Combination treatment of autoimmune disorders

Abstract

Provided is a method of treating rheumatoid arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a degrader of immunoglobulin G and an anti-arthritis agent. Also provided is a pharmaceutical composition comprising a degrader of immunoglobulin G and an anti-arthritis agent.

Description

COMBINATION TREATMENT OF AUTOIMMUNE DISORDERSFIELD OF THE INVENTION

[0001] The invention relates to medicinal preparations for the treatment of rheumatoid arthritis by a combination of two or more drugs. Specifically, the present invention related to treatment of rheumatoid arthritis by a degrader of immunoglobulin G and another therapeutic agent.BACKGROUND OF THE INVENTION

[0002] Rheumatoid arthritis (RA) is a form of inflammatory polyarthritis that can lead to joint destruction, deformity, and loss of function. The disease is usually characterized by swelling of the small joints, especially in the hands and feet. However, most joints in the body can eventually become affected. In addition to the joints, other manifestations of the disease can be seen, including subcutaneous nodules, eye inflammation, lowering of the white blood count, and lung disease. Frequent symptoms include fatigue and joint stiffness, especially in the morning and after prolonged periods of rest.

[0003] Presently, there is no known cure for rheumatoid arthritis. In the last few years, the discovery of the drugs modifying the earlier institution of disease and the availability of new classes of medications have greatly improved the expected disease outcomes. The goal of rheumatoid arthritis treatment now aims toward achieving the lowest possible level of arthritis disease activity and remission if possible, minimizing joint damage, and enhancing physical function and quality of life. While some classes of drugs are currently available in the field, there is a need for new medicines that can effectively treat or delay the progression of the disease. There is an urgent need for new therapeutic avenues capable of reducing the impact of rheumatoid arthritis for more patients.SUMMARY OF THE INVENTION

[0004] The invention is directed to the treatment of rheumatoid arthritis by a combination of two or more therapeutically effective agents.

[0005] In one embodiment, the invention provides a composition comprising a degrader of immunoglobulin G, and an anti-arthritis agent, where the degrader of immunoglobulin G has the structure:wherein [CPBM] is an IgG Binding Moiety that binds to IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety which covalently attaches to one or more [CRBM] and / or [CPBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0006] Preferably, the IgG Binding Moiety does not bind IgG in the FcRn region of IgG.

[0007] In another embodiment, the invention provides a composition comprising a degrader of immunoglobulin G, and an anti-arthritis agent, where the degrader of immunoglobulin G has the structure:wherein [CPBM] is an IgG Binding Moiety that binds to the Fclll region of IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety which covalently attaches to one or more [CRBM] and / or [CPBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0008] In a particular embodiment, the invention provides a composition comprising a degrader of immunoglobulin G, where the degrader of immunoglobulin G is Fcl I l-G N3, and an anti-arthritis agent.

[0009] In one embodiment, the anti-arthritis agent can be a disease-modifying anti-rheumatic drug (DMARD). In another embodiment, the anti-arthritis agent can be selected from the Markush group of disease-modifying anti-rheumatic drugs (DMARDs), consisting of tumor necrosis factor (TNF inhibitors),T-cell costimulatory blocking agents, B cell depleting agents, IL-1 receptor antagonists, and immunomodulatory and cytotoxic agents.

[0010] In another embodiment, the invention provides a method of reducing the level of IgG in a subject by administering to a subject a degrader of immunoglobulin G and an anti-arthritis agent. Reducing the level of IgG may be useful for conditions including IgG myeloma, liver disease, sarcoidosis, chronic infection, autoimmune disorders including rheumatoid arthritis, malignancy and parasitic diseases.

[0011] In another embodiment, the degrader of immunoglobulin G is administered to the subject or patient t >12 hours before administration of the anti-arthritis agent.

[0012] In several embodiments, FCIII-GN3 is administered intravenously at 50 mg, 125 mg, 250 mg, or 500 mg. At such doses, FCIII-GN3 has been shown to be safe and well-tolerated.

[0013] In a particular embodiment, the degrader of immunoglobulin G is administered subcutaneously to a subject or patient. In a particular embodiment, up to 500 mg is administered to a subject or patient. In another embodiment, the anti-arthritis agent is administered subcutaneously or by mouth to a subject or patient. For example, many NSAIDs can be administered by mouth.

[0014] In another embodiment, the invention provides a method of treating rheumatoid arthritis by administering to a patient in need of such treatment a therapeutically effective amount of a degrader of immunoglobulin G and an anti-arthritis agent.

[0015] In some embodiments, the anti-arthritis agent is a therapeutic antibody. In a particular embodiment, the therapeutic antibody is selected from the Markush group consisting of etanercept, adalimumab, infliximab, abatacept, rituximab, and anakinra.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 is a chart showing IgG degraders improve the efficacy of biologies through the removal of anti-drug antibodies (ADAs). FCIII-GN3 can be administered with biologies, removing antidrug antibodies and restoring efficacy. FCIII-GN3 is compatible with biologic therapeutics when dosed >12 hours before administration of Humira®. FCIII-GN3 dosed at 30 mg / kg SC followed by Humira® dosed at 3 mg / kg subcutaneously in non-human primates.

[0017] FIG. 2 is a chart showing IgG degraders improve the efficacy of biologies through the removal of anti-drug antibodies. FCIII-GN3 can be administered with biologies, removing anti-drug antibodies and restoring efficacy. FCIII-GN3 effectively removes anti-drug antibodies in non-humanprimates. Anti-drug antibodies induced by the administration of Humira® are reduced with a single dose of FCIII-GN3.

[0018] FIG. 3 is a chart showing IgG degraders improve the efficacy of biologies through the removal of anti-drug antibodies. FIG 3 shows changes in anti-TNFa activity following treatment with FCIII-GN3 in ADA+ cynomolgus monkeys. FCIII-GN3 can be administered with biologies, removing antidrug antibodies and restoring efficacy. FCIII-GN3 restores the effects of biologies through the removal of anti-drug antibodies. FCIII-GN3 effectively removes anti-drug antibodies in non-human primates. Using an NFa Neutralization Assay, Humira® activity was measured by assaying TNFa levels when FCIII-GN3 was dosed 24 hours before administering Humira®.DETAILED DESCRIPTION OF THE INVENTION

[0019] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Exemplary embodiments will hereinafter be described in detail. However, these embodiments are only exemplary, and the present disclosure is not limited thereto but rather is defined by the scope of the appended claims. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.INDUSTRIAL APPLICABILITY

[0020] Autoimmune diseases are a diverse group of conditions characterized by immune disturbances that cause aberrant B-cell reactivity and T-cell reactivity to normal constituents of the host. Pisetsky, Nature Review Nephrology, 1-16 (May 10, 2023). Autoimmune diseases can involve essentially any organ system and affect individuals of any age, with a much greater prevalence among women.Although some mechanisms unite these conditions into a single category, the clinical manifestations of autoimmune disease are varied. These clinical manifestations range from acute, life-threatening organ failure to subtle laboratory abnormalities that can easily escape notice. Laboratory testing for autoimmune disease uses well-validated assays to establish the presence of autoantibodies.

[0021] Even with the use of the current targeted therapies, up to half of those living with rheumatoid arthritis do not reach remission or still have low disease activity. Rheumatoid arthritis treatments like TNF inhibitors generally do not effectively reduce autoantibodies by themselves.

[0022] After the bispecific degrader (bifunctional degrader) and the bound target protein are endocytosed, they are released from the ASGPR through calcium depletion from the endosome and changes in binding site amino acid protonation due to decreased pH. The ASGPR is recycled back to thehepatocyte surface. Endocytosed proteins are trafficked to late endosomes, which are fused with lysosomes. Lysosomal proteases then degrade endocytosed proteins, permanently removing them from circulation.DEFINITIONS

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the biomedical art. The terminology used in the description describes particular embodiments only and is not intended to be limiting. The terms, such 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 relevant art and this specification and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0024] As used in this specification, except as otherwise expressly provided herein, each of the following terms have the meaning set forth below. Additional definitions are set forth throughout the application. In instances where a term is not specifically defined herein, that term is given the biomedical art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the invention.

[0025] The articles "a" and "an" have the plain meaning of one or more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0026] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0027] The term "abatacept" has the biomedical art-recognized meaning of a T-cell costimulatory blocking antibody. Abatacept is a biological DMARD (bDMARD) that is commercially available as Orencia®. See the U.S. Food & Drug Administration UNII code 7D0YB67S97.

[0028] The term "adalimumab" has the biomedical art-recognized meaning of a tumor necrosis factor inhibitor that is commercially available as Humira®.

