Treatment of IgG-related diseases

Abstract

A method is provided for treating a disease that is sensitive to a response by reducing the level of immunoglobulin G ("IgG"), comprising administering to a subject requiring such treatment (i) a loading dose of a first agent to reduce the level of IgG by a desired amount; and (ii) a therapeutically effective dose of a second agent to treat the disease, wherein the second agent is an IgG degrader.

Description

[Technical Field]

[0001] The present invention relates to the treatment of diseases. More specifically, the present invention relates to the treatment of susceptible diseases by reducing the level of immunoglobulin G ("IgG") using an IgG molecular degradation inducer. [Background technology]

[0002] Elevated IgG levels may be a contributing factor in the progression of diseases such as IgG myeloma, liver disease, sarcoidosis, chronic infections, autoimmune disorders, malignant diseases, and parasitic diseases.

[0003] Rheumatoid arthritis ("RA") is an autoimmune disorder that can lead to joint destruction, deformation, and loss of function. The disease is usually characterized by swelling of the small joints, especially the hands and feet, but eventually most of the joints in the body can be affected. In addition to joint problems, other signs of the disease may be present, such as subcutaneous nodules, eye inflammation, low white blood cell count, and lung disease. Common symptoms include fatigue and joint stiffness, especially in the morning and after long periods of rest.

[0004] Currently, there is no known treatment for rheumatoid arthritis. In recent years, the availability of drugs that modify early disease onset and new classes of pharmacotherapy has significantly improved expected disease outcomes. The goals of rheumatoid arthritis treatment now aim to achieve the lowest possible level of disease activity and, if possible, remission, minimize joint damage, and improve physical function and quality of life. While certain classes of drugs are currently available in the field, there is a need for new drugs that can effectively treat or slow disease progression. [Overview of the Initiative]

[0005] The present invention relates to the treatment of responsive diseases by reducing the level of immunoglobulin G in subjects requiring such treatment.

[0006] In one embodiment, a method is provided for treating a disease that is responsive to such treatment by reducing the level of IgG, comprising administering to a subject in need of such treatment (i) a loading dose of a first agent for reducing the level of IgG by a desired amount; and (ii) a therapeutically effective dose of a second agent for treating the disease, wherein the second agent is an IgG degradation inducer.

[0007] In another embodiment, a method is provided for reducing the level of immunoglobulin G ("IgG") in a subject, comprising administering to the subject (i) a loading dose of a first agent for reducing the level of IgG by a desired amount; and (ii) one or more doses of a second agent for maintaining the level of IgG within a therapeutically effective range.

[0008] [Detailed description of the invention] The following detailed description is provided to assist those skilled in the art in carrying out the invention. Exemplary embodiments are described in detail hereafter in this specification. However, these embodiments are merely illustrative, and this disclosure is not limited thereto, but is defined by the scope set out in the appended claims. Those skilled in the art can make modifications and variations of the embodiments described herein without departing from the spirit or scope of this disclosure.

[0009] Accordingly, these embodiments are merely described below for the purpose of illustrating aspects of this specification by reference to structures and schemes. As used herein, the terms “and / or” include any and all combinations of one or more of the related enumerated items. The term “or” means “and / or.” Expressions such as “at least one” qualify the entire list of elements, but not the individual elements of the list, when placed before the list of elements.

[0010] Naturally, when an element is said to be "on top of" another element, it may be in direct contact with the other element, or there may be an intervening element between them. On the other hand, when an element is said to be "directly" on top of another element, there are no intervening elements present.

[0011] Naturally, terms such as first, second, third, etc., may be used herein to describe various elements, components, regions, layers, and / or areas, but these elements, components, regions, layers, and / or areas should not be limited by these terms. These terms are used exclusively to distinguish one element, component, region, layer, or area from another element, component, region, layer, or area. Accordingly, a first element, component, region, layer, or area discussed below may be referred to as a second element, component, region, layer, or area without departing from the teachings of this embodiment.

[0012] When the terms “comprises” and / or “comprising” or “includes” and / or “including” are used herein, they specify the existence of the features, regions, integers, processes, operations, elements and / or components described, but are understood not to exclude the existence or addition of one or more other features, regions, integers, processes, operations, elements, components and / or groups thereof.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing specific embodiments and is not intended to limit them. Furthermore, terms such as those defined in commonly used dictionaries should be interpreted as having the meaning consistent with their meaning in the context of the relevant art and this disclosure, and not in an idealized or overly formal sense unless such a definition is explicitly provided herein.

[0014] When used in this Application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are provided throughout this Application. If a term is not specifically defined herein, it shall be given the meaning known in the art to a person skilled in the art applying the term in context to its use in describing the Invention.

