non-natural amino acids include those having a functional group selected from an azide, alkyne, alkene, amino-oxy, hydrazine, aldehyde, nitrone, nitrile oxide, cyclopropene, norbornene, isocyanide, aryl halide, and boronic acid functional group. In some aspects, one or more linker moieties may be employed to facilitate the conjugation of the target-binding moiety to the thiol-responsive moiety. Non-limiting examples of such linkers include ester linkers, amide linkers, maleimide or maleimide-based linkers, valine- citrulline linkers, hydrazone linkers, N-succinimidyl-4-(2-pyridyldithio)butyrate (SDPB) linkers, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linkers, vinylsulfone-based linkers, linkers that include polyethylene glycol (PEG), such as, but not limited to, tetraethyleneglycol, linkers that include propanoic acid, linkers that include caproleic acid, and linkers including any combination thereof. Attorney Docket No.11555-008WO1 Numerous strategies are available for conjugating the target-binding moiety and the thiol- responsive moiety through a linker moiety. For example, the targeting moiety may be derivatized by covalently attaching the linker moiety to the targeting moiety, where the linker moiety has a functional group capable of reacting with a chemical handle on the thiol- responsive moiety. In another example, the thiol-responsive moiety may be derivatized by covalently attaching the linker moiety to the thiol-responsive moiety, where the linker moiety has a functional group capable of reacting with a chemical handle on the target-binding moiety. The functional group on the linker moiety may vary and may be selected based on compatibility with the chemical handle on the target-binding moiety of the thiol-responsive moiety. In some aspects, a linker moiety is included in the compounds of Formula I as described herein. The linker moiety is a chemically stable bivalent group that attaches B to T in Formula I. In some aspects, the linker moiety, as described herein, can be used in either direction, i.e., either the left end is linked to B and the right end to T, or the left end is linked to T and the right end to B. In some aspects, the linker moiety is a chain of 2 to 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms, of which one or more carbons can be optionally replaced by a heteroatom such as O, N, S, or P. In some aspects, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 19, or 20 contiguous atoms. For example, the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous, or non-contiguous (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units). In some aspects, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous units which can be branched and which can be independently alkyl, aryl, heteroaryl, alkenyl, or alkynyl, cycloalkyl, or heterocycloalkyl substituents. In some aspects, the linker moiety can include or be comprised of one or more ethylene glycol, propylene glycol, lactic, and / or glycolic acid units. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art and can be modified to obtain the desired half-life and hydrophilicity. In certain aspects, these units can be flanked or interspersed with other moieties, such as, for example, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, etc., as desired to achieve the appropriate properties. Attorney Docket No.11555-008WO1 In some aspects, the linker moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted O, N, S, P or Si atoms. In some aspects, the linker moiety is flanked, substituted, or interspersed with an alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In some aspects, the linker moiety may be asymmetric or symmetric. In some aspects, the linker moiety can be a non-linear chain and can be, or include, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl cyclic moieties. In some aspects, the linker moiety is selected from L1: In some aspects, of a moiety of Formula L1, Formula L2, Formula L3, Formula L4, Formula L5, Formula L6, Formula L7, Formula L8, Formula L9, or Formula L10:

[0003] Attorney Docket No.11555-008WO1 (L9) wherein: X101and X102are independently at each occurrence selected from a bond, aryl, heteroaryl, cycloalkyl, heterocycle, NR130, C(R130)2, O, C(O), and S; R100, R101, R102, R103, and R104are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, C(S)-, -C(O)NR130-, -NR130C(O)-, -O-, -S-, -NR130-, -C(R130R130)-, -P(O)(OR106))-, -R(O)(OR106)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycloalkyl, cycloalkyl, heteroaryl, lactic acid, or glycolic acid, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) substituents independently selected from R140; R106is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R130is independently as each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -C(O)O(cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), alkenyl, or alkynyl; and R140is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl, cycloalkyl, heterocyloalkyl, aryl, or heteroaryl), -N(independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -NHSO2(alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -N(alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl)SO2alkyl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some aspects, R100, R101, R102, R103, and R104within the linker moiety are selected in such a manner that no two -C(=O)- moieties are adjected to each other; no two -O- or -NH- moieties are adjacent to each other; and / or no moieties are otherwise selected in an order such that an unstable molecule results (as defined as producing a molecule that has a shelf life at Attorney Docket No.11555-008WO1 ambient temperature of less than about six months, five months, or four months) due to decomposition caused by the selection and order of R100, R101, R102, R103, and R104. The following are non-limiting examples of linker moieties and / or moieties which comprise linker moieties in whole or in part that can be used in this disclosure. Based on this elaboration, those of skill in the art will understand how to use the full breadth of Linkers that will accomplish the goal of the disclosure. Non-limiting examples of moieties which may comprise the linker moiety, either in whole or in part, include, but are not limited to: a bond; -C(=O)-; -C≡C-; -NH-; -N(CH3)-; -O-; -CH2-; -(CH2)2-; -(CH2)3-; -(CH2)4-; -(CH2)5-; -(CH2)6-; -(CH2)7-; -(CH2)8-; -(CH2)9-; -(CH2)10-; -NH(C=O)-; -C(=O)NH-; -C(=O)CH2-; -C(=O)(CH2)2-; -C(=O)(CH2)3-; -C(=O)(CH2)4-; -C(=O)(CH2)5-; -C(=O)(CH2)6-; -CH2C(=O)-; -(CH2)2C(=O)-; -(CH2)3C(=O)-; -(CH2)4C(=O)-; -(CH2)5C(=O)-; -(CH2)6C(=O)-; -CH2NH-; -(CH2)2NH-; -(CH2)3NH-; -(CH2)4NH-; -(CH2)5NH-; -(CH2)6NH-; -NHCH2-; -NH(CH2)2-; -NH(CH2)3-; -NH(CH2)4-; -NH(CH2)5-; -NH(CH2)6-; -CH2O-; -(CH2)2O-; -(CH2)3O-; -(CH2)4O-; -(CH2)5O-; -(CH2)6O-; -OCH2-; -O(CH2)2-; -O(CH2)3-; -O(CH2)4-; -O(CH2)5-; -O(CH2)6-; ; in whole or in part, include, but are not limited to: , Attorney Docket No.11555-008WO1 , 5 , 10 Attorney Docket No.11555-008WO1 . moiety may comprise, either in whole or in part, a moiety selected from: , from: , , , , , and from: , . moiety may comprise, either in whole or in part, Attorney Docket No.11555-008WO1 In some aspects, the linker moiety may comprise, either in whole or in part, a moiety selected from: , selected from: . selected from: Attorney Docket No.11555-008WO1 . selected from: , some may or a from: Attorney Docket No.11555-008WO1 , selected from: . selected from: , Attorney Docket No.11555-008WO1 . selected from: . selected from: , Attorney Docket No.11555-008WO1 . comprise, either in whole or in part, a moiety selected from: , , ,

[0004] Attorney Docket No.11555-008WO1 , and all other variables are as defined herein. In some aspects, the linker moiety may comprise, either in whole or in part, a moiety selected from: , , Attorney Docket No.11555-008WO1 , a moiety selected from: H N N ,