[0029] The term "administer" has the biomedical art-recognized meaning of the direct application of a substance to the body of a subject or patient by (a) a medical practitioner by a medically authorized agent, or (b) the subject or patient at the direction and in the presence of the medical practitioner, whether such application by injection, inhalation, ingestion, or any other means. See 21 U.S.C. § 802(2). The administration of a therapeutic composition of matter can be by any convenient manner.

[0030] The term "an effective amount" and the term "a therapeutically effective amount" have the biomedical art-recognized meaning of an amount effective to achieve its intended purpose. The effect can be detected by any assay method known in the art. The precise effective amount for a subject depends on the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0031] The term "anakinra" has the biomedical art-recognized meaning of an interleukin-1 receptor antagonist protein that is commercially available as Kineret®. See the U.S. Food & Drug Administration UNII code 9013DUQ28K.

[0032] The term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or." Expressions such as "at least one of," when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0033] The term "anti-arthritis agent" has the biomedical art-recognized meaning of a therapeutically active substance capable of treating rheumatoid arthritis.

[0034] The term "antibody" (Ab) has the biomedical art-recognized meaning of a glycoprotein immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding portion thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CHi, CH2 and CH3- Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VHand VLregions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VHand VLcomprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including some cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, lgG2, lgG3 and lgG4. The term "antibody" includes, by way of example,both naturally occurring and non-naturally occurring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or nonhuman Abs; wholly synthetic Abs; and single chain antibodies. A nonhuman antibody can be humanized by recombinant methods to reduce its immunogenicity in man. Where not expressly stated, and unless the context indicates otherwise, the term "antibody" also includes an antigen-binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins and includes a monovalent and a divalent fragment or portion and a single-chain antibody.

[0035] The term "aspirin" has the plain meaning of the non-steroidal anti-inflammatory agent (NSAID) acetylsalicylic acid used to treat pain and inflammation. See CAS Number 50-78-2. See the U.S. Food & Drug Administration UNII code R16CO5Y76E. Aspirin is the oldest drug of the non-steroidal class.

[0036] The term "at least one of," when preceding a list of elements, modifies the entire list of elements and does not modify the individual elements of the list.

[0037] The term "azathioprine" has the biomedical art-recognized meaning of an immunomodulatory medication commercially available under the brand name Imuran®. See the CAS Number 446-86-6. See the U.S. Food & Drug Administration UNII code MRK240IY2L.

[0038] The term "B cell-depleting agent " has the biomedical art-recognized meaning of a diseasemodifying anti-rheumatic drug (DMARD). See Zhang, Xu, & Huang, Front. Immunol., 14, 1126421 (February 10, 2023).

[0039] The term "FCIII-GN3" has the proprietary meaning. For a description of FCIII-GN3, see Bunin et al., American Academy of Neurology (AAN) 2024 Annual Meeting (April 18, 2024).

[0040] The term "binding moiety" has the biomedical art-recognized meaning of a moiety on a binding protein, e.g., an antibody, an antibody variant, or an antigen-binding fragment thereof, that binds to the target.

[0041] The term "biologic" refers to molecules that are obtained or capable of being obtained through use of biological methods, commonly mammalian or plant cells, bacteria, insects, or yeast. The resultant products are commonly proteins. Biologies are commonly large molecules having molecular weight of 100 kDaltons or greater, 110 kDaltons or greater, 120 kDaltons or greater, 130 kDaltons or greater, 140 kDaltons or greater, or 150 kDaltons or greater, but are not limited thereto. Biologies also include biosimilar molecules (or biosimilars), which are molecular entities that are structurally similar to and have no clinically meaningful differences in terms of safety, purity, and potency from known biologies.

[0042] The term "celecoxib" has the biomedical art-recognized meaning of a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation, and commercially available under the brand name Celebrex® among others. See CAS Number 169590-42-5. See the U.S. Food & Drug Administration UNII code JCX84Q7J1L.

[0043] The term "Cellular Receptor Binding Moiety" has the meaning described in this specification. In several embodiments of this specification, the cellular receptor-binding moiety is an asialoglycoprotein receptor (ASGPR) binding group.

[0044] The term "choline magnesium salicylate" (Trilasate®) has the biomedical art-recognized meaning of a non-steroidal anti-inflammatory agent (NSAID) used to treat pain and inflammation.

[0045] The term "corticosteroid" has the biomedical art-recognized meaning of an anti-arthritis agent from the class of steroid hormones.

[0046] The term "cyclooxygenase-2 inhibitor" (COX-2 inhibitor) has the biomedical art-recognized meaning of a non-steroidal anti-inflammatory agent (NSAID) that directly target cyclooxygenase-2 (COX- 2), an enzyme responsible for inflammation and pain.

[0047] The term "cyclophosphamide" (cytophosphane) has the biomedical art-recognized meaning of an immunomodulatory medication used as chemotherapy and to suppress the immune system. See CAS Number 50-18-0. See the U.S. Food & Drug Administration UNII code 6UXW23996M.

[0048] The term "cyclosporine A" (ciclosporin) has the biomedical art-recognized meaning of an immunomodulatory agent and calcineurin inhibitor that is used as an immunosuppressant medication. See CAS Number 59865-13-3. See the U.S. Food & Drug Administration UNII code 83HN0GTJ6D.Cyclosporine A is commercially available as Neoral®, Sandimmune®, Cicloral (by Sandoz / Hexal), Gengraf® (by Abbott) and Deximune® (by Dexcel Pharma).

[0049] The term "degrader of immunoglobulin G" has the meaning described in this specification. For a description of the concept of a degrader of immunoglobulin G, see Bunin et al., American Academy of Neurology (AAN) 2024 Annual Meeting (April 18, 2024). Degraders of immunoglobulin G can be made using the Molecular Degrader of Extracellular Proteins (MoDE™) platform.

[0050] The term "diclofenac" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID) used to treat pain and inflammatory diseases such as gout. See CAS Number 15307-86-5. See the U.S. Food & Drug Administration UNII code 144O8QL0L1. Diclofenac is commercially available under the brand names Cataflam®, Voltaren®, and Arthrotec®, among others.

[0051] The term "dif lusinal" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID) and salicylic acid derivative with analgesic and anti-inflammatory activity.See CAS Number 22494-42-4. See the U.S. Food & Drug Administration UNII code 7C546U4DEN. Diflusinal is commercially available from Merck & Co. as Dolobid, and generic versions are also available.

[0052] The term "disease-modifying anti-rheumatic drug" (DMARD) has the biomedical art- recognized meaning of a molecule capable of slowing down the progression of rheumatoid arthritis. DMARDs are common therapeutics for rheumatic arthritis. See Okamura et al., Mod. Rheumatol., 25(4), 534-9 (July 2015), Okamura et al., Mod. Rheumatol., 25(2), 235-40 (March 2015), Yonemoto et al., Mod. Rheumatol., 26(1), 24-8 (2016), Okamura et aL, BMC Musculoskeletal Disord., 15, 393 (November 22, 2014), and Okamura et aL, Rheumatology (Oxford), 51(8), 1484-91 (August 2012).

[0053] The term "etanercept" (ETN) has the biomedical art-recognized meaning of a tumor necrosis factor inhibitor. Etanercept is a biological DMARD (bDMARD) used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine. See CAS Number 185243- 69-0. See the U.S. Food & Drug Administration UNII code OP401G7OJC. Etanercept is commercially available under the brand name Enbrel® among others.

[0054] The term "etodolac" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Etodolac Is commercially available as Lodine®.

[0055] The term "etoricoxib" has the biomedical art-recognized meaning of a COX-2 inhibitor. Etoricoxib Is commercially available as Arcoxia®.

[0056] The term "Fcl II-GN3" has the meaning described in this specification. Fcl ll-G N3 can be made using the Molecular Degrader of Extracellular Proteins (MoDE™) platform. Data was released from a Phase 1 single ascending dose (SAD) study with FCIII-GN3 in healthy human subjects. FCIII-GN3 was shown to rapidly and selectively lower IgG in a dose-dependent manner. Some subjects experienced IgG reductions as low as 50 to 70% of baseline. FCIII-GN3 demonstrated reduction of IgG without significantly impacting liver function test (LFTs), albumin, low density lipoprotein, cholesterol or other serum laboratory tests.

[0057] The term "Fcl 11" has the biomedical art-recognized meaning of a polypeptide region in the fragment crystallizable region (Fc region), that has been shown to bind competitively to hinge region on the Fc fragment of IgG with high affinity.

[0058] The term "FcRn" has the biomedical art-recognized meaning of a polypeptide region in the neonatal Fc receptor.