[0015] The indefinite articles "a" and "an," unless otherwise explicitly indicated by the context, refer to one or more (i.e., at least one) of the grammatical objects of the indefinite article. For example, "an element" means one or more elements.

[0016] As used herein, unless otherwise specified, the term “substituted” means a group or compound that is substituted for at least one hydrogen atom with deuterium, halogens (-F, -Cl, -Br, -I), hydroxyl groups (-OH), amino groups (-NH2), carboxyl groups (-CO2H), substituted or unsubstituted C1-C10 amino groups, nitro groups (-NO2), C1-C10 alkyl groups, C3-C10 cycloalkyl groups, C6-C12 aryl groups, C1-C10 alkoxy groups, C1-C10 trifluoroalkyl groups, such as trifluoromethyl groups (-CF3), or cyano groups (-CN).

[0017] Additional aspects are partially shown in the following description, and some will become clear from that description.

[0018] Starting materials useful for preparing the pharmaceutical compositions of the present invention are readily available on the market, or such materials can be prepared by those skilled in the art.

[0019] Solvates are compounds formed by solvation, which is a combination of solvent molecules and solute molecules or ions. Solvation is the interaction between a solute and a solvent that results in the stabilization of the solute species in solution. It can also refer to the solvated state in which ions in solution are complexed by solvent molecules. Different physical properties result from different solvates and their polymorphic forms, which in turn result in different orientations of neighboring molecules and intermolecular interactions 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.

[0020] In one embodiment, a method for treating rheumatoid arthritis is provided, comprising administering to a patient requiring such treatment a therapeutically effective dose of an immunoglobulin G ("IgG") molecular degradation inducer and an anti-arthritis agent.

[0021] In another embodiment, a pharmaceutical composition is provided comprising an immunoglobulin G degradation inducer and an anti-arthritis agent.

[0022] IgG degradation inducer In one embodiment, the IgG molecular degradation inducer ("IgG degradation inducer") has the following general chemical structure:

[0023] [ka] {In the structural formula, [CPBM] is an IgG-binding moiety (preferably a compound that selectively binds to IgG in the plasma of the subject or patient) that binds to IgG of the pathogenic type specified herein, which is related to and / or mediates the disease and / or is to be removed by the action of hepatocytes or other cells on circulating proteins; [CRBM] is a cell receptor binding moiety, preferably an [ASGPRBM] group, which is a binding moiety that binds to hepatocytes or other cells via the asialocrypoprotein receptor or other receptors specified herein, preferably on the surface of hepatocytes and other degradable cells in a patient or subject;

[0024] Each [CON] is a suitable connector chemical part that, if present, connects directly to the [CPBM] or [CRBM], or connects the [linker] to the [CPBM] or [CRBM]; The [linker] is a chemical moiety having a value of 1 to 15, covalently bonded to one or more [CRBM] and / or [CPBM] groups, optionally via [CON] groups containing [MULTICON] groups, and the [linker] itself may contain one or more [CON] or [MULTICON] groups; k' is an integer between 1 and 15; j' is an integer between 1 and 15; h and h' are each independent integers between 0 and 15; i L is an integer between 0 and 15; However, h, h' and i L At least one of them is provided to be at least 1. or its pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs. It may have.

[0025] Various IgG binding sites [CPBMs], cell receptor binding sites [CRBMs], and linking groups [linkers] and [CONs] are known in the art and are described, for example, in International Patent Publication No. WO2019 / 199634, published on October 17, 2019, and International Patent Publication No. WO2024 / 227119, published on October 31, 2024. The contents of these publications are incorporated herein by reference in their entirety.

[0026] In one embodiment of the above general chemical structure, [CPBM] has the following structure:

[0027] [ka] (v)PAM;D-PAM;D-PAM-Φ;TWKTSRISIF(SEQ ID NO: 1);FGRLVSSIRY(SEQ ID NO: 2);FcIII;FcBP-1;FcBP-2;Fc-III-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-L A peptide moiety selected from the group consisting of act-E] (sequence number 9); cyclo[(N-Ac)-Dap(A)-RWHYFK-Lact-E] (sequence number 10); cyclo[Link-M-WFRHYK] (sequence number 11); NKFRGKYK (sequence number 12); NARKFYKG (sequence number 13); FYWHCLDE (sequence number 14); FYCHWALE (sequence number 15); FYCHTIDE (sequence number 16); RRGW (sequence number 17); and KHRFNKD (sequence number 18). It may be an immunoglobulin G binding moiety [IgGBM] having; [CRBM] has the following structure:

[0028] [ka] which may be a cell receptor binding moiety having; each [CON], at each occurrence, independently,

Chemical Formula

Chemical Formula

[0029] In another embodiment, h and h' can be 1, 2, 3, 4, or 5, independently of each other.