[0005] Attorney Docket No.11555-008WO1 , , moiety selected from: , , Attorney Docket No.11555-008WO1 , selected from: , Attorney Docket No.11555-008WO1 , selected from: , , . Attorney Docket No.11555-008WO1 Pharmaceutical Compositions The chimeras described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically- acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administering. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. The active components of their compositions can be administered in a single dose or at continuous and distinct intervals, as can be readily determined by a person skilled in the art. Compositions, as described herein, comprising an active compound (i.e., a lysosome- targeting chimera described herein) and a pharmaceutically acceptable carrier or excipient of some sort, may be useful in a variety of medical and non-medical applications. For example, pharmaceutical compositions comprising an active compound and an excipient may be useful for the treatment or prevention of a cancer or an autoimmune disorder in a subject in need thereof. "Pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate-buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion), and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well-known in the art for use in pharmaceutical formulations and as described further herein. “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and / or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005). Attorney Docket No.11555-008WO1 Representative excipients include, but are not limited to, any non-toxic, inert solid, semisolid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one of skill in this art, the excipients may be chosen based on what the composition is useful for. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, the time course of delivery of the agent, etc., and can be administered to humans and / or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some aspects, the active compounds disclosed herein are administered topically. Representative diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof. Representative granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl Attorney Docket No.11555-008WO1 cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof. Representative surface active agents and / or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. Representative binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and / or combinations thereof. Attorney Docket No.11555-008WO1 Representative preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Representative antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Representative chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Representative antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Representative antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Representative alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Representative acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain aspects, the preservative is an anti-oxidant. In other aspects, the preservative is a chelating agent. Representative buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, Attorney Docket No.11555-008WO1 calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and combinations thereof. Representative lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof. Representative natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Representative synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. Additionally, the composition may further comprise a polymer. Representative polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides Attorney Docket No.11555-008WO1 and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid / acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide- propylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), polyanhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-1000], 1,2-Distearoyl-sn-glycero- 3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000], and 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000]), copolymers and salts thereof. Additionally, the composition may further comprise an emulsifying agent. Representative emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], Attorney Docket No.11555-008WO1 sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof. In certain aspects, the emulsifying agent is cholesterol. Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable compositions, such as injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain aspects, the particles are suspended in a carrier fluid comprising 1% (w / v) sodium carboxymethyl cellulose and 0.1% (v / v) Tween 80. The injectable composition can be sterilized, for example, by filtration through a bacteria- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, Attorney Docket No.11555-008WO1 which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles. Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols, and the like. Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required. The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, Attorney Docket No.11555-008WO1 cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate- controlling membrane or by dispersing the particles in a polymer matrix or gel. Methods of Use In another aspect, methods of using the lysosome-targeting chimeras of the present disclosure are also provided. In some aspects, the present disclosure provides methods for degrading a cell surface molecule or extracellular molecule. In some aspects, the methods include contacting the cell surface molecule or extracellular molecule with any of the lysosome-targeting chimeras of the present disclosure under conditions in which the lysosomal-targeting chimera shuttles the cell surface molecule or extracellular molecule to the lysosome for degradation. In some aspects, the method is performed in vitro (e.g., in a tube, cell culture plate, cell, or the like) and finds use, e.g., in testing or research applications. In other aspects, the method is performed in vivo (e.g., in an individual to whom the lysosome-targeting chimera is administered) and finds use, e.g., in clinical or therapeutic applications, such as methods of treating a disease or disorder (e.g., cancer) in a subject in need thereof. In some aspects, the present disclosure provides methods of treating a disease or disorder associated with a cell surface molecule or extracellular molecule in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a lysosome- targeting chimera described herein. In some aspects, the disease or disorder comprises a cancer. The term “neoplasia” or “cancer” is used throughout this disclosure to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or Attorney Docket No.11555-008WO1 cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue, and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal, and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe cancerous disease states and embraces or encompasses the pathological process associated with malignant, hematogenous, ascitic, and solid tumors. The cancers that may be treated by the compositions disclosed herein may comprise carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastomas. Carcinomas which may be treated by the compounds and compositions of the present disclosure include, but are not limited to, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky‐ cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian carcinoma, scirrhous Attorney Docket No.11555-008WO1 carcinoma, carcinoma scrota, signet‐ring cell carcinoma, carcinoma simplex, small cell carcinoma, solandoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and carcinoma vilosum. Representative sarcomas that may be treated by the compounds and compositions of the present disclosure include but are not limited to, liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors (including Ewing's sarcoma of bone, extraskeletal or non‐bone) and primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft‐part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST) and osteosarcoma (also known as osteogenic sarcoma) skeletal and extra‐skeletal, and chondrosarcoma. The compounds and compositions of the present disclosure may be used in the treatment of a lymphoma. Lymphomas that may be treated include mature B cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, precursor lymphoid neoplasms, Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders. Representative mature B cell neoplasms include, but are not limited to, B-cell chronic lymphocytic leukemia / small cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia), splenic marginal zone lymphoma, hairy cell leukemia, plasma cell neoplasms (such as plasma cell myeloma / multiple myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, and heavy chain diseases), extranodal marginal zone B cell lymphoma (MALT lymphoma), nodal marginal zone B cell lymphoma, follicular lymphoma, primary cutaneous follicular center lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, Epstein-Barr virus-positive DLBCL of the elderly, lyphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B- cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman’s disease, and Burkitt lymphoma / leukemia. Representative mature T cell and NK cell Attorney Docket No.11555-008WO1 neoplasms include, but are not limited to, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia / lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T- cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, lycosis fungoides / Sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders (such as primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma. Representative precursor lymphoid neoplasms include B-lymphoblastic leukemia / lymphoma not otherwise specified, B- lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities, or T-lymphoblastic leukemia / lymphoma. Representative Hodgkin lymphomas include classical Hodgkin lymphomas, mixed cellularity Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma. The compounds and compositions of the present disclosure may be used in the treatment of a leukemia. Representative examples of leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia, adult T-cell leukemia, clonal eosinophilias, and transient myeloproliferative disease. The compounds and compositions of the present disclosure may be used in the treatment of a germ cell tumor, for example, germinomatous (such as germinoma, dysgerminoma, and seminoma), non germinomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma) and mixed tumors. The compounds and compositions of the present disclosure may be used in the treatment of blastomas, for example, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme. Representative cancers which may be treated include, but are not limited to: bone and muscle sarcomas such as chondrosarcoma, Ewing’s sarcoma, malignant fibrous histiocytoma of bone / osteosarcoma, osteosarcoma, rhabdomyosarcoma, and heart cancer; brain and nervous system cancers such as astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, Attorney Docket No.11555-008WO1 medulloblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, and visual pathway and hypothalamic glioma; breast cancers including invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, male breast cancer, Phyllodes tumor, and inflammatory breast cancer; endocrine system cancers such as adrenocortical carcinoma, islet cell carcinoma, multiple endocrine neoplasia syndrome, parathyroid cancer, phemochromocytoma, thyroid cancer, and Merkel cell carcinoma; eye cancers including uveal melanoma and retinoblastoma; gastrointestinal cancers such as anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumors, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular cancer, pancreatic cancer, and rectal cancer; genitourinary and gynecologic cancers such as bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, prostate cancer, testicular cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor; head and neck cancers such as esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, and hypopharyngeal cancer; hematopoietic cancers such as acute biphenotypic leukemia, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid dendritic cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, intravascular large B-cell lymphoma, large granular lymphocytic leukemia, lymphoplasmacytic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, Mast cell leukemia, mediastinal large B cell lymphoma, multiple myeloma / plasma cell neoplasm, myelodysplastic syndromes, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone B cell lymphoma, non- Hodgkin lymphoma, precursor B lymphoblastic leukemia, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sezary syndrome, splenic marginal zone lymphoma, and T-cell prolymphocytic leukemia; skin cancers such as basal cell carcinoma, squamous cell carcinoma, skin adnexal tumors (such as sebaceous carcinoma), Attorney Docket No.11555-008WO1 melanoma, Merkel cell carcinoma, sarcomas of primary cutaneous origin (such as dermatofibrosarcoma protuberans), and lymphomas of primary cutaneous origin (such as mycosis fungoides); thoracic and respiratory cancers such as bronchial adenomas / carcinoids, small cell lung cancer, mesothelioma, non-small cell lung cancer, pleuropulmonary blastoma, laryngeal cancer, and thymoma or thymic carcinoma; HIV / AIDs-related cancers such as Kaposi sarcoma; epithelioid hemangioendothelioma; desmoplastic small round cell tumor; and liposarcoma. In some aspects, the disease or disorder comprises an autoimmune disorder. Representative examples of autoimmune disorders include, but are not limited to: autoimmune disorders of the integumentary system (e.g., alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, cermatomyositis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, gestational pemphigoid, hidradenitis suppurativa, lichen planus, lichen sclerosus, linear IgA disease, morphea, psoriasis, pemphigus vulgaris, scleroderma (systemic sclerosis), or vitiligo); autoimmune disorders of the digestive system (e.g., autoimmune enteropathy, autoimmune hepatitis, celiac disease, Crohn's disease, pernicious anemia, or ulcerative colitis); autoimmune disorders of the heart and vascular system (e.g., rheumatic heart disease, Kawasaki disease, giant cell arteritis, Takayasu's arteritis, Behçet's disease, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV), leukocytoclastic vasculitis, lupus vasculitis, rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), polymyalgia rheumatica, or urticarial vasculitis); autoimmune disorders of the urinary system (e.g., Goodpasture syndrome, IgA nephropathy, membranous nephropathy, lupus nephritis, interstitial nephritis, interstitial cystitis, or primary sclerosing cholangitis); autoimmune disorders of the nervous system (e.g., acute disseminated encephalomyelitis, acute motor axonal neuropathy, anti-NMDA receptor encephalitis, autoimmune encephalitis, Balo concentric sclerosis, Bickerstaff's encephalitis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, Hashimoto's encephalopathy, Lambert–Eaton myasthenic syndrome, multiple sclerosis, myasthenia gravis, neuromyelitis optica (Devic's disease), restless legs syndrome, stiff-person syndrome, Sydenham's chorea, or transverse myelitis); autoimmune disorders of the endocrine system (e.g., Addison's disease, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune polyendocrine syndrome type 1 (APS1), autoimmune