[0059] The term "hydroxychloroquine" has the biomedical art-recognized meaning of an immunomodulatory or cytotoxic agent, a disease-modifying anti-rheumatic drug . Hydroxychloroquine is commercially available as Plaquenil®.

[0060] The term "ibuprofen" has the plain meaning of a non-steroidal anti-inflammatory agent (NSAID). Ibuprofen is commercially available over the counter as Advil®, Motrin®, and Nuprin®, among others.

[0061] The term "IgG Binding Moiety" has the meaning described in this specification of a binding moiety in a composition of matter that binds to an IgG.

[0062] The term "indomethacin" has the biomedical art-recognized meaning of a non-steroidal anti-inflammatory agent (NSAID). Indomethacin is commercially available as Indocin®.

[0063] The term "infliximab" has the biomedical art-recognized meaning of a tumor necrosis factor inhibitor and therapeutic antibody. Infliximab is commercially available as Remicade®.

[0064] The term "interleukin-1 receptor antagonist" has the biomedical art-recognized meaning of a disease-modifying anti-rheumatic drug. See Boraschi, What Is IL-1 for? The functions of interleukin-1 across evolution. Front Immunol. 13, 872155 (April 6, 2022).

[0065] The term "interleukin-17A inhibitor" has the biomedical art-recognized meaning of a disease-modifying anti-rheumatic drug. See Zhang & Ddmling, Expert Opinion on Therapeutic Patents, 32(11), 1161-1173 (2022).

[0066] The term "isotype" refers, without limitation, to the antibody class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant region genes. In some embodiments, one or more amino acids of the isotype can be mutated to alter effector function.

[0067] The term "ketoprofen" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Ketoprofen is commercially available as Orudis® or Oruvail®.

[0068] The term "leflunomide" has the biomedical art-recognized meaning of an immunomodulatory or cytotoxic agent, a disease-modifying anti-rheumatic drug. Leflunomide is commercially available as Arava®.

[0069] The term "lumiracoxib" has the biomedical art-recognized meaning of a COX-2 inhibitor. Lumiracoxib is commercially available as Prexige®.

[0070] The term "meloxicam" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Meloxicam is commercially available as Mobic®.

[0071] The term "methotrexate" has the biomedical art-recognized meaning of an immunomodulatory or cytotoxic agent, a disease-modifying anti-rheumatic drug. Methotrexate is commercially available as Rheumatrex® or Trexall®.

[0072] The term "methylprednisolone" has the biomedical art-recognized meaning of a corticosteroid.

[0073] The term "nabumetone" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Nabumetone is commercially available as Relafen®.

[0074] The term "naproxen" has the plain meaning of a non-steroidal anti-inflammatory agent (NSAID). Naproxen is commercially available over the counter as Alleve®.

[0075] The term "nipocalimab" means the investigational, high-affinity, fully human, aglycosylated, effectorless, monoclonal antibody that is IgG-specific and designed to selectively block FcRn to reduce levels of circulating IgG antibodies, including autoantibodies and alloantibodies that underlie multiple conditions. Nipocalimab is an anti-FcRn being studied across three key segments in the antibody-driven space: prevalent rheumatological diseases, maternal-fetal diseases mediated by maternal alloantibodies, and rare autoantibody diseases.

[0076] The term "non-steroidal anti-inflammatory agent" (NSAID) has the biomedical art- recognized meaning of a member of a therapeutic drug class, which reduces pain, decreases inflammation, decreases fever, and prevents blood clots.

[0077] The term "oxaprozin" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Oxaprozin is commercially available as Daypro®

[0078] The term "patient" has the plain meaning of a person or other animal receiving or expected to receive medical treatment.

[0079] The term "pharmaceutical composition" has the biomedical art-recognized meaning of a mixture of substances suitable for administering to an individual that includes a pharmaceutical agent.

[0080] The term "pharmaceutically acceptable excipient" has the biomedical art-recognized meaning of an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use and human pharmaceutical use. A "pharmaceutically acceptable excipient," as used in the specification and claims, includes both one and more than one such excipient. A description of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences 23rd edition (Elsevier, 2020).

[0081] The term "pharmaceutically acceptable" has the biomedical art-recognized meaning of those compounds, anions, cations, materials, compositions, carriers, or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0082] The term "piroxicam" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Piroxicam is commercially available as Feldene®.

[0083] The term "prednisone" has the biomedical art-recognized meaning of a corticosteroid. Prednisone is commercially available.

[0084] The term "rheumatoid arthritis" (RA) has the biomedical art-recognized meaning of a chronic, symmetric, inflammatory disease involving the synovial joints. Aletaha & Smolen, JAMA. 320(13), 1360-1372 (October 2, 2018). Rheumatoid arthritis occurs when the immune system loses its normal state of balanced control and activates sustained inflammation in the soft inner lining of joints, called synovial tissue. See Arthritis Foundation. Rheumatoid arthritis: Causes, symptoms, treatments and more. This inflammation produces joint pain, swelling, and stiffness. This inflammation can lead to permanent damage and deformity in structural joint elements like cartilage and bone. See Arthritis Foundation. Significantly reduced physical function and health-related quality of life typically accompany these features. Malm et al., SAGE Open Med., 5, 2050312117713647 (June 7, 2017). Antibody systems, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are associated with RA, having been identified based on the antigens these antibodies bind to. van Delft & Huizinga, Journal of Autoimmunity, 110, 102392 (2020). Rheumatoid arthritis is the most common inflammatory arthritis and affects an estimated 13 million people worldwide. Cieza et al., The Lancet 396 (10267), 2006-2017 (2020). About 1.5 million people in the United States are affected by RA. See, See, Arthritis Foundation and World Health Organization, The global burden of disease: 2004 update. (Geneva, WHO Press, 2008).

[0085] The term "rituximab" has the biomedical art-recognized meaning of a B cell-depleting agent. Rituximab is commercially available as Rituxan®.

[0086] The term "secukinumab" has the biomedical art-recognized meaning of an interleukin-17A inhibitor.

[0087] The term "subject" has the plain meaning of a person or other animal that is being discussed, described, or dealt with.

[0088] The term "substituted" has the biomedical art-recognized meaning of a group substituted with deuterium, a halogen (-F, -Cl, -Br, -I), a hydroxy group (-OH), an amino group (-NH2), a carboxyl group (-CO2H), a substituted or unsubstituted C1-C10 amine group, a nitro group (-NO2), a C1-C10 alkyl group, a C3-C10 cycloalkyl group, a C6-C12 aryl group, a C1-C10 alkoxy group, a Cl to CIO trifluoroalkyl group such as a trifluoromethyl group (-CF3) and the like, or a cyano group (-CN) instead of at least one hydrogen of a substituting group or compound.

[0089] The term "sulfasalazine" has the biomedical art-recognized meaning of an immunomodulatory or cytotoxic agent, a disease-modifying anti-rheumatic drug. Sulfasalazine is commercially available as Azulfidine®.

[0090] The term "sulindac" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Sulindac is commercially available as Clinoril®.

[0091] The term "T-cell costimulatory blocking agent" has the biomedical art-recognized meaning of a class of disease-modifying anti-rheumatic drug that suppress the immune system.

[0092] The term "therapeutically effective" has the biomedical art-recognized meaning of an amount effective to achieve its intended purpose. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0093] The term "tolementin" has the biomedical art-recognized meaning of a non-steroidal antiinflammatory agent (NSAID). Tolementin is commercially available as Tolectin®.

[0094] The term "triamcinolone" has the biomedical art-recognized meaning of a corticosteroid. Triamcinolone is commercially available.

[0095] The term "tumor necrosis factor inhibitor" has the biomedical art-recognized meaning of a disease-modifying anti-rheumatic drug that that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. Cimzia® is a "Fc-free" biologic targeting TNF for rheumatoid arthritis.

[0096] The term "tumor necrosis factor" (TNF, TN Fa) has the biomedical art-recognized meaning of a cytokine that that causes the immune system to make a specific immune response.

[0097] The terms "comprises" and / or "comprising," or "includes" and / or "including" when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0098] The terms first, second, third, etc., may be used herein to describe various elements, components, regions, layers, and / or sections, but these elements, components, regions, layers, 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 element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be termed a secondelement, component, region, layer, or section without departing from the teachings of the embodiments.

[0099] When an element is referred to as being "on" another element, it can be directly in contact with the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present.

[0100] This specification does not concern a process for cloning humans, methods for modifying the germ line genetic identity of humans, uses of human embryos for industrial or commercial purposes, or procedures for modifying the genetic identity of animals likely to cause them suffering with no substantial medical benefit to humans or animals resulting from these processes.