[0030] In another embodiment, X 2 Each of these entities exists independently of CH2, NR 4 , or it could be C(O); R 1 It can be H; R 4 This can be H.

[0031] In another embodiment, Z B is non-existent or -C(O)-(CH2) IM - It is possible.

[0032] In another embodiment, [CPBM] has the following structure:

[0033] [ka] It could be [IgGBM]. In another embodiment, [CPBM] has the following structure:

[0034] [ka] It could be [IgGBM]. In another embodiment, [CPBM] has the following structure:

[0035] [ka] It could be [IgGBM]. In another embodiment, [CPBM] has the following structure:

[0036] [ka] It could be [IgGBM]. In another embodiment, [CPBM] has the following structure:

[0037] [ka] It could be [IgGBM].

[0038] In another embodiment, the compound has the structure: [ka] It may have. In another embodiment, the compound has the structure:

[0039] [ka] It may have. In another embodiment, the compound has the structure:

[0040] [ka] It may have.

[0041] In one embodiment, the IgG molecular degradation inducer ("IgG degradation inducer") has the following general chemical structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] One of them, or a pharmaceutically acceptable salt thereof It may have, in the formula, . In the above formula, “extracellular protein-targeting ligand” refers to an IgG-binding moiety [CPBM] or [IgGBM] (preferably a compound that selectively binds to IgG in the plasma of the subject or patient) that binds to IgG of the pathogenic type identified herein, which is related to and / or mediates the disease and / or is to be removed by the action of hepatocytes or other cells on circulating proteins.

[0042] In the above formula, X 1 O, S, N(R) 6 ), and C(R 4 )(R 4) are 1 to 5 bases selected independently from X 1 If there is one base, then X 1 O, S, N(R) 6 ), or C(R 4 )(R 4 ) and X 1 If there are two bases, X 1 One or fewer of the groups are O, S, or N(R) 6 ) and X 1 However, if there are 3, 4 or 5 bases, X 1 Two or fewer of the groups are O, S, or N(R) 6 ) and; R 2 teeth, (i) aryl, heterocyclic and heteroaryl rings containing an aryl and one or two heteroatoms independently selected from N, O and S, each of which may be substituted with one, two, three or four substituents; (ii) [ka] (iii) Each may be substituted with 1, 2, 3 or 4 substituents, -NR 8 -S(O)-R 3 , -NR 8 -C(S)-R 3 , -NR 8 -S(O)(NR 6 )-R 3 -N=S(O)(R 3 )2, -NR 8 C(O)NR 9 S(O)2R 3 , -NR 8 -S(O)2-R 10 , and -NR 8 -C(NR 6 )-R 3 ; and (iv) Hydrogen, R 10 , alkyl-C(O)-R 3 , -C(O)-R 3 , alkyl, haloalkyl, -OC(O)R 3 , and -NR 8-C(O)R 10 Selected from; R 10 These are aryl, alkyl-NR 8 -C(O)-R 3 , alkyl-aryl, alkyl-heteroaryl (having 1, 2, or 4 heteroatoms), alkyl-cyano, alkyl-OR 6 Alkyl-NR 6 R 8 , NR 8 -NR 6 -C(O)R 3 , NR 8 -S(O)2-R 3 , alkenyl, allyl, alkinyl, -NR 6 -alkenyl, -O-alkenyl, -NR 6 -alkynyl, -NR 6 -heteroaryl, -NR 6 - Selected from -aryl, -O-heteroaryl, -O-aryl, and -O-alkynyl, R 10 Each of these may be substituted with one, two, three, or four substituents; R 1 and R 5 These are independently hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0~C6 alkyl-S(O)2R 3 , C0~C6 alkyl-N(R 8 )-C(O)R 3 , C0~C6 alkyl-N(R 8 )-S(O)R 3, C0-C6 alkyl-N(R 8 )-C(S)R 3 , C0-C6 alkyl-N(R 8 )-S(O)2R 3 , C0-C6 alkyl-O-C(O)R 3 , C0-C6 alkyl-O-S(O)R 3 , C0-C6 alkyl-O-C(S)R 3 , -N=S(O)(R 3 )2, C0-C6 alkyl N3, and C0-C6 alkyl-O-S(O)2R 3 , each of which may be optionally substituted with 1, 2, 3 or 4 substituents; R 3 is, independently at each occurrence, selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 8 , and -NR 8 R 9 ; R 4 is, independently at each occurrence, selected from hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 ; R 6 and R 7 are, independently at each occurrence, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl, heterocycle, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R3 , and S(O)2R 3 Selected from; R 8 and R 9 Each element is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic elements; The ring is a 3- to 8-membered fused ring group, which may be substituted with 1, 2, 3, or 4 substituents; Each linker A The linker uses the ASGPR ligand. B A bond or part that connects two things by a covalent bond; Linker B is a linker A A bond or portion that covalently links to an extracellular protein-targeting ligand; Linker C Each linker A It is a chemical group that links to extracellular protein targeting ligands; Linker D Each linker A It is a chemical group that links to extracellular protein targeting ligands; Here, R 2 However, NR 6 -Alkenyl, -NR 6 -alkynyl, -NR 8 -C(O)R 10 , -NR 8 -S(O)2-alkenyl, -NR 8 -S(O)2-alkynyl, -NR 6 -heteroaryl, or -NR 6 - If it is an aryl ligand, the extracellular protein targeting ligand does not contain oligonucleotides; As appropriate substituents are added, as long as the valency allows, to produce stable compounds, such as alkyl, alkenyl, alkynyl, haloalkyl, and -OR 6 F, Cl, Br, I, -NR 6 R 7 , heteroalkyl, cyano, nitro, C(O)R 3 , [ka] Selected from. Various parts, [linker A ]...Linker B ]...Linker C ], [Linker D C ], [ring], and X 1 This is publicly known in the art, for example, in International Patent Publication No. WO2021 / 155317, published on 5 August 2021, and International Patent Publication No. WO2022 / 235699, published on 10 November 2022, and the contents of these published documents are incorporated herein by reference in their entirety.