polyendocrine syndrome type 2 Attorney Docket No.11555-008WO1 (APS2), autoimmune polyendocrine syndrome type 3 (APS3), diabetes mellitus type 1, endometriosis, Graves' disease, Hashimoto's thyroiditis, Ord's thyroiditis, or Sjögren syndrome); autoimmune disorders of the respiratory system (e.g., Goodpasture syndrome, eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), idiopathic pulmonary fibrosis, interstitial lung disease, pulmonary alveolar proteinosis, rheumatoid lung disease, or sarcoidosis); autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, immune thrombocytopenia, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, or paroxysmal nocturnal hemoglobinuria); autoimmune disorders of the reproductive system (e.g., autoimmune orchitis, autoimmune oophoritis, endometriosis, or premature ovarian failure); autoimmune disorders of the eyes (e.g., autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves' ophthalmopathy, intermediate uveitis, ligneous conjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac's syndrome, sympathetic ophthalmia, or Tolosa–Hunt syndrome); autoimmune disorders of the muscular system (e.g., dermatomyositis, fibromyalgia, inclusion body myositis, myositis, myasthenia gravis, neuromyotonia, paraneoplastic cerebellar degeneration, or polymyositis); and autoimmune comorbidities (e.g., chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, POEMS syndrome, Raynaud's phenomenon, primary immunodeficiency, or pyoderma gangrenosum). In some aspects, the disease or disorder comprises a cardiovascular disease, for example, coronary artery disease, peripheral arterial disease, cerebrovascular disease (including stroke), renal artery stenosis, aortic aneurysm, cardiomyopathy, hypertensive heart disease, heart failure, pulmonary heart disease, cardiac dysrhythmias, endocarditis, myocarditis, eosinophilic myocarditis, valvular heart disease, congenital heart disease, or rheumatic heart disease. Further representative diseases or disorders which may be treated via the methods described herein include, but are not limited to: diseases or disorders associated with the immune checkpoint or which may be treated via administration of an immune checkpoint inhibitor; diseases or disorders associated with platelet aggregation (e.g., thrombotic diseases such as myocardial infarction or ischemic stroke); multiple sclerosis; Non-Hodgkin’s lymphoma; gastric cancer; Hodgkin’s lymphoma; ovarian cancer; colorectal cancer; head and neck cancer; non-small cell lung cancer; solid tumors; breast cancer; lymphoblastic leukemia; hair cell leukemia; diffuse large B-cell lymphoma; follicular leukemia; chronic lymphocytic Attorney Docket No.11555-008WO1 leukemia; B-cell lymphoma; triple negative breast cancer; metastatic urothelial cancer; multiple myeloma; melanoma; cervical cancer; systemic lupus erythematosus; metastatic uveal melanoma; hemophilia A; acute lymphoblastic leukemia; rheumatoid arthritis; Crohn’s disease; high cholesterol; generalized myasthenia gravis; atopic dermatitis; ulcerative colitis; wet age-related macular degeneration; diabetic macular edema; psoriasis; and atopic dermatitis. In some aspects, the compounds or compositions described herein may be administered in combination or alternation with one or more additional therapeutic agents. As used herein, the term “therapeutic agent” includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (either human or a nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regard as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merk Index (14thEdition), the Physician’s Desk Reference (64thEdition), and The Pharmacological Basis of Therapeutics (12thEdition), and they include, without limitation, medicaments; vitamins; mineral supplements, substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiandrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta blockers, and beta-agonists), antihypertensives, diuretics, vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, bone growth stimulants and bone resorption inhibitors, immunosuppressives, muscle Attorney Docket No.11555-008WO1 relaxants, psychostimulants, sedatives, tranquilizers, proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced), and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double and single- stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules and other biologically active macromolecules such as, for examples, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. The active ingredient may be administered by any route. In some aspects, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra- arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. In general, the appropriate route of administration will depend upon a variety of factors, including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc. Attorney Docket No.11555-008WO1 The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any counterindications. Dosage can vary and can be administered in one or more doses daily for one or several days. Kits Kits for practicing the methods described herein are further provided. By “kit” is intended any manufacture (e.g., a package or a container) comprising at least one reagent, e.g., any one of the compounds described herein. The kit can be promoted, distributed, or sold as a unit for performing the methods described herein. Additionally, the kits can contain a package insert describing the kit and methods for its use. Any or all of the kit reagents can be provided within containers that protect them from the external environment, such as in sealed containers or pouches. Also disclosed are kits that comprise a composition comprising a compound disclosed herein in one or more containers. The disclosed kits can optionally include pharmaceutically acceptable carriers and / or diluents. In one aspect, a kit includes one or more other components, adjuncts, or adjuvants, as described herein. In another aspect, a kit includes one or more agents, such as those agents described herein. In one aspect, a kit includes instructions or packaging materials that describe how to administer a compound or composition of the kit. Containers of the kit can be made of any suitable material, e.g., glass, plastic, or metal, and Attorney Docket No.11555-008WO1 of any suitable size, shape, or configuration. In one aspect, a compound and / or agent disclosed herein is provided in the kit as a solid, such as a tablet, pill, or powder form. In another aspect, a compound and / or agent disclosed herein is provided in the kit as a liquid or solution. In one aspect, the kit comprises an ampoule or syringe containing a compound and / or agent disclosed herein in liquid or solution form. In view of the described compounds, compositions, and methods, hereinbelow are described certain more particular aspects of the disclosure. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein or that the particular aspects are somehow limited in some way other than the inherent meanings of the language and formulas literally used therein. Aspect 1. A lysosome-targeting chimera comprising: at least one target-binding moiety capable of specifically binding a cell surface molecule or an extracellular molecule; and at least one thiol-responsive moiety. Aspect 2. The lysosome-targeting chimera of aspect 1, wherein the lysosome-targeting chimera is of Formula I B-L-T (I) wherein: B comprises the target-binding moiety; L is selected from a bond and a linker moiety; and T comprises the thiol-responsive moiety. Aspect 3. The lysosome-targeting chimera of aspect 1 or aspect 2, wherein the target- binding moiety comprises an antibody (such as Fv, scFv, Fab, F(ab’)2, Fab’, (scFv”)2, diabodies nanobodies, single domain antibodies (VHH), chimeric antibodies, monoclonal antibodies, fully human antibodies, humanized whole antibodies or antibody fragments), a fusion protein (for example, comprising an antigen-binding portion of an antibody and a non- antibody protein or fragment thereof); a ligand (such as a ligand for a cell surface receptor); or an aptamer. Attorney Docket No.11555-008WO1 Aspect 4. The lysosome-targeting chimera of any one of aspects 1-3, wherein the target- binding moiety is capable of specifically binding a cell surface molecule. Aspect 5. The lysosome-targeting chimera of aspect 4, wherein the cell surface molecule is associated with a disease or disorder. Aspect 6. The lysosome-targeting chimera of aspect 4 or aspect 5, wherein the cell surface molecule comprises a cell surface receptor. Aspect 7. The lysosome-targeting chimera of any one of aspects 4-6, wherein the cell surface molecule is present on a cell associated with a disease or disorder, for example, a cancer cell or an immune cell. Aspect 8. The lysosome-targeting chimera of any one of aspects 4-7, wherein the cell surface molecule is selected from PSMA, FcRn, PD-L1, PD1, CTLA4, CD41 (integrin alpha- IIb), CD52, BAFF, FGFR2, CD 30 (TNFR2F8), CD3, EpCAM, EGFR, IGF-1 receptor (CD221), HER2, CD22, CD19, CD20, CD79a, Trop-2, Nectin-4, BCMA, Folate receptor alpha, LAG-3, tissue factor, IFNAR1, G protein-coupled receptor 5D, gp100, cMET, Factor IXa, and Factor X. Aspect 9. The lysosome-targeting chimera of any one of aspects 4-8, wherein the target- binding moiety comprises an antibody selected from atezolizumab, avelumab, sugemalimab, cosibelimab, durvalumab, avelumab, cemiplimab, camrelizumab, serplulimab, penpulimab, sintilimab, toripalimab, retifanlimab, dostarlimab, pembrolizumab, nivolumab, tremelimumab, ipilimumab, abciximab, alemtuzumab, belimumab, bemarituzumab, brentuximab, catumaxomab, cetuximab, necitumumab, panitumumab, cixutumumab, trastuzumab, margetuximab, pertuzumab, inotuzumab, moxetumomab, loncastuximab, rituximab, ibritomomab, tositimomab, ofatumumab, ublituximab, ocrelizumab, obinutuzumab, polatuzumab, sacituzumab, enfortumab, belantamab, , mirvetuximab, relatlimab, tisotumab, anifrolumab, odronextamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, teclistamab, tebentafusp, amivantamab, emicizumab, and blinatumomab. Aspect 10. The lysosome-targeting chimera of any one of aspects 1-3, wherein the target- binding moiety is capable of specifically binding an extracellular molecule. Aspect 11. The lysosome-targeting chimera of aspect 10, wherein the extracellular molecule is associated with a disease or disorder. Attorney Docket No.11555-008WO1 Aspect 12. The lysosome-targeting chimera of aspect 10 or aspect 11, wherein the extracellular molecule comprises a ligand for a cell surface receptor, an antibody, a secreted protein that accumulates in disease, a cholesterol carrier, an infectious disease toxin, an infectious particle, a clotting factor, a chemokine or cytokine, a proteinaceous hormone, a proteinaceous mediator of a mood disorder, a proteinaceous mediator of energy homeostasis, a proteinaceous allergen or antibody against such allergen, or a proteinaceous toxin. Aspect 13. The lysosome-targeting chimera of any one of aspects 10-12, wherein the extracellular molecule is selected from TNF-α, VEGF-A, PCSK9, IL-13, IL-23p19, Ang-2, and IL-17A,F. Aspect 14. The lysosome-targeting chimera of any one of aspects 10-13, wherein the target-binding moiety comprises an antibody selected from adalimumab, infliximab, bevacizumab, alirocumab, rozanolixizumab, mirikizumab, faricimab, bimekizumab, and tralokinumab. Aspect 15. The lysosome-targeting chimera of any one of aspects 1-14, wherein the thiol- responsive moiety is capable of binding to one or more thiol groups on a surface of a cell. Aspect 16. The lysosome-targeting chimera of any one of aspects 1-15, wherein the thiol- responsive moiety comprises a synthetic polymer, a natural polymer, or a modified natural polymer. Aspect 17. The lysosome-targeting chimera of any one of aspects 1-16, wherein the thiol- responsive moiety comprises a random copolymer. Aspect 18. The lysosome-targeting chimera of any one of aspects 1-17, wherein the thiol- responsive moiety comprises a block copolymer. Aspect 19. The lysosome-targeting chimera of any one of aspects 1-18, wherein the thiol- responsive moiety comprises a polymer having one or more thiol-reactive groups (e.g., sulfide or disulfide) within a main chain of the polymer. Aspect 20. The lysosome-targeting chimera of any one of aspects 1-18, wherein the thiol- responsive moiety comprises a polymer having a main chain and one or more side chains comprising one or more thiol-reactive groups. Aspect 21. The lysosome-targeting chimera of aspect 20, wherein the main chain comprises a polymethacrylate, a polyacrylate, a polyester, a polyamide, a polycarbonate, a polycarbamate, a polyurethane, a polynorbornene, a poly(oxanorbornene), a Attorney Docket No.11555-008WO1 polycaprolactone, a polylactide, a polylactide-co-glycolide, a polyoxazoline, a polypeptide, or combinations thereof. Aspect 22. The lysosome targeting chimera of aspect 20 or aspect 21, wherein the one or more thiol-reactive groups are selected from a thiol, disulfide (such as a linear or cyclic disulfide), a maleimide or derivatives thereof (such as a dibromomaleimide), an alkene, an alkyne, a bis-sulfone, a selenide, or a diselenide. Aspect 23. The lysosome-targeting chimera of any one of aspects 20-22, wherein the thiol-responsive moiety comprises one or more R groups having the structure: wherein: R1is selected from an aliphatic group, an oligo(alkylene) glycol, and a poly(alkylene) glycol, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) Z groups as allowed by valency; R2is selected from an aliphatic group, an oligo(alkylene) glycol, a poly(alkylene) glycol, a therapeutic agent (such as a chemotherapeutic or radiotherapeutic agent), a label (such as a radiolabel or a fluorophore), a nanomaterial (such as a nanodot), or a proteolysis-targeting chimera (PROTAC), each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) Z groups as allowed by valency; Z is independently selected at each occurrence from halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, RxO-(C0-C3 alkyl)-, RxS-(C0-C3 alkyl)-, (RxRyN)-(C0-C3 alkyl)-, RxO-C(O)-(C0-C3alkyl)-, RxS-C(O)-(C0-C3alkyl)-, (RxRyN) C(O)-(C0-C3alkyl)-, RxO- S(O)2-(C0-C3 alkyl)-, (RxRyN) S(O)2-(C0-C3 alkyl)-, RzC(O)-O-(C0-C3 alkyl)-, RzC(O)- (RxN)-(C0-C3alkyl)-, RzS(O)2-O-(C0-C3alkyl)-, RzS(O)2-(RxN)-(C0-C3alkyl)-, RzC(O)-(C0- C6 alkyl)-, RzS(O)-(C0-C3 alkyl)-, and RzS(O)2-(C0-C3 alkyl)-, each of which may be Attorney Docket No.11555-008WO1 optionally substituted by one or more (for example, 1, 2, 3, or 4) Y groups as allowed by valency; Rxand Ryare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -ORx, -SRx, and -NRxRy, each of which may be optionally substituted with one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, and thiol. Aspect 24. The lysosome-targeting chimera of aspect 23, wherein the thiol-responsive moiety comprises a polymer comprising structural units of ; wherein R is as defined in aspect 23; R3, R3’, R4, and R4’are independently selected from hydrogen, halogen, a C1-C12aliphatic group, a C1-C12 alkoxy; R5and R5’are independently selected from hydrogen, halogen, and a C1-C12 aliphatic group; Attorney Docket No.11555-008WO1 L1and L2are independently a linking group (for example, selected , wherein R7is hydrogen or C1-C6 alkyl); and (for example, an oligo(alkylene) glycol or a poly(alkylene) glycol). Aspect 25. The lysosome-targeting chimera of any one of aspects 2-24, wherein B is a bond. Aspect 26. The lysosome-targeting chimera of any one of aspects 2-24, wherein B is a linker moiety selected from:

[0006] Attorney Docket No.11555-008WO1 (L9) wherein: X101and X102are independently at each occurrence selected from a bond, aryl, heteroaryl, cycloalkyl, heterocycle, NR130, C(R130)2, O, C(O), and S; R100, R101, R102, R103, and R104are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, C(S)-, -C(O)NR130-, -NR130C(O)-, -O-, -S-, -NR130-, -C(R130R130)-, -P(O)(OR106))-, -R(O)(OR106)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycloalkyl, cycloalkyl, heteroaryl, lactic acid, or glycolic acid, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) substituents independently selected from R140; R106is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R130is independently as each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -C(O)O(cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), alkenyl, or alkynyl; and R140is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, - NH(alkyl, cycloalkyl, heterocyloalkyl, aryl, or heteroaryl), -N(independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -NHSO2(alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -N(alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl)SO2alkyl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Aspect 27. A method of degrading a cell surface molecule or an extracellular molecule, comprising: Attorney Docket No.11555-008WO1 contacting the cell surface molecule or the extracellular molecule with a lysosome-targeting chimera of any one of aspects 1-26 under conditions where the lysosome-targeting chimera shuttles the cells surface molecule or the extracellular molecule to a lysosome for degradation. Aspect 28. The method of aspect 27, wherein the lysosome-targeting chimera enhances degradation of the cell surface molecule or extracellular molecule relative to the degradation of the cell surface molecule or extracellular molecule in the presence of the target-binding moiety alone. Aspect 29. The method of aspect 27 or aspect 28, wherein the method is performed in vitro. Aspect 30. The method of aspect 27 or aspect 28, wherein the method is performed in vivo. Aspect 31. A pharmaceutical composition comprising a lysosome-targeting chimera of any one of aspects 1-26 and a pharmaceutically acceptable carrier or excipient. Aspect 32. A method of treating a disease or disorder associated with a cell surface molecule or extracellular molecule in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a lysosome-targeting chimera of any one of aspects 1-26 or a pharmaceutical composition of aspect 31. Aspect 33. The method of aspect 32, wherein the disease or disorder comprises a cancer or an autoimmune disorder. Aspect 34. The method of aspect 32, wherein the disease or disorder is selected from: diseases or disorders associated with the immune checkpoint or which may be treated via administration of an immune checkpoint inhibitor; diseases or disorders associated with platelet aggregation (e.g., thrombotic diseases such as myocardial infarction or ischemic stroke); multiple sclerosis; Non-Hodgkin’s lymphoma; gastric cancer; Hodgkin’s lymphoma; ovarian cancer; colorectal cancer; head and neck cancer; non-small cell lung cancer; solid tumors; breast cancer; lymphoblastic leukemia; hair cell leukemia; diffuse large B-cell lymphoma; follicular leukemia; chronic lymphocytic leukemia; B-cell lymphoma; triple negative breast cancer; metastatic urothelial cancer; multiple myeloma; melanoma; cervical cancer; systemic lupus erythematosus; metastatic uveal melanoma; hemophilia A; acute lymphoblastic leukemia; rheumatoid arthritis; Crohn’s disease; high cholesterol; generalized myasthenia gravis; atopic dermatitis; ulcerative colitis; wet age-related macular degeneration; diabetic macular edema; psoriasis; and atopic dermatitis. Attorney Docket No.11555-008WO1 Aspect 35. The method of aspect 32, wherein the cell surface molecule is selected from PSMA, FcRn, PD-L1, PD1, CTLA4, CD41 (integrin alpha-IIb), CD52, BAFF, FGFR2, CD 30 (TNFR2F8), CD3, EpCAM, EGFR, IGF-1 receptor (CD221), HER2, CD22, CD19, CD20, CD79a, Trop-2, Nectin-4, BCMA, Folate receptor alpha, LAG-3, tissue factor, IFNAR1, G protein-coupled receptor 5D, gp100, cMET, Factor Ixa, and Factor X. Aspect 36. The method of aspect 32, wherein the extracellular molecule is selected from TNF-α, VEGF-A, PCSK9, IL-13, IL-23p19, Ang-2, and IL-17A,F. Aspect 37. The method of any one of aspects 32-36, wherein the subject is a human. Aspect 38.The method of any one of aspects 32-37, wherein the lysosome-targeting chimera or pharmaceutical composition is administered in combination or alternation with one or more additional therapeutic agents. Aspect 39. The method of any one of aspects 32-38, wherein the lysosome-targeting chimera or pharmaceutical composition is administered via intravenous injection, subcutaneous injection, or aerosolization. A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims. By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below. EXAMPLES The following examples are set forth below to illustrate the compounds, compositions, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other Attorney Docket No.11555-008WO1 reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. Example 1. Polymeric Lysosome-Targeting Chimeras: Extracellular Targeted Protein Degradation Without Co-opting Lysosome-Targeting Receptors Extracellular targeted protein degradation (eTPD) is an emerging modality to regulate protein levels without genomic interruption. Current strategies co-opt lysosome-targeting receptors (LTRs) that are ubiquitously present in most cells, offering a high success rate of eTPD across cell types and tissues. Yet, exploring LTR-independent access to eTPD would introduce an arguably nimble molecular design paradigm that opens up new opportunities in many diseases. Opening up the binding complementarity requirement from LTRs to any overexpressed cell surface receptor offers to endow eTPD platforms with new cellular targeting capabilities. This example describes polymeric lysosome-targeting chimeras (PolyTACs), a polymer-antibody conjugate based platform for the targeted degradation of membrane-bound and soluble proteins without the need for involving LTRs. Mechanistic investigations suggest a non-classical uptake pathway that is attributed to the membrane tension caused by the multivalent interaction between the PolyTACs and the overexpressed functionalities on the cell surface. The utility of PolyTACs in eTPD has been demonstrated with three therapeutically relevant membrane proteins. Additionally, the same design principle has also been leveraged to bind and drag soluble extracellular proteins into the lysosome. The design and fabrication simplicity, non-reliance on LTRs, and tissue-targeting capabilities open up new avenues for eTPD in many disease-specific applications. Introduction Potent downregulation of the activity of a specific protein along with diminution of its scaffolding functions, without the need for a well-defined active site binding pocket in the target protein, have propelled targeted protein degradation (TPD) as the more versatile alternate to drug design based on occupancy based inhibitors1–3. Conceptually, most of these degraders are based on two ligand functionalities brought together by a linker, where one of the ligands binds to the target protein of interest and the other ligand binds to an effector protein that ultimately directs the former to a cellular degradation machinery4. This molecular chimera-based approach of leveraging the cell’s own machinery to downregulate specific Attorney Docket No.11555-008WO1 protein function started with TPD of intracellular proteins using the proteasome and autophagosome, where the effector proteins are based on E3 ligases and autophagosome receptors respectively. Considering that extracellular proteins constitute >25% of the human proteome and are implicated in many important human pathologies5, more recently, this concept was elegantly extended to extracellular proteins using lysosome targeting chimeras (LYTACs)6–8. Here, the protein of interest is targeted by an antibody and a ligand conjugated to the antibody targets an effector protein based on lysosome-targeting receptors (LTRs), such as the mannose-6-phosphate receptor or the asialoglycoprotein receptor7. While the advantage of leveraging the LTRs is that these are ubiquitously present in most cells, we posited that an LTR-independent extracellular TPD (eTPD) would offer new opportunities for degrading membrane proteins in specific cells or tissues. In this manuscript, we disclose a versatile LTR-independent polymeric lysosome targeting chimera (PolyTAC) platform with the potential for opening up new avenues for eTPD. PolyTACs are based on antibody-polymer conjugates, where the antibody targets the specific extracellular protein for degradation, and the polymer is designed to make multivalent contact with the cell membrane. In designing these PolyTACs, we were inspired by a combination of three now well-accepted observations. First, targeted therapy is often based on overexpressed receptors on the surface of pathological cells and tissues9. Therefore, incorporating multiple ligand moieties on a scaffold will enhance target specificity. Second, multivalency from ligand-bearing artificial scaffolds not only offers superselectivity to target the overexpressed receptors on cells but also enhances endocytosis-mediated cellular uptake10–13. This suggests that if an antibody is conjugated to a polymer that makes a multivalent contact with a cell surface, it will cause both the receptor targeted by the antibody to be endocytosed along with the polymer. Third, the biggest challenge in delivering biologics to cells involves the difficulty in endosomal escape14,15, which means most of these scaffolds that are taken up through the endosome fuse with the lysosome. Put together, the antibody in the PolyTAC binds to a specific targeted receptor, and when the antibody-conjugated polymer makes a multivalent contact with the cell surface, the scaffold along with the targeted cell surface protein is shepherded to the lysosome for degradation. For the multivalent contact with the cell surface, we envisaged leveraging the thiol moieties resulting from the overexpression of redox-controlling proteins on cancer cells due to their aberrant redox status16,17. The reduced cysteines, also known as exofacial thiols, on these cell surfaces, are intriguing biomarkers of oxidative stress and have been utilized for cell-specific Attorney Docket No.11555-008WO1 targeting18–23. Here, we describe a plug-and-degrade PolyTAC platform, where the conjugation of thiol-reactive polymeric binders to antibodies converts the latter from target- specific inhibitors into target-specific degraders (FIG. 1A). This lysosomal trafficking approach that circumvents the dependence on lysosome-targeting and lysosomal-sorting proteins represents a paradigm shift, opening new avenues for cell-specific eTPD. Results Construction of PolyTACs. As a representative example of the PolyTACs concept, we targeted the degradation of programmed death-ligand 1 (PD-L1), as it is also known to be overexpressed on the surface of many cancer cells24. To test the possibility of leveraging thiol overexpression to degrade PD-L1, atezolizumab (Atz) and pyridyl disulfide (PDS) were used as the anti-PD-L1 antibody and thiol-reactive functionality in the polymer chain respectively in the PolyTAC, Atz-P10 (FIG. 1A). Reversible addition-fragmentation chain transfer polymerization was used to prepare the P10methacrylate copolymer, containing ~10 repeat units of the thiol-reactive PDS-ethyl methacrylate and ~40 repeating units of the hydrophilic pentaethyleneglycol methacrylate (FIG.5). A tetrazine unit was installed at the polymer chain terminus as the handle for conjugation with the antibody. The Atz antibody was modified with a trans-cyclooctene (TCO) functionality using an NHS-ester reaction with the lysines on the antibody (FIG. 6A)25. PolyTACs were then successfully prepared via the click reaction between the tetrazine and the TCO moieties, as indicated by the migration of Atz-P10 and Atz- P0away from Atz in gel electrophoresis (FIG. 6B). A combination of BCA assay and the relative fluorescence from Cy5-labeled P10 was used to characterize the Atz-P10 PolyTAC that contains an average of 3 polymer chains per antibody (FIGs.7A-7D). Degradation of PD-L1 using PolyTACs. We then evaluated PD-L1 degradation by Atz-P10in MDA-MB-231 cells. This cell line is chosen for its overexpression of both PD-L1 and exofacial thiols. To further validate this, these cells were assessed by maleimide-R phycoerythrin (Mal-PE) staining and the observed high expression level of exofacial thiols (FIGs. 8A-8B) is consistent with prior studies16,22,23. Similarly, PD-L1 expression was assessed by western blot. When these cells were treated with Atz-P10, a dose-dependent PD- L1 degradation was observed with a half-maximal degradation concentration (DC50) of ~100 nM and a degradation maximum (Dmax) of ~70% at 1 µM in 24 h (FIGs. 1B-1C). Higher potency is observed for 48 h treatment with a DC50 of 10 nM and a similar Dmax (FIGs. 9A- 9B). Compared to state-of-the-art platforms such as LYTACs and KineTACs,6,26PolyTACs Attorney Docket No.11555-008WO1 