[0101] Additional aspects will be set forth in part in the description which follows and, in part, will be apparent from the description.IgG DEGRADER

[0102] In an embodiment, the degrader of IgG ("IgG degrader") may have the following general chemical structure:wherein [CPBM] is an IgG Binding Moiety which binds to pathogenic forms of IgG as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient);[CRBM] is a Cellular Receptor Binding Moiety, preferably an [ASGPRBM] group, which is a binding moiety which binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors as identified herein which are on the surface of hepatocytes and other degrading cells, preferably in a patient or subject; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety having a valency from 1 to 15 which covalently attaches to one or more [CRBM] and / or [CPBM] group, optionally through a [CON], including a [MULTICON] group, wherein said [LINKER] optionally itself contains one or more [CON] or [MULTICON] group(s); k' is an integer from 1 to 15; j' is an integer from 1 to 15; h and h' are each independently an integer from 0 to 15; iLis an integer from 0 to 15; with the proviso that at least one of h, h' and i is at least 1, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.

[0103] Some IgG Binding Moieties [CPBM], Cellular Receptor Binding Moieties [CRBM], and connecting group [LINKER] and [CON] are known in the art and described, for example, in International Publication No. WO 2019 / 199634 published October 17, 2019, and International Publication No. WO 2019 / 199634 published October 17, 2019, the contents of which publications are incorporated herein in their entireties by reference.

[0104] In an embodiment of the above general chemical structure, [CPBM] may be an immunoglobulin G binding moiety [IgGBM] having the structure:v) a peptide moiety selected from the group consisting of PAM (protein A mimetic peptide); D-PAM (D-protein A mimetic); D-PAM-(D (phenylacetyl-D-PAM, a dendrimeric peptide ligand); TWKTSRISIF (SEQ ID NO:1); FGRLVSSIRY (SEQ ID NO:2); Fell I; FcBP-1; FcBP-2; Fc-I ll-4c; EPIHRSTLTALL (SEQ ID NO:3); APAR (SEQ ID NO:4); FcRM; HWRGWV (SEQ ID NO:5); HYFKFD (SEQ ID NO:6); HFRRHL (SEQ ID NO:7); HWCITGWV (SEQ ID NO:8); D2AAG; DAAG; cyclo[(N-Ac)S(A)-RWHYFK-Lact-E] (SEQ ID NO:9); cyclo[(N-Ac)-Dap(A)-RWHYFK-Lact-E] (SEQ ID NQ:10); cyclo[Link-M-WFRHYK] (SEQ ID NO:11); NKFRGKYK (SEQ ID NO:12); NARKFYKG (SEQ ID NO:13); FYWHCLDE (SEQ ID NO:14); FYCHWALE (SEQ ID NO:15);FYCHTIDE (SEQ ID NO:16); RRGW (SEQ ID NO:17); and KHRFNKD (SEQ ID NO:18);each [CON] may independently be at each occurrence selected from the group consisting of:wherein:K'" may be 1, 2, 3, or 4;RMmay be H or C1-C3alkyl;X1may be O; each occurrence of X2may be independently CH2, O, NR4, or C(O); each occurrence of R1and R4may be independently H or C1-C3alkyl;ZBmay be absent (a bond), -(CH2)IM-, -C(O)-(CH2)IM-, or -C(O)-(CH2)IM-NRM-; each occurrence of IM may be independently 1, 2, or 3; k' may be 1; each occurrence of j may be independently 1, 2, 3, 4, or 5; j' may be 1; h and h' may be each independently 1, 2, 3, 4, 5, 6, 7, or 8; iLmay be 1; each occurrence of n may be independently 2 or 3; each occurrence of n" may be independently 2, 3, 4, or 5; or a salt, stereoisomer, or solvate thereof.

[0105] In another embodiment, h and h' may be each independently 1, 2, 3, 4, or 5.

[0106] In another embodiment, each occurrence of X2may be independently CH2, NR4, or C(O);R1may be H; andR4may be H.

[0107] In another embodiment, ZBmay be absent or -C(O)-(CH2)IM--

[0108] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0109] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0110] In another embodiment, the [CPBM] may be the [IgGBM] of structure :

[0111] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0112] In another embodiment, the [CPBM] may be the [IgGBM] of structure:

[0113] In another embodiment, [CPBM] may be an IgG binding moiety and [CRBM] may be a cellular receptor binding moiety described in International Patent Application No. PCT / US2024 / 026709 filed April 28, 2024, the content of which application is incorporated herein in its entirety by reference.

[0114] In another embodiment, the compound may have the structure:

[0115] In another embodiment, the compound may have the structure:

[0116] The Fcl I l-G N3 (FCIII-GN3) compound shows over 90% lowering of IgG in non-human primates with repeat dosing.

[0117] FCIII-GN3 has an advantageous mechanism of action differentiated from the neonatal Fc receptor (FcRn) targeting biologies. FCIII-GN3 can be combined with most standard-of-care rheumatoid arthritis biologies described in this specification. FcRn-targeting therapeutics cannot be co-administered with many biologies. FcRn-targeting therapeutics increase the clearance of any biologic that contains an Fc region, e.g., Humira® and approved biosimiliars targeting TNF for rheumatoid arthritis, Enbrel®, Rituxan®, and Cosentyx®. By contrast, FCIII-GN3 can be used in conjunction with commonly prescribed biologic therapeutics for rheumatoid arthritis.

[0118] FCIII-GN3 advantageously provides a differentiation from FcRn targeting agents in its fast onset of action (dose-dependent and rapid IgG reductions within hours of administration), deeper reductions in IgG, no anticipated mechanism of action effects on albumin or cholesterol, subcutaneous self-administration, and ability to use in combination with other biologies.

[0119] In another embodiment, the compound may have the structure:

[0120] In an embodiment, the molecular degrader of IgG ("IgG degrader") may have one of the following general chemical structures:or a pharmaceutically acceptable salt thereof

[0121] In the above formulae, "Extracellular Protein Targeting Ligand" refers to an IgG Binding Moiety [CPBM] or [IgGBM] which binds to pathogenic forms of IgG as identified herein, which are related to and / or mediate a disease state and / or condition and is to be removed by the action of hepatocytes or other cells on the circulating protein (the compounds preferably selectively binding to the IgG in plasma of the subject or patient).

[0122] In the above formulae,X1is 1 to 5 groups independently selected from O, S, N(R6). and C(.R4)(R4), wherein if X1is 1. group thenX1is O. S, N(R6), or C(R4)(R4), if X1is 2 groups then no more than I group of X* is O, S, or N(R6), if X1is 3, 4, or 5 groups then no more than 2 groups of X1are O, S, or N(R6),R2is selected from(i) ary-1, heterocycle, and heteroaiyi containing I or 2 heteroatoms independently selected from N, O, and S, each of which atyi, heterocycle, and heteroaryl is optionally substituted with 1. 2, 3, or 4 substituents,(ii)(iii) -NR*-S(O)-R\ -NR8-C(S)-R3- -NNRR8-S(O))(NR6) -R3,, -N=S(O)(R3)2, -NR8C(O)NR9S(O)2R3, -NR8-S(O)2-R10, and -NR8-C(NR6)-R3each of which is optionally substituted with 1, 2, 3, or 4 substituents; and(iv) hydrogen, R10alkyl-C(O)-R3, -C(O)-R3, alkyl, haloalkyl, -OC(O)R3and -NR8-C(O)R10‘;R,nis selected from aryl, alkyl-NRs-C(C))-R\ alkyl-aryl, alkyl-heleroaryl with I. 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR6, alkyl-NR6R*, NR8-NR6-C(O)R\ NR8-S(0)2-R\ alkenyl, allyl, alkynyl, -NR.6-alkenyl, -O-alkenyl, -NR6-alkynyl. -NR6--heteroaryl, -NR6-aryl, -O-heleroaryl, -O-aryl, and -O-alkynyl , each of which R10is optionally substituted with 1 , 2, 3, or 4 substituents,R1and R5are independently selected from hydrogen, heteroalkyl, C6-C6alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl. Br, L aryl, arylalkyl, heteroaryl, heteroarylalkyl. heterocycle, heterocycloalkyl, haloalkoxy. -O-alkenyl, -O-alkynyl, C0-C6alkyl- OR6C0-C6alkyl-SR6, C0-C6a kyl-NReR3. C0-C6alkyl-C(0)R3C0-C6alkyl-S(0)R\ C0-C6alkyl- C(S)R3, C0-C6alkyl-S(O)2R3, C0-C6alkyl-N(R8).C(0)R3C0-C6alkyl-N(R8)-S(0)R3, C0-C6alkyl- N(R8)-C(S)R3. C0-C6alkyl-N(R*)-S(O)2R3C0-C6alkyl-O-C)(OjR3, C0-C6alkyl-O-S(O)R3, C0- C6alkyl-O-C{S)R\ -N= S(OXR3)2, C0-C6.alkylN3, and C0-C6alkyl-O-S(O)2R3, each of which is optionally substituted with 1, 2, 3, or 4 substituents;R’ at each occurrence is independently selected from hydrogen, alkyl, heteroalkyl haloalkyl (including; -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR8, and -NRSR , R6is independently selected at each occurrence from hydrogen, heteroalkyl, aikyi, haloalkyl arylalkyi, heteroaryl alkyl, alkenyl, alkynyl, aryl heteroaryi. heterocycle. -OR6, -NR*R.', C(O}Rl S(O)R3, C(S)R3and S(O)2R3,R* and R;are independently selected at each occurrence from hydrogen, beteroalkyl, alkyl arylalkyl, heteroarylaikyl, alkenyl, alkynyl, aryl haloalkyl, heteroaryl, heterocycle, -alkyl-OR8. - alkyl-NR8R9. C(O)R3S(O)R3C(S)R3and S(O)2R3R8and R?’ are independently selected at each occurrence from hydrogen, beteroaikyi, alkyl, arylalkyl, heteroarylallcyl, alkenyl, alkynyl., atyl. heteroaryi, and heterocycle;Cycle is a 3-8 membered fused cyclic group optionally substituted with 1, 2. 3, or 4 substituents; each Linker* is a bond or a moiety that covalently links the ASGPR ligand to Linker* ,Linker3is a bond or a moiety that covalently links Linker* to an Extracellular Protein Targeting Ligand;Linker4' is a chemical group that links each Linker* to the Extracellular Protein Targeting Ligand; andLinker" is a chemical group that links each Linker* to the Extracellular Protein Targeting Ligand; and wherein, when R2is NR6-alkenyl, -NR^alkynyl-NR^CCOJR’”, -NR8-S(O)2-aitenyL -NRs-S(O)2-alkynyl, -NR'-heteroaryl, or -NR6-aryl, then Extracellular Protein Targeting Ligand does not compose an oligonucleotide, and the optional substituents are selected from alkyl, alkenyl . alkynyl, haloalkyl, -OR", F, Ci.Br, I, -NR6R7heteroalkyl, cyano, nitro, C(O)R3valence such that a stable compound results