[0043] loading dose A first agent suitable for use according to the present invention may be any agent effective in reducing the IgG level in a subject by a desired amount. The first agent may be the same as or different from the second agent, i.e., the IgG degradation inducer.

[0044] A first type of agent that can be used according to the present invention includes, for example, neonatal Fc receptors (FcRn) and enzymes.

[0045] Representative FcRn include efgultigimod alfa, rozanolixizumab, batoclimab, nipoclimab, and SYNT001. Efgultigimod is a modified human IgG1-derived Fc fragment with amino acid modifications, available from Argenx under the brand name Vyvgart. Rozanolixizumab is a humanized anti-FcRn monoclonal antibody for subcutaneous (SC) administration, available from UCB, Inc. under the brand name Rystiggo. Batoclimab is a fully human, IgG1 monoclonal anti-FcRn antibody under development by Immunovant Sciences GmbH, with its Fc portion modified to reduce antibody-dependent cell-mediated cytotoxicity. Nipoclimab is a deglycosylated, fully human, IgG1 monoclonal anti-FcRn antibody under development by Johnson & Johnson, exhibiting high affinity for FcRn. SYNT001 is a humanized, immunogenic, reduced-immunogenicity IgG4 monoclonal antibody containing the S241P mutation, currently under development by Alexion Pharmaceuticals, Inc.

[0046] Typical enzymes include cysteine ​​proteases such as immunofidase, which is a cysteine ​​protease derived from the immunoglobulin G-degrading enzyme of Streptococcus pyogenes and is available from Hansa Biopharma under the trademark name Idefirix.

[0047] disease Diseases suitable for treatment according to the present invention may be any disease that responds well to a reduction in IgG levels. Examples of such diseases include IgG myeloma, liver disease, sarcoidosis, chronic infection, autoimmune disorders, malignant diseases, and parasitic diseases. [Examples]

[0048] Utilizing new modalities that have the potential to transform the treatment of immunological and inflammatory disorders.

[0049] A Phase 1 clinical study in human subjects was conducted using an IgG degradation inducer (an ASGPR bispecific degradation inducer known as BHV-1300). Results in healthy subjects confirmed that BHV-1300 rapidly and selectively reduced IgG in a dose-dependent manner in the first three cohorts (see Figure 1). Preliminary IgG reduction data were consistent with preclinical experience-based models, and dose-dependent and time-dependent IgG reduction was observed even in the initial low-dose cohort. Some subjects experienced IgG reductions as low as 50–70% from baseline, even in these first three low-dose cohorts. The model suggests that additional cohorts in the Phase 1 study may achieve >70–80% reductions in IgG. BHV-1300 demonstrated IgG reduction without significant effects on LFT, albumin, or LDL cholesterol. BHV-1300 has so far been safe, well-tolerated, and has not shown any serious or severe adverse events. Most AEs were mild, appeared unrelated to the study drug, and resolved spontaneously. As expected from the molecular selectivity for IgG, there was no reduction in mean IgA, mean IgM, or mean IgE in the week following administration compared to placebo. No adverse trends were observed in vital signs or ECG. The Phase 1 SAD study is currently ongoing, and Cohort 4 is in progress. Given the levels of IgG reduction observed to date, we plan to have approximately six cohorts of BHV-1300. Given the promising results of the SAD study to date, the MAD study will proceed in patients with rheumatoid arthritis. Table 1B below lists the total IgG values ​​of subjects in clinical trials at 50 mg, 125 mg, and 250 mg doses at different time points.