demonstrated comparative degradation capabilities, with similar DC50and Dmax, without co- opting lysosome-targeting chimeras. Interestingly, the Dmaxis quite time-independent at least from 1 to 48 h. That is, at 1 µM concentration, PolyTACs show comparable degradation of PD- L1 (60-70%) in MDA-MB-231 cells for 1, 6, 12, 24, 48 h treatments (FIGs.10A-10B). These results suggest facile protein binding, trafficking, and degradation. With flow cytometry to probe the PD-L1 remnants on the cell surface, we observed a similar decrease in the surface expression of PD-L1 by ~70% for Atz-P10 relative to no treatment in 24 h, while only ~20% reduction was observed for Atz alone at the same concentration (1 µM) (FIGs. 1D-1E). Confocal laser scanning microscopy (CLSM) images also revealed a significant decrease in PD-L1 expression at the cell surface upon treatment with Atz-P10compared to the treatment with Atz alone or no treatment (FIG. 1F), further supporting the observations in flow cytometry and western blot. To test whether multivalency is useful for PD-L1 degradation, the PD-L1 degradation capability of Atz-P10 was compared with several analogues as controls - including antibody alone (Atz), antibody with one PDS unit per linker (Atz-PDS), and antibody with appended polymer with no PDS units (Atz-P0). All controls exhibit a much lower ability to degrade PD- L1 even at 1 µM concentration, compared to Atz-P10 (FIGs 1G-1I). Also, P10 alone exhibited an insignificant difference in PD-L1 levels, compared to the no treatment control. Moreover, co-treatment with individual P10 and Atz showed similar degradation efficiency to Atz alone, as did the subsequent treatment of Atz followed by P10(FIGs. 11A-11B). These findings indicate that the antibody-polymer conjugates, Atz-P10, is a component used to induce considerable PD-L1 degradation, suggesting the multivalent interactions as the driver behind the observed degradation with the PolyTAC. Mechanism of extracellular targeted protein degradation by PolyTACs. Next, we sought to understand the mechanism of PolyTAC-mediated degradation. To determine whether PolyTACs proceed with protein degradation via lysosomes or proteasomes, MDA-MB-231 cells were pre-treated with either PBS, bafilomycin A1 (Baf, an inhibitor of lysosome acidification), or MG132 (a proteasome inhibitor), followed by incubation with medium alone, Atz, or Atz-P10(FIGs.2A-2B). Baf dramatically compromised the PD-L1 degradation capability of Atz-P10, showing insignificant differences compared to Atz alone, whereas MG132 had no impact on PD-L1 degradation by Atz-P10. These findings suggest that PolyTACs mediate protein degradation by trafficking protein targets to lysosomes. Attorney Docket No.11555-008WO1 Comparison of Atz-P10with other controls in PD-L1 degradation suggests that the antibody binding to the protein target and the polymer-appended functionalities engaging with exofacial thiols are both factors for multivalency-induced endocytosis and subsequent degradation in the lysosome. First, we investigated whether the target protein binding by the antibody is used for degradation. We evaluated the PD-L1 degradation in MDA-MB-231 cells when the cells were pre-treated with Atz for 1 h and then with Atz-P10for 24 hours (FIGs. 2C-2D). The prior presence of Atz substantially diminished the protein degradation capability of Atz-P10, showing similar PD-L1 degradation to that of Atz alone. This is attributed to the masking of cell surface PD-L1 by Atz and therefore preventing Atz-P10 from engaging with PD-L1. Next, we explored the role of exofacial thiols in the PolyTAC. N-ethylmaleimide (NEM) has been shown to be effective in blocking the exofacial thiols via thiol-maleimide conjugation to inhibit the thiol-mediated uptake22,23. If the thiol-PDS interaction is used in the observed multivalency-driven PD-L1 degradation, then pre-treating MDA-MB-231 cells with NEM should impair the degradation capability of Atz-P10. Indeed, the degradation ability of Atz- P10 is completely muted when pre-treated with NEM (FIGs.2E-2F). Together, these findings indicate that both antibody and the polymer-appended PDS functionalities are used to initiate endocytosis and lysosomal trafficking for effective eTPD. Cellular internalization of PolyTACs. We further investigated the endocytic mechanisms by which PolyTACs cause the lysosomal degradation of membrane proteins. To explore potential endocytic mechanisms, we studied PD-L1 degradation mediated by Atz-P10in the presence of various inhibitors (FIG. 12A). Inhibitors of clathrin-mediated endocytosis (dynasore, pitstop 2, and chlorpromazine) did not significantly impact PD-L1 degradation compared to controls. Similarly, inhibitors of caveolae-mediated endocytosis (methyl-β- cyclodextrin and genistein) and an inhibitor of macropinocytosis (5-(N-ethyl-N-isopropyl)- amiloride) had negligible effects on the degradation capability of Atz-P10. These results suggest that PolyTACs induce endocytosis and lysosomal trafficking via clathrin- and caveolae-independent pathways. We observed that inhibition of endolysosomal acidification by bafilomycin completely compromises PD-L1 degradation (FIG. 2A), which suggests an endosomal pathway for PolyTAC entry into cells. Similarly, pre-blocking the protein target or the exofacial thiols also suppresses PolyTAC-mediated protein degradation (FIGs. 2C, 2E), which reiterates the role of multivalent interactions. With these observations, combined with the lack of dependence Attorney Docket No.11555-008WO1 on the classical endocytosis inhibitors, we propose that the endocytic uptake in the case of PolyTACs is likely caused by the polyvalent interactions induced membrane tension. Polyvalent interactions between the polymer and the cell membrane associated thiols concurrently offer both adhesion energy and membrane deformation to cause atypical endocytosis. In fact, there is some literature precedence for this possibility. Lipid-binding virions and virus-like materials have been shown to induce membrane deformation and clathrin-independent endocytosis through multivalent lipid binding27. Similarly, the engulfment of giant unilamellar vesicles, mediated by multivalent interactions with nanoparticles, has been shown to be driven by multivalency-induced membrane tension28. If the multivalency-based adhesion energy indeed offers the driving force for the endocytic uptake, we hypothesized that we should observe protein degradation by PolyTACs even at 4 °C. Note that classical endocytosis pathways are significantly muted at 4 °C. While the observed degradation of PD-L1 by Atz-P10 was about ~59% at 37 °C for 1 h, the degree of degradation decreased only to ~39% at 4 °C (FIG. 12B). Taken together, these findings suggest that multivalency through antibody / surface protein binding and PDS / exofacial thiol interactions elevates cell membrane tension and promotes endosome formation, ultimately trafficking antibody-bound protein targets into the lysosome for degradation. Testing the PolyTACs scope with other cell surface proteins. To investigate the broad applicability of this platform for the degradation of different surface protein targets with overexpressed exofacial thiols, we also assembled representative PolyTACs of Sac-P10and Cet-P10 that are based on sacituzumab and cetuximab antibodies respectively (FIG. 3A). These antibodies bind to trophoblast cell surface antigen 2 (Trop2) and epidermal growth factor receptor (EGFR), overexpressed in SKBR3 and MDA-MB-231 cells respectively. Trop2 is a type-I transmembrane glycoprotein that is overexpressed in a wide range of epithelial cancers29and has been a target for oncology, highlighted by the recent approval of an antibody-drug conjugate (ADC), Trodelvy, for triple negative breast cancer30. The P10 polymer was conjugated on to sacituzumab using the procedures described above for Atz-P10to produce the Sac-P10. Treatment of SKBR3 cells with 1 µM concentration of this PolyTAC caused a decrease in Trop2 levels by ~55%, while the sacituzumab antibody by itself caused only ~25% reduction, as quantified by western blot (FIGs. 3B-3C). As Trop2 is also overexpressed in MDA-MB-231 cells, we also tested the effect of Sac-P10 in these cells and found that Sac-P10 causes a substantially better degradation of Trop2 (~65%) too, compared to the antibody alone (~10%). (FIG. 13) The cell-line dependent degree of degradation of Attorney Docket No.11555-008WO1 specific epitopes is attributed to the inherent internalization efficiency of cells, abundance of the cell surface protein target, and expression level of exofacial thiols26,31. Next, we targeted EGFR, a transmembrane glycoprotein that is also upregulated in many cancer cells, along with the exofacial thiols32. We incorporated the P10 with cetuximab (Cet), an FDA-approved anti-EGFR antibody, to achieve the Cet-P10 for EGFR degradation. The treatment of Cet-P10 at 1 µM for 48 h in MDA-MB-231 cells caused 60% EGFR degradation, whereas negligible degradation was observed in the treatment of Cet alone at the same concentration (FIGs.3D-3E). We further tested the combination degradation using PolyTACs targeting different surface proteins (FIG.3F). MDA-MB-231 cells were co-treated with Atz- P10 and Sac-P10 for 24 hours, followed by the quantification of remaining PD-L1 and Trop-2 expression. The co-treatment demonstrated comparable degradation capability of PD-L1 and Trop-2 to that of using individual degraders (FIGs.3F-3G), indicating that sufficient exofacial thiols are present to initiate concurrent degradation of two different proteins. PolyTACs enable intracellular uptake of soluble extracellular proteins. Next, we tested the possibility of the antibody component of the PolyTACs binding to soluble extracellular proteins and leveraging the polyvalent thiol-disulfide interaction to transport them into cells and traffic them to the lysosome (FIG. 4A). Soluble proteins, such as vascular endothelial growth factor (VEGF) and Immunoglobulin G (IgG), are associated with signal transductions in cancer and autoimmune diseases33. Therefore, there is an interest in recruiting these soluble extracellular proteins inside the cells and trafficking them to the lysosome. As a proof-of- concept, we first targeted rabbit-IgG to determine whether PolyTACs could drag soluble proteins with different constructs into cells via multivalency. The P10 polymer was conjugated to goat anti-rabbit IgG (α-rabbit IgG) to produce representative PolyTACs (α-rabbit IgG-P10), with ~3 polymer chains per antibody. We first investigated whether the α-rabbit IgG-P10 would promote cellular uptake of AF647-labeled rabbit IgG in comparison to α-rabbit IgG alone. From flow cytometry, a 5-fold increase in MFI of AF647-labeled rabbit IgG was observed in the treatment that contains α-rabbit IgG-P10, relative to rabbit IgG alone. Also, there is no difference in the uptake of rabbit IgG when the treatment contains α-rabbit IgG, relative to rabbit IgG alone (FIG. 4B). This once again confirms the polyvalency role of the polymer and the antibody binding to the target soluble protein for trafficking. This assertion is further supported by the substantially enhanced signal of AF647 from rabbit IgG plus α- rabbit IgG-P10 in CLSM images (FIG. 4E). The AF647 signal from rabbit IgG plus α-rabbit Attorney Docket No.11555-008WO1 IgG-P10was mainly co-localized with LysoTracker Green (FIG.14), demonstrating the rabbit IgG mainly trapped inside the lysosome following endocytosis. We further tested the uptake and trafficking using a smaller soluble protein VEGF by conjugating bevacizumab (Beva), an antibody against VEGF, to P10 to generate the Beva-P10. MDA-MB-231 cells were incubated with FITC-labeled VEGF165 (FITC-VEGF) along with Beva or Beva-P10. We observed an1.8-fold increase in MFI of FITC-VEGF in the presence of Beva-P10, but only a 1.2-fold increase in the presence of Beva, relative to the FITC-VEGF by itself (FIG.4C). Beva itself is known to possess some propensity to be taken up by the cells34. The increase in VEGF uptake in the presence of Beva-P10further supports the importance of multivalent interactions between exofacial thiols and PolyTACs. Next, we wanted to extend this idea to a small molecule ligand instead of the antibody in the PolyTAC. NeutrAvidin-647 (NA-647), an Alexa Fluor-647 (AF647)-labeled protein, was used as a model protein to test for PolyTAC-driven protein uptake and lysosomal trafficking. Accordingly, biotinylated-P10(Biotin-P10) and biotinylated-P0(Biotin-P0) were synthesized as representative examples. Biotin-P10 was synthesized by first obtaining a biotinylated RAFT reagent, which was then co-polymerized with PDS-methacrylate and PEG-methacrylate. The same RAFT reagent was used to polymerize PEG-methacrylate alone to generate Biotin-P0. (FIG.15). When incubated with NA-647 alone or NA-647 plus Biotin-P10or Biotin-P0for 24 h, Biotin-P10 clearly exhibits increased fluorescence in cells by 3-fold compared with NA- 647 alone, whereas Biotin-P0 showed a negligible difference in fluorescence relative to NA- 647 alone (FIG. 4D). This flow cytometry based results were further supported by fluorescence microscopy experiments based on CLSM (FIG. 16). High colocalization of green and red fluorescence, from