[0123] Several moieties [LinkerA], [Linker8], [Linker0], [LinkeDc], [Cycle], and X1are known in the art and described, for example, in International Publication No. WO 2021 / 155317 published August 5, 2021, and International Publication No. WO 2022 / 235699 published November 10, 2022, the contents of which publications are incorporated herein in their entireties by reference.

[0124] In another embodiment, the compound may be a compound described in InternationalPatent Application No. PCT / US2024 / 026709 filed April 28, 2024, the content of which application is incorporated herein in its entirety by reference.

[0125] In another embodiment, the compound may have the structure:

[0126] In another embodiment, the compound may have the structure:

[0127] In another embodiment, the compound may have the structure:ANTI-ARTHRITIS AGENT

[0128] The anti-arthritis agent may be a disease-modifying anti-rheumatic drug, a non-steroidal anti-inflammatory agent, or a corticosteroid.DISEASE-MODI FYI NG ANTI-RHEUMATIC DRUGS

[0129] In one embodiment, the anti-arthritis agent may be a disease-modifying anti-rheumatic drug ("DMARD").

[0130] The disease-modifying anti-rheumatic drug may be a biologic.

[0131] The disease-modifying anti-rheumatic drug may be an antibody.

[0132] In an embodiment, the disease-modifying anti-rheumatic drug may be a tumor necrosis factor inhibitor, such as etanercept (Enbrel®), adalimumab (Humira®), or infliximab (Remicade®).

[0133] In another embodiment, the disease-modifying anti-rheumatic drug may be a T-cell costimulatory blocking agent, for example, abatacept (Orencia®).

[0134] In another embodiment, the disease-modifying anti-rheumatic drug may be a B celldepleting agent, such as rituximab (Rituxan®).

[0135] In another embodiment, the disease-modifying anti-rheumatic drug may be an interleukin-1 ("IL-1") receptor antagonist, for example, anakinra (Kineret®).

[0136] In another embodiment, the disease-modifying anti-rheumatic drug may be an interleukin- 17A ("IL-17A") inhibitor, for example, secukinumab (Cosentyx®).

[0137] In another embodiment, the disease-modifying anti-rheumatic drug may be an immunomodulatory or cytotoxic agent such as azathioprine (Imuran®), cyclophosphamide, and cyclosporine A (Neoral®, Sandimmune®).

[0138] In another embodiment, the disease-modifying anti-rheumatic drug may be methotrexate (Rheumatrex®, Trexall®).

[0139] In another embodiment, the disease-modifying anti-rheumatic drug may be hydroxychloroquine (Plaquenil®).

[0140] In another embodiment, the disease-modifying anti-rheumatic drug may be sulfasalazine (Azulfidine®).

[0141] In another embodiment, the disease-modifying anti-rheumatic drug may be leflunomide (Arava®).NON-STEROI DAL ANTI-INFLAMMATORY AGENTS

[0142] In another aspect, the anti-arthritis agent may be a non-steroidal anti-inflammatory agent ("NSAID"). The major effect of these agents is to reduce acute inflammation thereby decreasing pain and improving function. All of these drugs also have mild to moderate analgesic properties independent of their anti-inflammatory effect. It is important to note, however, that these drugs alone do not change the course of the disease of rheumatoid arthritis or prevent joint destruction.

[0143] There are many NSAIDs from which to choose. At full dosages, all are potentially equally effective. The toxicities of the currently available non-aspirin NSAIDs are similar. Many different NSAIDS are commercially available, some over the counter, including ibuprofen (Advil®, Motrin®, Nuprin®) and naproxen (Alleve®) and many others are available by prescription including meloxicam (Mobic®), etodolac (Lodine®), nabumetone (Relafen®), sulindac (Clinoril®), tolementin (Tolectin®), choline magnesium salicylate (Trilasate®), diclofenac (Cataflam®, Voltaren®, Arthrotec®), diflusinal (Dolobid®), indomethacin (Indocin®), ketoprofen (Orudis®, Oruvail®), meloxicam (Mobic®), oxaprozin (Daypro®), and piroxicam (Feldene®). Longer-acting NSAIDs that allow daily, or twice daily dosing may improve compliance. The NSAID class also includes drugs known as COX-2 inhibitors that are also effective in controlling inflammation. An agent currently available in the United States is celecoxib, Celebrex®. Other agents are etoricoxib (Arcoxia®) and lumiracoxib (Prexige®).CORTICOSTEROI DS

[0144] In another aspect, the anti-arthritis agent may be a corticosteroid. Corticosteroids (such as prednisone; methylprenisolone, Medrol®) have both anti-inflammatory and immunoregulatory activity. They can be given orally, intravenously, intramuscularly or can be injected directly into the joint. Corticosteroids are useful in early disease as temporary adjunctive therapy while waiting for DMARDs to exert their anti-inflammatory effects. Corticosteroids are also useful as chronic adjunctive therapy in patients with severe disease that is not well controlled on NSAIDs and DMARDs.

[0145] Intra-articular corticosteroids (e.g., triamcinolone or methylprednisolone and others) are effective for controlling a local flare in a joint without changing the overall drug regimen.METHOD OF MANUFACTURE

[0146] The starting materials useful for making the degrader of immunoglobulin G are readily commercially available or can be prepared by those skilled in the art.

[0147] Solvates are compounds formed by solvation, which is the combination of solvent molecules with molecules or ions of the solute. Solvation is an interaction of a solute with the solvent, which leads to stabilization of the solute species in the solution. One may also refer to the solvated state, whereby an ion in a solution is complexed by solvent molecules. The difference in the physical properties of different solvates and polymorphic forms thereof results from different orientations and intermolecular interactions of adjacent molecules in the solid. Polymorphic forms of compounds or solvates can be distinguished by X-ray diffraction and by other methods such as, infrared spectroscopy or Raman spectroscopy.

[0148] Other assays to test the degrader of immunoglobulin G made by the method of manufacture include (1) a standard TR-FRET Ternary Complex Assay, and (2) the Lumit FcRn Binding Immunoassay (Promega).METHODS FOR TESTING THE REMOVAL OF IgG FROM A SUBJECT

[0149] Anti-citrullinated protein antibodies (ACPAs) are autoantibodies against citrullinated proteins and may be reliable markers for the early diagnosis of rheumatoid arthritis. Liu et aL, Front. Med. (Lausanne), 8, 802934 (January 12, 2022). Up to 80% of patients living with rheumatoid arthritis are seropositive for anti-citrullinated protein antibodies, and / or RF or both, van Delft & Huizinga, Journal of Autoimmunity, 110, 102392 (2020).