[0050] [Table 1] [ka] Figure 1: Data show the rapid, dose-dependent, maximum mean reduction (% change from baseline) of IgG levels per cohort observed within 24 hours post-administration in the ongoing Phase 1 study of BHV-1300. IgG1-4 analyzed at Mayo Clinic Laboratories, Rochester MN.

[0051] Throughout this application, various published documents are referenced by author name and date, or by patent number or patent publication number. The disclosures of these published documents are incorporated into this application by reference in whole, so as to further illustrate the latest art known to those skilled in the art as of the date of the invention described herein and claimed herein. However, the references of references herein should not be construed as an admission that such references are prior art of the present invention.

[0052] Those skilled in the art will recognize a great many equivalents of the specific procedures described herein, or will be able to identify such equivalents using a number of experiments of a sort. Such equivalents are considered to be within the scope of the present invention and are covered by the subsequent claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and examples herein may be used. Furthermore, it is intended that specific items within the list of items, or subsets of items within a larger group of items, may be combined with other specific items, subsets of items, or larger groups of items, whether or not such combinations are specifically disclosed herein.

Claims

1. A method for treating a disease sensitive to a response by reducing the level of immunoglobulin G ("IgG"), comprising the steps of administering to a subject requiring such treatment (i) a loading dose of a first agent to reduce the level of IgG by a desired amount; and (ii) a therapeutically effective dose of a second agent for treating the disease, wherein the second agent is an IgG degrader.

2. The method according to claim 1, wherein the desired amount is about 20-99% of the baseline IgG level of the subject before administration of the first drug.

3. The method according to claim 2, wherein the desired amount is about 40-99% of the baseline IgG level of the subject before administration of the first drug.

4. The method according to claim 3, wherein the desired amount is about 60-99% of the baseline IgG level of the subject before administration of the first drug.

5. The method according to claim 1, wherein the IgG% level in the subject before administration of the second drug is less than 90% of the baseline IgG level in the subject before administration of the first drug.

6. The method according to claim 5, wherein the IgG% level in the subject before administration of the second drug is less than 70% of the baseline IgG level in the subject before administration of the first drug.

7. The method according to claim 6, wherein the IgG% level in the subject before administration of the second drug is less than 50% of the baseline IgG level in the subject before administration of the first drug.

8. The method according to claim 1, wherein the IgG% level in the subject before administration of the second drug is less than 1500 mg / dL.

9. The method according to claim 8, wherein the IgG% level in the subject before administration of the second drug is less than 1000 mg / dL.

10. The method according to claim 9, wherein the IgG% level in the subject before administration of the second drug is less than 800 mg / dL.

11. The method according to claim 10, wherein the IgG% level in the subject before administration of the second drug is less than 600 mg / dL.

12. The method according to claim 1, wherein the first drug is neonatal Fc receptor (FcRn).

13. The method according to claim 12, wherein the FcRn is selected from efgartigimod alpha, rozanolixizumab, batoclimab, nipocalimab, and SYNT001.

14. The method according to claim 1, wherein the first drug is an enzyme.

15. The method according to claim 14, wherein the enzyme is a cysteine ​​protease.

16. The method according to claim 14, wherein the c-cysteine ​​protease is an imlifidase.

17. The method according to claim 1, wherein the second agent is an IgG degrading agent.

18. The method according to claim 17, wherein the IgG degrading agent has the following structure: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1, wherein the first drug is an IgG degrading agent.

20. The method according to claim 19, wherein the IgG degrading agent has the following structure: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

21. A method for reducing the level of immunoglobulin G ("IgG") in a subject, comprising the steps of (i) administering a loading dose of a first agent to reduce the level of IgG by a desired amount; and (ii) administering one or more doses of a second agent to maintain the level of IgG within a therapeutically effective range to the subject.

22. The method according to claim 21, wherein the therapeutic range is about 20 to 99% of the baseline IgG level of the subject before administration of the first drug.

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