lysotracker and NA-647 respectively, indicates that Biotin- P10 successfully traffics the complex of NA-647 plus Biotin-P10 into lysosome. These results, together with the observed PolyTAC-mediated cellular uptake and trafficking of α-rabbit IgG and VEGF, show that PolyTACs can serve to combine the receptor-ligand interactions with a soluble extracellular protein with multivalent interaction between exofacial thiols to promote cellular uptake and lysosomal trafficking. Next, we evaluated the temporal evolution of the PolyTAC-mediated uptake with α-rabbit IgG as the target protein. Cellular uptake of IgG occurred in a time-dependent manner with the highest increment in cellular internalization, relative to IgG alone by ~5 folds in 6 h. A steady increase in the uptake is observed with time that appears to saturate around 48 h (FIG. 4F). Comparison of the initial rate for the PolyTAC uptake with the rate observed for the Attorney Docket No.11555-008WO1 Rabbit-IgG by itself translates to ~5.5 times higher rate of cellular uptake by the PolyTAC. We also evaluated the impact of the amount of PolyTAC relative to that of the target Rabbit IgG in the medium. At 0.1 equivalent of α-rabbit IgG-P10 PolyTAC, no observable difference is seen relative to the control. At 0.5 equivalent, a modest increase of ~2 is observed. At 2 equivalents or more, a 5x enhancement is observed (FIG. 4G). Next, we evaluated whether the multivalency between the exofacial thiols and the disulfides in the PolyTACs is responsible for the observed enhancements in the soluble extracellular protein uptake. Indeed, when the exofacial thiols of the cells were pre-blocked by NEM, the observed increase in IgG uptake was completely nullified (FIG.4H). To ascertain whether the PolyTAC uptake mechanism along with the soluble extracellular proteins is similar to that observed for the membrane-bound proteins above, we first evaluated the uptake efficiency of rabbit IgG in the presence of the corresponding PolyTAC α-rabbit IgG-P10at 4 ºC (FIG. 17A). Compared to the same experiment at 37 ºC, the IgG level in MDA-MB-231 cells at 4 ºC was reduced by 95%, as determined by flow cytometry. The uptake experiment at 4 ºC significantly affects endocytosis by inhibiting the process. This suggests that PolyTAC-mediated uptake is energy-dependent. While the degradation of membrane-bound proteins is not drastically affected at 4 ºC, the impact of lower temperature on the uptake efficiency of soluble proteins is significant. Next, we investigated the endocytic pathways by evaluating the rabbit IgG uptake efficiency in the presence of the PolyTAC, when pretreated with various inhibitors for clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis (FIGs. 17B-17C). Similar to that observed with membrane-bound proteins, none of the inhibitors significantly reduced the PolyTAC- mediated uptake of rabbit IgG. These results suggest that the uptake pathway of PolyTACs for both soluble extracellular proteins and membrane-bound proteins is likely driven by the polyvalency-based cell membrane tension. The modest temperature dependence in the case of membrane protein uptake and a stronger dependence in the case of soluble extracellular proteins suggests the strong adhesion offered by the high binding affinity of antibody with its cell surface epitope, in addition to the multivalent interaction from the polymer, offers a significant driving force for the membrane deformation based cellular uptake in the former case. While not wishing to be bound by any one theory, our findings indicate that multivalency is a driving force directing both soluble and membrane-bound proteins into the intracellular domain via a membrane stress-driven endocytosis that ultimately leads to lysosomal degradation of the target proteins. Attorney Docket No.11555-008WO1 Conclusion In summary, this example shows that PolyTACs is a versatile platform for extracellular targeted degradation for both membrane-bound and soluble proteins. We find that PolyTAC- mediated protein degradation is driven by the binding of antibodies to protein targets, combined with the multivalent interaction between specific functionalities on the polymer and on the cell surface. These simpler requirements obviate the need to co-opt LTRs that open up opportunities for cell-specific targeting, such as in cells that display a high density of exofacial thiols. Evaluating the cellular uptake and degradation capability of PolyTACs in the presence of various cellular pathway inhibitors indicates that the observed eTPD indeed occurs through lysosomal degradation. Interestingly, we also find that cellular uptake does not occur through classical pathways such as micropinocytosis, clathrin-mediated, or caveolae-mediated endocytosis. While not wishing to be bound by any theory, the process can be driven by the membrane stress generated by the multivalent interactions between the PolyTAC and the complementary cell surface functionalities. This LTR-independent access to eTPD introduces an arguably nimble molecular design paradigm that opens up new opportunities in many diseases, especially in the context of cell- or tissue-specific protein degradation. Because when the LTR-dependence is relaxed, the ligands on the polymer chain can now be used for any cell surface receptors, as demonstrated with exofacial thiols here. A simplefeature of these representative PolyTACs is that these can be assembled rapidly with great synthetic ease, a key element in translating these findings to the clinic. PolyTACs represent a paradigm shift as an LTR-free platform for extracellular protein degradation, offering potential applications in diseases with limited or no LTR availability. Overall, we anticipate that the PolyTAC platform will offer a general strategy for eTPD with an impact in therapies beyond what is currently possible. Materials and Methods General information Antibody Source(#) Usage, Dilution Attorney Docket No.11555-008WO1 Cetuximab Medchem (#HY- Functional P9905) Unless otherwise mentioned, all chemicals and proteins were used as received from Sigma- Aldrich or Fisher Scientific.1H NMR spectra were recorded on a 400 MHz Bruker NMR spectrometer. ESI-MS analyses were performed with Bruker MicroTOF II ESI. Bio-Rad ChemiDoc imaging system was used to image the gels and blots and ImageLab software was used to analyze the blots. Fluorescent images were recorded on Nikon with CrestV2-2xTIRF confocal microscope. Flow cytometry was based on BD LSRFortessa and the data collected was analyzed on FACSDiva Software. MALDI-MS analyses were performed with Bruker Autoflex III time-offlight mass spectrometer. The molecular weight and dispersity of polymers were recorded via gel permeation chromatography (GPC, Angilent) using a PMMA standard with a refractive index and DMF (0.01% LiCl) as the eluent (flow rate: 1 mL / min). Synthesis Attorney Docket No.11555-008WO1 Synthesis of pyridyl disulfide ethyl methacrylate: 1 g (5.34 mmol, 1 equiv.) of 2-(pyridine- 2-yldisulfanyl)ethanol and 649 mg (6.41 mmol, 1.2 equiv.) of triethylamine were dissolved in 5 mL of DCM and reaction mixture was cooled in an ice bath. Then, 670 mg (6.41 mmol, 1.2 equiv.) of methacryloyl chloride was dropwisely added to the reaction mixture and allowed stirring for 18 h at room temperature. The product was purified by washing the crude mixture with distilled water and with saturated brine solution. Finally, it was dried over sodium sulfate anhydrous, and the organic layer was purified via flash column chromatography using hexane / ethyl acetate (10-40% ethyl acetate). Yield: 92 %.1H-NMR (400 MHz, d-chloroform) (δ ppm): 8.45-8.49 (d, 1H), 7.67-7.69 (d, 1H), 7.59-7.64 (t, 1H), 7.06-7.10 (t, 1H), 6.11 (s, 1H), 5.57-5.58 (t, 1H), 4.37-4.41 (t, 2 H), 3.07-3.10 (t, 2H), 1.93 (s, 1H). The polymer binder, P10, a random copolymer of pyridyl disulfide methacrylate (PDSMA) and poly(ethylene glycol) methyl ether methacrylate (EGMA, Mn= 300 g / mol), is prepared by RAFT polymerization. The PDSMA monomer was as described previously, and the EGMA monomer was commercially available (see Kanjilal, P., Singh, K., Das, R., Matte, J. & Thayumanavan, S. Antibody Polymer Conjugates (APCs) for Active Targeted Therapeutic Delivery. Biomacromolecules 24, 3638–3646 (2023)). To synthesize the polymer, 10 mg (0.0248 mmol) of 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, 63.26 mg (0.2477 mmol) of PDSMA, 297.3 mg (0.99 mmol) of EGMA (Mn = 300 g / mol), 0.81 mg (0.00495 mmol) of 2,2′-azobis(2-methylpropionitrile) (AIBN), and 1 mL DMF were charged into a flask. Following 3 cycles of freeze-pump-thaw process for deoxygenation, the flask was immersed in an oil bath at 70 °C for 18 h. The monomer conversion of PDSMA and EGMA were evaluated by1H-NMR to determine the degree of polymerization of each monomer. Then, the polymer was precipitated from cold ether. The molecular weight distribution of polymer was determined by gel permeation chromatography (GPC) in DMF containing 0.01 M LiCl against PMMA as standard. The Cy5-labeled P10was used to quantify the number of polymer binders conjugated on each antibody. A similar condition with an additional 4.59 mg (0.02477 mmol) of 2-(tert- butylamino)ethyl methacrylate was added to the polymerization. Following the same purification steps as above, the polymer was charged in vials containing 4 mL TFA solution (20 % v / v in DCM) at 25 °C for 18 h to remove the t-butyl protecting group. The polymer was purified by precipitation in cold ether 3 times. For dye conjugation, the polymer, N-(3- dimethylaminopropyl)-N′-ethylcarbodiimide, and N,N-dimethylpyridin-4-amine, and Attorney Docket No.11555-008WO1 cyanine5 NHS ester were charged into a vial containing anhydrous DCM. The mixture was stirred at 25 °C for 18 h, followed by purification via dialysis (MWCO: 3.5 kDa) against deionized water. The control polymer, P0, was synthesized by a similar condition.10 mg (0.0248 mmol) of 4- cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, 372 mg (1.24 mmol) of EGMA (Mn = 300 g / mol), 0.81 mg (0.00495 mmol) of 2,2′-azobis(2-methylpropionitrile) (AIBN), and 1 mL DMF were charged into a flask. Following 3 cycles of freeze-pump-thaw process for deoxygenation, the flask was immersed in an oil bath at 70 °C for 18 h. The monomer conversion and EGMA was evaluated by1H-NMR to determine the degree of polymerization. Then, the polymer was precipitated from cold ether. The molecular weight distribution of polymer was determined by GPC in DMF containing 0.01 M LiCl against PMMA as standard. Synthesis of biotinylated RAFT agent: 100 mg (0.257 mmol, 1 equiv.) of 4-cyano-4- [(dodecylsulfanylthiocarbonyl)sulfanyl]pentanol, 188 mg (0.77 mmol, 3 equiv.) of biotin, 120 mg (0.77 mmol, 3 equiv.) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 32 mg (0.257 mmol, 1 equiv.) of 4-(dimethylamino)pyridine were dissolved in anhydrous DMF (5 mL), and the mixture was stirred at room temperature for 18 h. The mixture was then washed by brine (10 mL) and ethyl acetate (150 mL), followed by purification via flash chromatography using DCM / methanol (0-5% methanol). Yield: 84 %.1H-NMR (400 MHz, d-DMSO) (δ ppm): 6.43 (s, 1H), 6.36 (s, 1H), 4.28-4.31 (t, 1H), 4.11- 5.15 (m, 1H), 4.04-4.08 (t, 2H), 3.37-3.40 (t, 2H), 3.07-3.12 (m, 1H), 2.80-2.84 (m, 1H), 2.56- 2.59 (d, 1H), 2.28-2.33 (t, 2H), 2.09-2.27 (m, 2H), 1.85 (s, 3H), 1.71-1.84 (m, 2H), 1.39-1.69 (m, 6H), 1.24-1.38 (m, 20H). ESI-MS (m / z) expected [M+Na]+:638.97, observed: [M+Na]+: 638.38. Synthesis of biotin-P10 and biotin-P0: For the preparation of biotin-P10 and biotin-P0, we followed the similar conditions of P10and P0mentioned above except for the biotinylated- RAFT agent. The monomer conversion was evaluated by1H-NMR to determine the degree of polymerization. Then, the polymer was precipitated from cold ether. The molecular weight distribution of polymer was determined by GPC in DMF containing 0.01 M LiCl against PMMA as standard. Preparation of the degraders Attorney Docket No.11555-008WO1 Tetrazine conjugation of polymer: The condition for the conjugation of tetrazine was the same for all polymers.0.00325 mmol of polymer, 3 mg (0.02 mmol) of PEG3-tetrazine, 3 mg (0.02 mmol) of EDC, 1 mg (0.0067 mmol) of DMAP, 1 mL DMF were charged in a vial. The reaction was stirred at 25 °C for 18 h, followed by precipitation from cold hexane and dialysis (MWCO: 3.5 kDa) against deionized water. The conjugation efficiency of tetrazine on polymer was determined by1H-NMR. TCO conjugation of antibody: The pH value of antibody solution (120 µM) was adjusted to pH 8.8 via buffer exchange by using ultracentrifugation (MWCO: 50 kDa) for 3 times and concentrated to 80 µM. Then TCO-PEG4-NHS ester (20 molar eq., 64 mM in DMSO) was slowly added to the antibody solution (1 molar eq.) and incubated in an agitating dry block heating mixer at 25 °C (500 rpm) for 2 h. To remove residual TCO-PEG4-NHS ester, the solution was washed by PBS (pH 7.4) via ultracentrifugation (MWCO: 50 kDa) for 3 cycles at 4 °C (10,000 g) for 15 min each. In the final cycle, the TCO-PEG4 conjugated antibody was concentrated to 80 µM. Preparation of polymer-antibody conjugates: Pre-determined volume of TCO-PEG4 conjugated antibody (80 µM) was mixed with the same volume of tetrazine-conjugated