[0150] DAS28-CRP is a tool used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count and swollen joint count (both out of 28 evaluated joints), patient's global assessment of disease activity, and CRP. Nielung et al., Arthritis, 2015(1), 401690 (2015). Change from baseline in DAS28-CRP measures the change in disease activity, where a negative change indicates an improvement. CRP is a type of protein that increases during inflammatory conditions, such as rheumatoid arthritis. Sproston & Ashworth, Front. Immunol., 9, 754 (April 13, 2018), Nielsen et al. BMJ, 345, e5244 (2012).

[0151] ACR20 / 50 / 70 / 90 response is defined as at least 20 / 50 / 70 / 90 percent improvement from baseline in the number of tender and swollen joints, and at least 20 / 50 / 70 / 90 percent improvement from baseline in three of the following five criteria: patient's assessment of pain by visual analog scale, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function measured by HAQ-DId and CRP. Medicine Matters. At a glance: Common scores used in rheumatology (2018).

[0152] HAQ-DI is a 20-question instrument assessing eight functional areas, range: 0-3, 0=no difficulty, 3=inability to perform a task in that area. Medicine Matters. At a glance: Common scores used in rheumatology (2018).

[0153] The invention is further illustrated by the following non-limiting EXAMPLES.EXAMPLE 1.PHARMACOKINETICS OF ADALIMUMAB IN CYNOMOLGUS MONKEYS FOLLOWING DOSING WITH FCIII-GN3, A FIRST-IN- CLASS MOLECULAR DEGRADER OF IgG.

[0154] BACKGROUND: FCIII-GN3 is a first-in-class molecular degrader of extracellular protein (MoDE) that is being developed for individuals living with antibody-positive, moderate to severe rheumatoid arthritis. This is a difficult-to-treat population with significant unmet need despite effective combination therapy with biological disease-modifying antirheumatic drugs and methotrexate. Tumor necrosis factor (TNF)-alpha inhibitors, such as adalimumab, are widely used in the management of individuals who have inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) and are an important component in combination therapy. Secondary failure on a TNF-based regimen is often associated with the development of anti-drug antibodies (ADAs) against these biological agents.

[0155] FCIII-GN3 is a bifunctional molecule with the potential to target and then deliver pathogenic IgG autoantibodies and immune complexes to asialoglycoprotein receptors on hepatocytes for internalization and lysosomal degradation. MoDE degraders, such as FCIII-GN3, may also be able to reduce anti-drug antibodies that have formed against biological DMARDs, restoring their earlier beneficial effects.

[0156] OBJECTIVES: This EXAMPLE was undertaken to test the effect of FCIII-GN3 on adalimumab exposures in cynomolgus monkeys.

[0157] METHODS: Six groups of three male naive cynomolgus monkeys (N = 18) were administered adalimumab as a single 3 mg / kg subcutaneous injection at various times (-4 days, +2 hours, +6 hours, +12 hours, +24 hours, and +48 hours) relative to a single 30 mg / kg intravenous bolus of FCIII-GN3.Plasma samples were collected at 24 hours post FCIII-GN3 administration. Serum samples were collected pre-dose (0) and at 2, 24, 48, 72, 96, 120, 144, 168, 336, and 504 hours post adalimumab administration. Concentrations of FCIII-GN3 in plasma samples were determined by liquid chromatography tandem mass spectrometry. Concentrations of adalimumab in serum samples were assayed by enzyme-linked immunosorbent assay (ELISA).

[0158] RESULTS: Adalimumab and FCIII-GN3 pharmacokinetics results are provided in TABLE 1.Exposure (maximum concentration and area under the curve) to adalimumab was lowest when the drug was administered two hours after FCIII-GN3 and relatively similar at all other dosing times. Plasma concentrations of FCIII-GN3 at 24 hours post-administration showed less than 1.5-fold differences across the 6 groups.

[0159] CONCLUSION: These data demonstrate that FCIII-GN3 does not adversely affect exposure to adalimumab and provide supporting evidence that MoDE IgG degraders, e.g., FCIII-GN3, can be effectively used in combination with TNF inhibitors in the management of difficult-to-treat autoimmune disease. These results represent a key differentiating feature from neonatal Fc receptor inhibitors, which are known to adversely affect the exposure to and effectiveness of Fc-containing biologies, including adalimumab.EXAMPLE 2. IgG DEGRADER FCIII-GN3 DEMONSTRATES THE ABILITY TO REMOVE ANTi-bDMARD ANTI-DRUG ANTIBODIES AND ALLOWS FOR CO-ADMINISTRATION WITH FC-CONTAINING BIOLOGICS.

[0160] BACKGROUND: FCIII-GN3 is a molecular degrader of extracellular protein (MoDE™) in development for treating IgG-driven autoimmune diseases, including rheumatoid arthritis. MoDEs are bifunctional molecules that reduce pathogenic IgG autoantibodies and immune complexes through asialoglycoprotein receptor (ASGPR)-mediated lysosomal degradation in the liver.

[0161] TNFa inhibitors and other biologic DMARDs (bDMARDs) do not achieve sustained remission in many patients. The development of neutralizing anti-drug antibodies (ADAs) reduces the efficacy of these agents.

[0162] Unlike other IgG targeting approaches, such as FcRN inhibitors, FCIII-GN3 can be coadministered with Fc-containing bDMARDs. It has the potential to lower pathogenic autoantibodies and immune complexes and optimize the efficacy of bDMARDs by reducing anti-drug antibodies.

[0163] METHODS: Assays were conducted in cynomolgus monkeys to (1) assess the pharmacokinetics of adalimumab when co-administered with FCIII-GN3 and (2) evaluate the ability of FCIII-GN3 to remove adalimumab anti-drug antibodies and restore anti-TNFa activity.

[0164] STUDY 1: Six groups of cynomolgus monkeys (3 / group, N=18) received single doses of adalimumab (3 mg / kg subcutaneously xl) at various times relative to FCIII-GN3 (30 mg / kg IV xl). Concentrations of FCIII-GN3 and adalimumab were determined by LCMS and ELISA, respectively.

[0165] STUDY 2: Cynomolgus monkeys received adalimumab (10 mg / kg) in CFA followed by two Q.W doses of adalimumab in PBS (10 mg / kg). Anti-drug antibody-positive cynomolgus monkeys were randomized to Groups 1 and 2, and Anti-drug antibody-negative cynomolgus monkeys were placed in Group 3. Group 2 received an active drug (FCIII-GN3 50 mg / kg IV xl). Groups 1 and 3 received a placebo. After 24 hours, all cynomolgus monkeys received adalimumab (3 mg / kg subcutaneously xl). Readouts included adalimumab PK, adalimumab's neutralizing activity of TNF-a, total IgG, and PK of FCIII-GN3.

[0166] RESULTS: In Study 1, adalimumab PK, at all the time points from 6 hours to 48 hours postdosing with FCIII-GN3, was within 20% of historical values. Concentrations of FCIII-GN3 at 24 hours postdose showed a <1.5x difference across the six groups. See TABLE 1.

[0167] In Study 2, 3 / 5 of the cynomolgus monkeys in Group 2 had improvement in anti-drug antibody (ADA) titers following treatment with FCIII-GN3, as compared with 0 / 5 untreated Anti-drug antibody-positive cynomolgus monkeys. There were significant improvements in adalimumab anti-TNFa activity in FCIII-GN3 treated ADA+ cynomolgus monkeys compared to placebo-treated monkeys (Group 2 FCIII-GN3 vs. Group 1 Vehicle, respectively. See FIG. 2.

[0168] CONCLUSION: This EXAMPLE demonstrates that FCIII-GN3 does not adversely affect exposure to adalimumab. FCIII-GN3 can reduce neutralizing anti-drug antibodies. MoDE IgG degraders can be coadministered with bDMARDs in rheumatoid arthritis. MoDE degraders are a combinatorial therapeutic approach for difficult-to-treat rheumatoid arthritis and other rheumatologic diseases, enabling the removal of anti-drug antibodies, pathogenic autoantibodies, and immune complexes as key differentiated features compared to other approaches.EXAMPLE 3.MOLECULAR DEGRADERS OF EXTRACELLULAR PROTEIN (MODES™) RAPIDLY AND EFFECTIVELY REMOVE INTERSTITIAL IGG AND DISEASE-RELEVANT IMMUNE COMPLEXES THROUGH ENDO-LYSOSOMAL DEGRADATION IN THE LIVER.