polymer (1.6 mM, 20 molar eq.) and incubated in an agitating dry block heating mixer at 25 °C (500 rpm) for 1 h. The reaction mixture was purified by using ultracentrifugation (MWCO: 100 kDa) for 3 cycles at 4 °C (10,000 g) for 15 min each. In the final cycle, the polymer- conjugated antibody was concentrated to 100 µM on the basis of antibody concentration. The final concentration of the antibody in the solution was determined by BCA assay against the calibration curve. SDS-PAGE gel to confirm polymer−antibody conjugation The SDS-PAGE gel was used as a primary confirmation of successful antibody polymer conjugations. For each separate gel run, 5 µg of free antibody or antibody polymer conjugates were mixed with 10 µL gel loading buffer and were loaded in Bio-Rad 4-15% precast polyacrylamide gel (10 wells). The gel was run in 1X SDS running buffer at a constant voltage of 130 V for 1 h. Finally, it was stained in Coomassie stain solution for 5 hours followed by destaining using 45% v / v methanol and 10% v / v acetic acid solution, as needed. Afterwards, a Bio-Rad ChemiDoc imaging system was used to image and analyze the gel. Determination of the number of polymers conjugated on antibodies on average: The pEGMA / pPDS analogue, Cy5-labeled pEGMA / pPDS, was used to determine the number of Attorney Docket No.11555-008WO1 polymers conjugated on antibodies on average against the calibration curve of Cy5-labeled pEGMA / pPDS. The linear calibration curve of Cy5-labeled pEGMA / pPDS from 0.2-10 µM was built from the fluorescence intensity of Cy5 (ex / em = 640 nm / 670 nm) in PBS buffer (pH 7.4). The concentration of polymers of degraders was determined by fluorescence of Cy5 against calibration curve; and the concentration of antibody of degraders was determined by BCA assay against calibration curve. # polymers per degraders is thus determined by CM,polymer / CM, antibody. Cell culture MDA-MB231 cells were cultured containing Dulbecco’s Modified Eagle Medium / Nutrient Mixture F-12 (DMEM / F12). SK-BR-3 cells were cultured in McCoy's 5A Medium. All Culture media was supplemented with 10% fetal bovine serum (FBS), and 1% antibiotic (100 units / mL of penicillin, and 100 μg / mL of streptomycin). Cells were incubated in a T75 cell culture flask in a humidified S26 incubator with 5% CO2at 37 °C. Protein degradation analysis by western blotting (WB) Adherent cells were plated (200,000 cells per well in a 24-well plate) one day before the experiment. Cells were incubated with 500 µl of complete growth medium with an indicated concentration of PolyTAC or controls for the indicated amount of time. Cells were then washed with PBS two times and lysed with RIPA buffer supplemented with 1x protease / phosphatase inhibitor cocktail (Cell signaling) on ice for 30 min under shaking. The cells were scraped, transferred to Eppendorf tubes, and centrifuged at 140,000 rpm for 15 min at 4 °C. The supernatant was collected, and the protein concentration was determined by BCA assay (Pierce). Equal amounts of lysate were loaded onto a 4–20% Mini-PROTEAN® TGX™ Precast Protein Gels by SDS–PAGE. The gel was then transferred onto a nitrocellulose membrane using the iBlot 2 Gel Transfer Device. The nonspecific binding sites were blocked with 5% nonfat milk for 1 h. Then the membrane was cut into two corresponding to POI and control protein. Then incubated with primary antibody (diluted 1:2000) overnight at 4 °C and washed two times with TBS-T. Subsequently, the membrane was incubated with a secondary antibody (diluted 1:10000) for 1h at room temperature and washed two times with TBS-T. The membrane was incubated in Clarity Western ECL Substrate for 7 min and imaged using the Biorad ChemiDoc instrument. The grayscale values of images were analyzed by ImageLab software. Attorney Docket No.11555-008WO1 General procedure for the evaluation of cellular uptake of soluble proteins via flow cytometry For streptavidin exp: streptavidin-A647 was pre-mixed with biotin-P10(or biotin-P0) for 30 minutes, followed by treating MDA-MB-231 with the mixture (streptavidin-647 at 200 nM, and biotin-polymer at 800 nM) for 6 hours. Then cells were washed with PBS twice, followed by trypsinization and centrifugation to collet pellets for flow cytometry. For flow, we collected the healthy, single cells with APC signal for quantitative comparison between groups. For VEGF exp: VEGFA-FITC was pre-mixed with Bevacizumab-P10 (or Bevacizumab-P0) for 30 minutes, followed by treating MDA-MB-231 with the mixture (VEGFA-FITC at 50 nM, and biotin-polymer at 100 nM) for 6 hours. Then cells were washed with PBS twice, followed by trypsinization and centrifugation to collet pellets for flow cytometry. For flow, we collected the healthy, single cells with FITC signal for quantitative comparison between groups. For Rabbit IgG exp: rabbit-IgG-647 was pre-mixed with goat anti-rabbit IgG-P10 (or goat anti-rabbit IgG-P0) for 30 minutes, followed by treating MDA-MB-231 with the mixture (rabbit-IgG-647 at 50 nM, and biotin-polymer at 100 nM) for 6 hours. Then cells were washed with PBS twice, followed by trypsinization and centrifugation to collet pellets for flow cytometry. For flow, we collected the healthy, single cells with APC signal for quantitative comparison between groups Confocal laser scanning microscopy (CLSM) for live-cell imaging Adherent cells were plated (30,000 cells per well in a 4-well 35mm plate) one day before the experiment. Cells were incubated with 500 µl of complete growth medium with an indicated concentration of PolyTAC or controls for the indicated amount of time. Cells were then washed with PBS and replaced the media with fluorophores needed for imaging. Cells were imaged with a Nikon CrestV2 confocal microscope and images using a 60x or 100x, oil objective. PD-L1 degradation experiment using confocal microscopy MDA-MB-231 cells were plated in a 35 mm glass bottom plate at 0.3 × 106confluency one day before the experiment. The next day, the medium was replaced.1 µM of Atz and Atz-P10 Attorney Docket No.11555-008WO1 was then added to the cells and incubated for 24h. Cells were washed twice with PBS and incubated with 10 µL of PD-L1 (Extracellular Domain Specific) Rabbit mAb (Alexa Fluor® 647 Conjugate) and kept at 37 ºC for 15 min before imaging. The cells were washed with PBS and added fresh media. Hoechst 33342 was added 15 min prior to the imaging. The live cells were imaged using a Nikon CrestV2 confocal microscope and images were analyzed by ImageJ. Streptavidin uptake experiment using confocal microscopy MDA-MB-231 cells were plated in a 35 mm glass bottom plate at 0.3 × 106confluency one day before the experiment. The next day, the medium was replaced. Streptavidin (500 nM) and Biotin 20% PDS polymer (2 µM) were premixed and kept for 30 min, then added to the MDA-MB-231 cells and incubated for 24h. Cells were washed twice with PBS and incubated with 10 µL of Lysotracker and Hoechst 33342 and kept at 37 ºC for 15 min before imaging. The live cells were imaged using a Nikon CrestV2 confocal microscope and images were analyzed by Image J. IgG uptake experiment using confocal microscopy MDA-MB-231 cells were plated in a 35 mm glass bottom plate at 0.3 × 106confluency one day before the experiment. The next day, the medium was replaced. Rabbit-IgG-647 was pre- mixed with goat anti-rabbit IgG-P10 (or goat anti-rabbit IgG-P0) for 30 minutes, followed by treating MDA-MB-231 with the mixture (rabbit-IgG-647 at 50 nM) for 6 hours. Cells were washed twice with PBS, incubated with 10 µL of Lysotracker and Hoechst 33342, and kept at 37 ºC for 15 min before imaging. The live cells were imaged using a Nikon CrestV2 confocal microscope and images were analyzed by ImageJ. Qualification of exofacial thiols expression of MDA-MB-231 by PE-Mal staining Adherent cells were plated (200,000 cells per well in a 24-well plate) one day before the experiment. Cells were then washed with cold PBS two times, followed by trypsinization and centrifugation (1200 rpm, 5 min). The supernatant was discarded, followed by adding 200 µl of PE-Mal or PE (1 µM in PBS) staining agents for 15 min incubation. Cells were then washed with cold PBS two times. The supernatant was removed and replenished flow buffer solution (200 µL) for flow cytometry. Attorney Docket No.11555-008WO1 References for Example 1 1. Dale, B. et al. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer 1–17 (2021) doi:10.1038 / s41568-021-00365-x. 2. Song, J. et al. Targeted protein degradation in drug development: Recent advances and future challenges. Eur. J. Med. Chem.261, 115839 (2023). 3. Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov 16, 101–114 (2017). 4. Békés, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 21, 181–200 (2022). 5. Wells, J. A. & Kumru, K. Extracellular targeted protein degradation: an emerging modality for drug discovery. Nat. Rev. Drug Discov.1–15 (2023) doi:10.1038 / s41573-023-00833-z. 6. Banik, S. M. et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291–297 (2020). 7. Ahn, G. et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat Chem Biol 17, 937–946 (2021). 8. Ahn, G. et al. Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science 382, eadf6249 (2023). 9. Jin, H., Wang, L. & Bernards, R. Rational combinations of targeted cancer therapies: background, advances and challenges. Nat. Rev. Drug Discov.22, 213–234 (2023). 10. Martinez-Veracoechea, F. J. & Frenkel, D. Designing super selectivity in multivalent nano-particle binding. Proc. Natl. Acad. Sci.108, 10963–10968 (2011). 11. Dubacheva, G. V., Curk, T., Frenkel, D. & Richter, R. P. Multivalent Recognition at Fluid Surfaces: The Interplay of Receptor Clustering and Superselectivity. J. Am. Chem. Soc.141, 2577–2588 (2019). 12. Xu, Z. et al. Programmable Assembly of Multivalent DNA‐Protein Superstructures for Tumor Imaging and Targeted Therapy. Angew. Chem. Int. Ed.61, e202211505 (2022). 13. Radford, D. C. et al. Multivalent HER2-binding polymer conjugates facilitate rapid endocytosis and enhance intracellular drug delivery. J. Control. Release 319, 285–299 (2020). Attorney Docket No.11555-008WO1 14. He, W. et al. Nanocarrier‐Mediated Cytosolic Delivery of Biopharmaceuticals. Adv Funct Mater 1910566 (2020) doi:10.1002 / adfm.201910566. 15. Pei, D. How Do Biomolecules Cross the Cell Membrane? Acc Chem Res 55, 309–318 (2022). 16. Popielarski, M., Ponamarczuk, H., Stasiak, M., Watała, C. & Świątkowska, M. Modifications of disulfide bonds in breast cancer cell migration and invasiveness. Am. J. cancer Res.9, 1554–1582 (2019). 17. Arnér, E. S. J. & Holmgren, A. The thioredoxin system in cancer. Semin. Cancer Biol.16, 420–426 (2006). 18. Liguori, I. et al. Oxidative stress, aging, and diseases. Clin Interv Aging 13, 757–772 (2018). 19. Frijhoff, J. et al. Clinical Relevance of Biomarkers of Oxidative Stress. Antioxid. Redox Signal.23, 1144–1170 (2015). 20. Torres, A. G. & Gait, M. J. Exploiting cell surface thiols to enhance cellular uptake. Trends Biotechnol.30, 185–190 (2012). 21. Sahaf, B., Heydari, K., Herzenberg, L. A. & Herzenberg, L. A. Lymphocyte surface thiol levels. Proc. Natl. Acad. Sci.100, 4001–4005 (2003). 22. Goerdeler, F. et al. Thiol-Mediated Uptake of a Cysteine-Containing Nanobody for Anticancer Drug Delivery. ACS Cent. Sci.9, 1111–1118 (2023). 23. Slezak, A. J. et al. Tumor Cell-Surface Binding of Immune Stimulating Polymeric Glyco- Adjuvant via Cysteine-Reactive Pyridyl Disulfide Promotes Antitumor Immunity. ACS Cent. Sci.8, 1435–1446 (2022). 24. Yamaguchi, H., Hsu, J.-M., Yang, W.-H. & Hung, M.-C. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat. Rev. Clin. Oncol.19, 287–305 (2022). 25. Sarrett, S. M. et al. Inverse electron demand Diels–Alder click chemistry for pretargeted PET imaging and radioimmunotherapy. Nat. Protoc.16, 3348–3381 (2021). 26. Pance, K. et al. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat. Biotechnol.41, 273–281 (2023). Attorney Docket No.11555-008WO1 27. Groza, R. et al. Adhesion energy controls lipid binding-mediated endocytosis. Nat. Commun.15, 2767 (2024). 28. Fernandez, A., Krishna, J., Anson, F., Dinsmore, A. D. & Thayumanavan, S. Consequences of Noncovalent Interfacial Contacts between Nanoparticles and Giant Vesicles. Angew. Chem. Int. Ed.61, (2022). 29. Zeng, P. et al. Impact of TROP2 expression on prognosis in solid tumors: A Systematic Review and Meta-analysis. Sci. Rep.6, 33658 (2016). 30. Bardia, A. et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. New Engl. J. Med.384, 1529–1541 (2021). 31. Gramespacher, J. A., Cotton, A. D., Burroughs, P. W. W., Seiple, I. B. & Wells, J. A. Roadmap for Optimizing and Broadening Antibody-Based PROTACs for Degradation of Cell Surface Proteins. ACS Chem. Biol.17, 1259–1268 (2022). 32. Uribe, M. L., Marrocco, I. & Yarden, Y. EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance. Cancers 13, 2748 (2021). 33. Cao, Y., Langer, R. & Ferrara, N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat. Rev. Drug Discov.22, 476–495 (2023). 34. Karpinska, A., Magiera, G., Kwapiszewska, K. & Hołyst, R. Cellular Uptake of Bevacizumab in Cervical and Breast Cancer Cells Revealed by Single-Molecule Spectroscopy. J. Phys. Chem. Lett.14, 1272–1278 (2023). The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