[0169] BACKGROUND: Extracellular IgG degraders (e.g., FCIII-GN3) from the innovative molecular degraders of extracellular protein (MoDE) drug platform are being developed to treat IgG-mediated autoimmune diseases, including rheumatoid arthritis. IgG MoDEs target IgG and IgG-immune complexes in the circulation and disease-relevant tissues.

[0170] IgG MoDEs are bifunctional molecules engineered to bind simultaneously to IgG molecules and to hepatic asialoglycoprotein (ASGPR) receptors, leading to internalization and endolysosomal degradation of IgG in the liver. This EXAMPLE assayed the ability of IgG MoDEs to also remove interstitial IgG and disease-relevant IgG-immune complexes.

[0171] METHODS: Large, multimeric human IgG-immune complexes (i.e., IgG-IgM, and IgG-lgA) were generated in vitro. The ability of FCIII-GN3 to mediate cellular uptake and degradation of these IgG- immune complexes was assessed in vitro using an endocytosis assay with human ASGPR expressing HEK- 293T cells. The ability to remove interstitial IgG and disease relevant IgG-immune complexes in tissues was examined in vivo in mice by a combination of laboratory techniques, e.g., by Meso Scale Discovery (MSD) and immunofluorescence. The specificity of this mechanism of action was confirmed by conducting studies in mice lacking the expression of ASGPR.

[0172] RESULTS: In the endocytosis assay, IgG MoDEs, e.g. FCIII-GN3, mediated robust cellular uptake of human IgG-immune complexes with EC5o in the single to double digit nanomolar range in HEK cells expressing ASGPR. In mice, complete clearance of IgG from liver, spleen, kidney, bone marrow, fat, meninges, and neuromuscular junction was observed within 48 hours of dosing. Immune complex uptake and degradation in the liver were noted within 1-2 hours of dosing. IgG signal was colocalized with a lysosomal marker. Studies in mice lacking ASGPR expression confirmed that Ig uptake and degradation in the liver following treatment with IgG degraders was specifically mediated by ASGPR.

[0173] CONCLUSION: In these in vitro and in vivo studies, extracellular IgG degraders, e.g., FCIII-GN3 from the MoDE drug platform demonstrated the ability to remove interstitial IgG and disease-relevant immune complexes through endo-lysosomal degradation in the liver. This modality offers a differentiated therapeutic strategy for treating a spectrum of autoimmune conditions by targeting pathogenic autoantibodies and immune complexes that have a function in disease onset, progression, and end organ damage.EQUIVALENTS

[0174] Persons having ordinary skill in the biomedical art recognize or are able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description can be employed. Furthermore, specific items within lists of items or subset groups of items within larger groups of items can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.REFERENCES

[0175] Persons having ordinary skill in the biomedical art can use these patents, patent applications, and scientific references as guidance to predictable results when making and using the invention.PATENT LITERATURE.

[0176] Inti. Pat. PubL WO 2019 / 023501 (Kleo Pharmaceuticals, Inc.), Universal ABT compounds and uses thereof, published January 31, 2019.

[0177] Inti. Pat. Publ. WO 2019 / 136442 (Kleo Pharmaceuticals, Inc.), Cdl6a binding agents and uses thereof, published July 11, 2019.

[0178] Inti. Pat. Publ. WO 2019 / 199621 (Yale University), Bi-functional molecules to degrade circulating proteins, published October 17, 2019.

[0179] Inti. Pat. Publ. WO 2019 / 199634 (Yale University), Bifunctional small molecules to target the selective degradation of circulating proteins, published October 17, 2019.

[0180] Inti. Pat. Publ. WO 2021 / 02052 (Kleo Pharmaceuticals, Inc.), Directed conjugation technologies, published May 27, 2021.

[0181] Inti. Pat. Publ. WO 2021 / 155317 (Avilar Therapeutics, Inc.), ASGPR-binding compounds for the degradation of extracellular proteins, published August 5, 2021.

[0182] Inti. Pat. Publ. WO 2022 / 235699 (Avilar Therapeutics, Inc.), Potent ASGPR-binding compounds for the degradation of immunoglobulins and other proteins, published November 10, 2022. NON-PATENT LITERATURE.

[0183] Aletaha & Smolen, Diagnosis and management of rheumatoid arthritis: A review. JAMA. 320(13), 1360-1372 (October 2, 2018).

[0184] Arthritis Foundation. Rheumatoid arthritis: Causes, symptoms, treatments and more.

[0185] Boraschi, What Is IL-1 for? The functions of interleukin-1 across evolution. Front Immunol. 13, 872155 (April 6, 2022).

[0186] Bruce & Fries, The health assessment questionnaire (HAQ). Clin. Exp. Rheumatol., 23 (Suppl. 39): S14-S18 (2005).

[0187] Bunin et al., Novel bispecific degrader FCIII-GN3 achieves rapid, robust, selective, and transient IgG reduction in preclinical models including nonhuman primates, American Academy of Neurology (AAN) 2024 Annual Meeting (April 18, 2024).

[0188] Cieza et al., Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet 396, (10267), 2006-2017 (2020).

[0189] Dinon et al., Structural refinement of protein A mimetic peptide. J. Mol. Recognit., 24(6), 1087-94 (November-December 2011).

[0190] Liu et al., Anti-citrullinated protein antibody generation, pathogenesis, clinical application, and prospects. Front Med (Lausanne), 8, 802934 (January 12, 2022).

[0191] Malm et aL, Quality of life in patients with established rheumatoid arthritis: A phenomenographic study. SAGE Open Med., 5, 2050312117713647 (June 7, 2017).

[0192] Medicine Matters. At a glance: Common scores used in rheumatology (2018).

[0193] Nielsen et al. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ, 345, e5244 (2012).

[0194] Nielung et al., Validity and agreement between the 28-joint disease activity score based on C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis. Arthritis, 2015(1), 401690 (2015).

[0195] Okamura et al., Efficacy at 52 weeks of daily clinical use of iguratimod in patients with rheumatoid arthritis. Mod. Rheumatol., 25(4), 534-9 (July 2015).

[0196] Okamura et al., Efficacy of the clinical use of iguratimod therapy in patients with rheumatoid arthritis. Mod. Rheumatol., 25(2), 235-40 (March 2015).

[0197] Okamura et al., Evaluation of tocilizumab therapy in patients with rheumatoid arthritis based on FDG-PET / CT. BMC Musculoskeletal Disord., 15, 393 (November 22, 2014).

[0198] Okamura et al., The assessment of biologic treatment in patients with rheumatoid arthritis using FDG-PET / CT. Rheumatology (Oxford), 51(8), 1484-91 (August 2012).

[0199] Sproston & Ashworth, Role of C-reactive protein at sites of inflammation and infection. Front. Immunol., 9, 754 (April 13, 2018).

[0200] van Delft & Huizinga, An overview of autoantibodies in rheumatoid arthritis, Journal of Autoimmunity, 110, 102392 (2020).

[0201] World Health Organization. The global burden of disease: 2004 update. (Geneva, WHO Press, 2008).

[0202] Yonemoto et aL, Comparison of golimumab 100-mg monotherapy to golimumab 50 mg plus methotrexate in patients with rheumatoid arthritis: Results from a multicenter, cohort study. Mod. Rheumatol., 26(1), 24-8 (2016).

[0203] Zhang & Domling, Small molecule modulators of IL-17A / IL-17RA: A patent review (2013- 2021). Expert Opinion on Therapeutic Patents, 32(11), 1161-1173 (2022).

[0204] Zhang, Xu, & Huang, B cell depletion therapies in autoimmune diseases: Monoclonal antibodies or chimeric antigen receptor-based therapy? Front. Immunol., 14, 1126421 (February 10, 2023).TEXTBOOKS AND TECHNICAL REFERENCES.

[0205] Current Protocols in Immunology (CPI), Coligan et al., eds. (John Wiley and Sons, Inc., 2003) (ISBN 0471142735, 9780471142737).

[0206] Current Protocols in Molecular Biology (CPMB), Ausubel, ed. (John Wiley and Sons, Inc., 2014), (ISBN 047150338X, 9780471503385).

[0207] Current Protocols in Protein Science (CPPS), Coligan, ed. (John Wiley and Sons, Inc., 2005).

[0208] Encyclopedia of Molecular Cell Biology and Molecular Medicine, Porter et aL, (eds.), published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908).

[0209] Greene & Wuts, Protecting Groups in Organic Synthesis, 3rdedition (John Wiley & Sons, 1999).

[0210] Immunology (2006). Werner Luttmann, published by Elsevier.

[0211] Janeway's Immunobiology, (2014). Murphy, Allan, & Weaver (eds.), Taylor & Francis Limited, (ISBN 0815345305, 9780815345305).