Attorney Docket No.11555-008WO1 WHAT IS CLAIMED IS:

1. A lysosome-targeting chimera comprising: at least one target-binding moiety capable of specifically binding a cell surface molecule or an extracellular molecule; and at least one thiol-responsive moiety.

2. The lysosome-targeting chimera of claim 1, wherein the lysosome-targeting chimera is of Formula I B-L-T (I) wherein: B comprises the target-binding moiety; L is selected from a bond and a linker moiety; and T comprises the thiol-responsive moiety.

3. The lysosome-targeting chimera of claim 1 or claim 2, wherein the target-binding moiety comprises an antibody (such as Fv, scFv, Fab, F(ab’)2, Fab’, (scFv”)2, diabodies nanobodies, single domain antibodies (VHH), chimeric antibodies, monoclonal antibodies, fully human antibodies, humanized whole antibodies or antibody fragments), a fusion protein (for example, comprising an antigen-binding portion of an antibody and a non-antibody protein or fragment thereof); a ligand (such as a ligand for a cell surface receptor); or an aptamer.

4. The lysosome-targeting chimera of any one of claims 1-3, wherein the target-binding moiety is capable of specifically binding a cell surface molecule.

5. The lysosome-targeting chimera of claim 4, wherein the cell surface molecule is associated with a disease or disorder.

6. The lysosome-targeting chimera of claim 4 or claim 5, wherein the cell surface molecule comprises a cell surface receptor.

7. The lysosome-targeting chimera of any one of claims 4-6, wherein the cell surface molecule is present on a cell associated with a disease or disorder, for example, a cancer cell or an immune cell.Attorney Docket No.11555-008WO1 8. The lysosome-targeting chimera of any one of claims 4-7, wherein the cell surface molecule is selected from PSMA, FcRn, PD-L1, PD1, CTLA4, CD41 (integrin alpha-IIb), CD52, BAFF, FGFR2, CD 30 (TNFR2F8), CD3, EpCAM, EGFR, IGF-1 receptor (CD221), HER2, CD22, CD19, CD20, CD79a, Trop-2, Nectin-4, BCMA, Folate receptor alpha, LAG- 3, tissue factor, IFNAR1, G protein-coupled receptor 5D, gp100, cMET, Factor IXa, and Factor X.

9. The lysosome-targeting chimera of any one of claims 4-8, wherein the target-binding moiety comprises an antibody selected from atezolizumab, avelumab, sugemalimab, cosibelimab, durvalumab, avelumab, cemiplimab, camrelizumab, serplulimab, penpulimab, sintilimab, toripalimab, retifanlimab, dostarlimab, pembrolizumab, nivolumab, tremelimumab, ipilimumab, abciximab, alemtuzumab, belimumab, bemarituzumab, brentuximab, catumaxomab, cetuximab, necitumumab, panitumumab, cixutumumab, trastuzumab, margetuximab, pertuzumab, inotuzumab, moxetumomab, loncastuximab, rituximab, ibritomomab, tositimomab, ofatumumab, ublituximab, ocrelizumab, obinutuzumab, polatuzumab, sacituzumab, enfortumab, belantamab, , mirvetuximab, relatlimab, tisotumab, anifrolumab, odronextamab, epcoritamab, glofitamab, mosunetuzumab, talquetamab, teclistamab, tebentafusp, amivantamab, emicizumab, and blinatumomab.

10. The lysosome-targeting chimera of any one of claims 1-3, wherein the target-binding moiety is capable of specifically binding an extracellular molecule.

11. The lysosome-targeting chimera of claim 10, wherein the extracellular molecule is associated with a disease or disorder.

12. The lysosome-targeting chimera of claim 10 or claim 11, wherein the extracellular molecule comprises a ligand for a cell surface receptor, an antibody, a secreted protein that accumulates in disease, a cholesterol carrier, an infectious disease toxin, an infectious particle, a clotting factor, a chemokine or cytokine, a proteinaceous hormone, a proteinaceous mediator of a mood disorder, a proteinaceous mediator of energy homeostasis, a proteinaceous allergen or antibody against such allergen, or a proteinaceous toxin.

13. The lysosome-targeting chimera of any one of claims 10-12, wherein the extracellular molecule is selected from TNF-α, VEGF-A, PCSK9, IL-13, IL-23p19, Ang-2, and IL-17A,F.Attorney Docket No.11555-008WO1 14. The lysosome-targeting chimera of any one of claims 10-13, wherein the target- binding moiety comprises an antibody selected from adalimumab, infliximab, bevacizumab, alirocumab, rozanolixizumab, mirikizumab, faricimab, bimekizumab, and tralokinumab.

15. The lysosome-targeting chimera of any one of claims 1-14, wherein the thiol- responsive moiety is capable of binding to one or more thiol groups on a surface of a cell.

16. The lysosome-targeting chimera of any one of claims 1-15, wherein the thiol- responsive moiety comprises a synthetic polymer, a natural polymer, or a modified natural polymer.

17. The lysosome-targeting chimera of any one of claims 1-16, wherein the thiol- responsive moiety comprises a random copolymer.

18. The lysosome-targeting chimera of any one of claims 1-17, wherein the thiol- responsive moiety comprises a block copolymer.

19. The lysosome-targeting chimera of any one of claims 1-18, wherein the thiol- responsive moiety comprises a polymer having one or more thiol-reactive groups (e.g., sulfide or disulfide) within a main chain of the polymer.

20. The lysosome-targeting chimera of any one of claims 1-18, wherein the thiol- responsive moiety comprises a polymer having a main chain and one or more side chains comprising one or more thiol-reactive groups.

21. The lysosome-targeting chimera of claim 20, wherein the main chain comprises a polymethacrylate, a polyacrylate, a polyester, a polyamide, a polycarbonate, a polycarbamate, a polyurethane, a polynorbornene, a poly(oxanorbornene), a polycaprolactone, a polylactide, a polylactide-co-glycolide, a polyoxazoline, a polypeptide, or combinations thereof.

22. The lysosome-targeting chimera of claim 20 or claim 21, wherein the one or more thiol-reactive groups are selected from a thiol, disulfide (such as a linear or cyclic disulfide), a maleimide or derivatives thereof (such as a dibromomaleimide), an alkene, an alkyne, a bis- sulfone, a selenide, or a diselenide.

23. The lysosome-targeting chimera of any one of claims 20-22, wherein the thiol- responsive moiety comprises one or more R groups having a structure:Attorney Docket No.11555-008WO1 wherein:R1is selected from an aliphatic group, an oligo(alkylene) glycol, and a poly(alkylene) glycol, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) Z groups as allowed by valency; R2is selected from an aliphatic group, an oligo(alkylene) glycol, a poly(alkylene) glycol, a therapeutic agent (such as a chemotherapeutic or radiotherapeutic agent), a label (such as a radiolabel or a fluorophore), a nanomaterial (such as a nanodot), or a proteolysis-targeting chimera (PROTAC), each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) Z groups as allowed by valency; Z is independently selected at each occurrence from halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, RxO-(C0-C3alkyl)-, RxS-(C0-C3alkyl)-, (RxRyN)-(C0-C3alkyl)-, RxO-C(O)-(C0-C3 alkyl)-, RxS-C(O)-(C0-C3 alkyl)-, (RxRyN) C(O)-(C0-C3 alkyl)-, RxO- S(O)2-(C0-C3alkyl)-, (RxRyN) S(O)2-(C0-C3alkyl)-, RzC(O)-O-(C0-C3alkyl)-, RzC(O)- (RxN)-(C0-C3 alkyl)-, RzS(O)2-O-(C0-C3 alkyl)-, RzS(O)2-(RxN)-(C0-C3 alkyl)-, RzC(O)-(C0- C6alkyl)-, RzS(O)-(C0-C3alkyl)-, and RzS(O)2-(C0-C3alkyl)-, each of which may be optionally substituted by one or more (for example, 1, 2, 3, or 4) Y groups as allowed by valency; Rxand Ryare independently selected at each occurrence from hydrogen, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;Attorney Docket No.11555-008WO1 Rzis independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0- C3alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3alkyl)-, -ORx, -SRx, and -NRxRy, each of which may be optionally substituted with one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, and thiol.

24. The lysosome-targeting chimera of claim 23, wherein the thiol-responsive moiety comprises a polymer comprising structural units of ; whereinR is as defined in claim 23; R3, R3’, R4, and R4’are independently selected from hydrogen, halogen, a C1-C12 aliphatic group, a C1-C12alkoxy; R5and R5’are independently selected from hydrogen, halogen, and a C1-C12aliphatic group; L1and L2are independently a linking group (for example, selectedAttorney Docket No.11555-008WO1 R6is a hydrophilic moiety (for example, an oligo(alkylene) glycol or a poly(alkylene) glycol).

25. The lysosome-targeting chimera of any one of claims 2-24, wherein B is a bond.

26. The lysosome-targeting chimera of any one of claims 2-24, wherein B is a linker moiety selected from: (L1)wherein: X101and X102are independently at each occurrence selected from a bond, aryl, heteroaryl, cycloalkyl, heterocycle, NR130, C(R130)2, O, C(O), and S;Attorney Docket No.11555-008WO1 R100, R101, R102, R103, and R104are independently at each occurrence selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, C(S)-, -C(O)NR130-, -NR130C(O)-, -O-, -S-, -NR130-, -C(R130R130)-, -P(O)(OR106))-, -R(O)(OR106)-, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, heterocycloalkyl, cycloalkyl, heteroaryl, lactic acid, or glycolic acid, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) substituents independently selected from R140; R106is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; R130is independently as each occurrence selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -C(O)O(cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), alkenyl, or alkynyl; and R140is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, - NH(alkyl, cycloalkyl, heterocyloalkyl, aryl, or heteroaryl), -N(independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -NHSO2(alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl), -N(alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl)SO2alkyl, -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

27. A method of degrading a cell surface molecule or an extracellular molecule, comprising: contacting the cell surface molecule or the extracellular molecule with a lysosome-targeting chimera of any one of claims 1-26 under conditions where the lysosome-targeting chimera shuttles the cell surface molecule or the extracellular molecule to a lysosome for degradation.

28. The method of claim 27, wherein the lysosome-targeting chimera enhances degradation of the cell surface molecule or extracellular molecule relative to the degradation of the cell surface molecule or extracellular molecule in presence of the target-binding moiety alone.

29. The method of claim 27 or claim 28, wherein the method is performed in vitro.

30. The method of claim 27 or claim 28, wherein the method is performed in vivo.Attorney Docket No.11555-008WO1 31. A pharmaceutical composition comprising a lysosome-targeting chimera of any one of claims 1-26 and a pharmaceutically acceptable carrier or excipient.

32. A method of treating a disease or disorder associated with a cell surface molecule or extracellular molecule in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a lysosome-targeting chimera of any one of claims 1-26 or a pharmaceutical composition of claim 31.

33. The method of claim 32, wherein the disease or disorder comprises a cancer or an autoimmune disorder.

34. The method of claim 32, wherein the disease or disorder is selected from: diseases or disorders associated with the immune checkpoint or which may be treated via administration of an immune checkpoint inhibitor; diseases or disorders associated with platelet aggregation (e.g., thrombotic diseases such as myocardial infarction or ischemic stroke); multiple sclerosis; Non-Hodgkin’s lymphoma; gastric cancer; Hodgkin’s lymphoma; ovarian cancer; colorectal cancer; head and neck cancer; non-small cell lung cancer; solid tumors; breast cancer; lymphoblastic leukemia; hair cell leukemia; diffuse large B-cell lymphoma; follicular leukemia; chronic lymphocytic leukemia; B-cell lymphoma; triple negative breast cancer; metastatic urothelial cancer; multiple myeloma; melanoma; cervical cancer; systemic lupus erythematosus; metastatic uveal melanoma; hemophilia A; acute lymphoblastic leukemia; rheumatoid arthritis; Crohn’s disease; high cholesterol; generalized myasthenia gravis; atopic dermatitis; ulcerative colitis; wet age-related macular degeneration; diabetic macular edema; psoriasis; and atopic dermatitis.

35. The method of claim 32, wherein the cell surface molecule is selected from PSMA, FcRn, PD-L1, PD1, CTLA4, CD41 (integrin alpha-IIb), CD52, BAFF, FGFR2, CD 30 (TNFR2F8), CD3, EpCAM, EGFR, IGF-1 receptor (CD221), HER2, CD22, CD19, CD20, CD79a, Trop-2, Nectin-4, BCMA, Folate receptor alpha, LAG-3, tissue factor, IFNAR1, G protein-coupled receptor 5D, gp100, cMET, Factor IXa, and Factor X.

36. The method of claim 32, wherein the extracellular molecule is selected from TNF-α, VEGF-A, PCSK9, IL-13, IL-23p19, Ang-2, and IL-17A,F.

37. The method of any one of claims 32-36, wherein the subject is a human.Attorney Docket No.11555-008WO1 38. The method of any one of claims 32-37, wherein the lysosome-targeting chimera or pharmaceutical composition is administered in combination or alternation with one or more additional therapeutic agents.

39. The method of any one of claims 32-38, wherein the lysosome-targeting chimera or pharmaceutical composition is administered via intravenous injection, subcutaneous injection, or aerosolization.

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