[0212] Laboratory Methods in Enzymology: DNA, (2013). Lorsch (ed.) Elsevier (ISBN 0124199542).

[0213] Larock, Comprehensive Organic Transformations, 2ndedition (John Wiley & Sons, 1999).

[0214] Lewin's Genes XI, (2014). published by Jones & Bartlett Publishers (ISBN-1449659055).

[0215] Merck Manual of Diagnosis and Therapy, 19thedition (Merck Sharp & Dohme Corp., 2018).

[0216] Molecular Biology and Biotechnology: A Comprehensive Desk Reference, (1995). Meyers (ed.), published by VCH Publishers, Inc. (ISBN 1-56081-569-8).

[0217] Molecular Cloning: A Laboratory Manual, 4th ed., Green and Sambrook, (2012). Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (ISBN 1936113414).

[0218] Remington's, Pharmaceutical Sciences 23rdedition (Elsevier, 2020).

[0219] Smith & March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition (John Wiley & Sons, 2001).

[0220] Throughout this application, some publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application to describe the state of the art more fully as known to those skilled therein as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgment that such reference is prior art to the present invention.

[0221] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.SEQUENCE LISTINGSequence Number (ID) : 1Length: 10Molecule Type: AAFeatures Location / Qualifiers :- source, 1. .10> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .10Residues :TWKTSRISIF 10Sequence Number (ID) : 2Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .10> mol_type, protein> organism, synthetic construct- PEPTIDE, 1. .10Residues :FGRLVSSIRY 10Sequence Number (ID) : 3Length: 12Molecule Type: AAFeatures Location / Quali f iers :- source, 1. .12> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .12Residues :EPIHRSTLTA LL 12Sequence Number (ID) : 4Length: 4Molecule Type: AAFeatures Location / Qualifiers :- source, 1. .4> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .4Residues :APAR 4Sequence Number (ID) : 5Length: 6Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .6> mol_type, protein> organism, synthetic construct- PEPTIDE, 1. .6Residues :HWRGWV 6Sequence Number (ID) : 6Length: 6Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .6> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .6Residues :HYFKFD 6Sequence Number (ID) : 7Length: 6Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .6> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .6Residues :HFRRHL 6Sequence Number (ID) : 8Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .8> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .8Residues :HWCITGWV 8Sequence Number (ID) : 9Length: 10Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .10> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .10- CROSSLNK, 1. .10> note, Ala and Glu form a ring.- MOD_RES, 2> note, Ser is N-acylated.- MOD_RES, 9> note, Xaa = lactic acidResidues :ASRWHYFKXE 10Sequence Number (ID) : 10Length: 10Molecule Type: AAFeatures Location / Qualifiers :- source, 1. .10> mol type, protein> organism, synthetic construct- CROSSLNK, 1. .10> note, Ala and Glu form a ring.- PEPTIDE, 1. .10- MOD_RES, 2> note, Xaa = N-aceylated 2 , 3-diaminopropionic acid- MOD_RES, 9> note, Xaa = lactic acidResidues :AXRWHYFKXE 10Sequence Number (ID) : 11Length: 7Molecule Type: AAFeatures Location / Qualifiers :- source, 1. .7> mol_type, protein> organism, synthetic construct- MOD_RES, 1> note, Met HN2 is substituted with glutaric acid.- PEPTIDE, 1. .7- CROSSLNK, 1. .7> note, Glutaric acid forms a ring between Lys and MetResidues :MWFRHYK 7Sequence Number (ID) : 12Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .8> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .8Residues :NKFRGKYK 8Sequence Number (ID) : 13Length: 8Molecule Type: AAFeatures Location / Qualifiers :- source, 1. .8> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .8Residues :NARKFYKG 8Sequence Number (ID) : 14Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .8> mol_type, protein> organism, synthetic construct- PEPTIDE, 1. .8Residues :FYWHCLDE 8Sequence Number (ID) : 15Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .8> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .8Residues :FYCHWALE 8Sequence Number (ID) : 16Length: 8Molecule Type: AAFeatures Location / Qualifiers:- source, 1. .8> mol type, protein> organism, synthetic constructPEPTIDE, 1. .8Residues :FYCHTIDESequence Number (ID) : 17Length: 4Molecule Type: AAFeatures Location / Quali tiers :- source, 1. .4> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .4Residues :RRGW 4Sequence Number (ID) : 18Length: 7Molecule Type: AAFeatures Location / Qualifiers :- source, 1. .7> mol type, protein> organism, synthetic construct- PEPTIDE, 1. .7Residues :KHRFNKD 7

Claims

CLAIMS1. A composition comprising a degrader of immunoglobulin G, and an anti-arthritis agent, wherein the degrader of immunoglobulin G has the structure:wherein [CPBM] is an IgG Binding Moiety that binds to IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety that binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] and / or [CPBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

2. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:wherein [CPBM] is an IgG Binding Moiety that binds to the Fclll region of IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety that binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] and / or [CPBM] group.

3. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

4. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

5. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

6. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

7. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

8. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

9. The composition of claim 1, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

10. A method of reducing the level of IgG in a subject by administering to a subject a degrader of immunoglobulin G and an anti-arthritis agent, comprising wherein the degrader of immunoglobulin G has the following structure:wherein [CPBM] is an IgG Binding Moiety that binds to IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety that binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to[CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] and / or [CPBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

11. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:wherein [CPBM] is an IgG Binding Moiety that binds to the Fclll region of IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety that binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to[CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] and / or [CPBM] group.

12. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

13. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

14. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

15. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

16. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

17. The method of claim 10, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

18. The method of claim 10, wherein the degrader of immunoglobulin G is injected subcutaneously.

19. The method of claim 10, wherein the anti-arthritis agent is injected subcutaneously or taken by mouth.

20. A method of treating rheumatoid arthritis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a degrader of immunoglobulin G and an anti-arthritis agent, wherein the degrader of immunoglobulin G has the following structure:wherein [CPBM] is an IgG Binding Moiety that binds to IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety that binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] and / or [CPBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

21. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:wherein [CPBM] is an IgG Binding Moiety that binds to the Fclll region of IgG;[CRBM] is a Cellular Receptor Binding Moiety, which is a binding moiety that binds to hepatocytes or other cells through asialoglycoprotein receptors or other receptors on the surface of hepatocytes and other degrading cells; each [CON] is an optional connector chemical moiety which, when present, connects directly to [CPBM] or to [CRBM] or connects the [LINKER] to [CPBM] or to [CRBM] and[LINKER] is a chemical moiety that covalently attaches to one or more [CRBM] and / or [CPBM] group, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof.

22. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

23. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

24. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

25. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

26. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

27. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

28. The method of claim 20, wherein the degrader of immunoglobulin G has the following structure:or a pharmaceutically acceptable salt thereof.

29. The method of claim 20, wherein the anti-arthritis agent is a disease-modifying anti-rheumatic drug, a non-steroidal anti-inflammatory agent (NSAID), a corticosteroid, or any combination thereof.

30. The method of claim 29, wherein the disease-modifying anti-rheumatic drug (DMARD) is selected from the group consisting of a tumor necrosis factor inhibitor, a T-cell costimulatory blocking agent, a B cell depleting agent, an interleukin-1 receptor antagonist, an immunomodulatory or cytotoxic agent, and an interleukin-17A inhibitor31. The method of claim 30, wherein the tumor necrosis factor inhibitor is selected from the group consisting of etanercept, adalimumab, and infliximab.

32. The method of claim 30, wherein the T-cell costimulatory blocking agent is abatacept.

33. The method of claim 30, wherein the B cell-depleting agent is rituximab.

34. The method of claim 30, wherein the interleukin-1 receptor antagonist is anakinra.

35. The method of claim 30, wherein the immunomodulatory or cytotoxic agent is selected from the group consisting of azathioprine, cyclophosphamide, and cyclosporine A.

36. The method of claim 30, wherein the interleukin-17A inhibitor is secukinumab.

37. The method of claim 29, wherein the disease-modifying anti-rheumatic drug (DMARD) is selected from the group consisting of methotrexate, hydroxychloroquine, sulfasalazine, or leflunomide.

38. The method of claim 29, wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin, ibuprofen, naproxen, meloxicam, etodolac, nabumetone, sulindac, tolementin, choline magnesium salicylate, diclofenac, diflusinal, indomethacin, ketoprofen, meloxicam, oxaprozin, piroxicam, and any combination thereof.

39. The method of claim 29, wherein the non-steroidal anti-inflammatory agent is a COX-2 inhibitor selected from the group consisting of celecoxib, etoricoxib, and lumiracoxib.

40. The method of claim 29, wherein the corticosteroid is selected from the group consisting of prednisone, methylprednisolone, and triamcinolone.

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