Fully human post-translationally modified antibody therapeutics

Abstract

To provide methods and compositions for the delivery of fully human post-translationally modified therapeutic monoclonal antibodies and antigen-binding fragments thereof.SOLUTION: The fully human post-translationally modified therapeutic monoclonal antibodies are delivered by gene therapy methods, in particular as recombinant adeno-associated virus (rAAV) vectors, to the appropriate tissue. Methods of manufacturing the AAV vectors, pharmaceutical compositions, and methods of treatment are also provided. In addition, methods of producing therapeutic antibodies that are "biobetters" as fully human post-translationally modified therapeutic antibodies are provided. These fully human post-translationally modified therapeutic antibodies can be administered to a subject in need of treatment with the therapeutic antibody.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] 0. Sequence Listing This application has been filed electronically in ASCII format and is incorporated by reference in its entirety. Contains a sequence listing incorporated herein at The ASCII copy is named 38013_0001P1_SL.txt and contains 69 It is 0.185 bytes in size.

[0002] 1. Introduction a fully human post-translationally modified (HuPTM) therapeutic monoclonal antibody ("mAb"), or HuPTM antigen-binding fragments of therapeutic mAbs (e.g., fully human glycosylated fragments of therapeutic mAbs) The antibody (HuGly) Fab) is used to diagnose a disease or condition that is amenable to treatment with a therapeutic mAb. Compositions and methods for delivering steroid hormone-lowering drugs to transfused human subjects are described. [Background technology]

[0003] 2. Background of the invention Therapeutic mAbs have been shown to be effective in treating a number of diseases and conditions. However, these drugs are only effective for a short time, so they are not suitable for long-term use. Repeated injections are required, which often results in a significant treatment burden for the patient . Summary of the Invention

[0004] 3. Summary of the Invention HuP™ mAb or a HuP™ antigen-binding fragment of a therapeutic mAb (e.g., a therapeutic The fully human glycosylated Fab (HuGlyFab) of the mAb was prepared by treatment with the therapeutic mAb. a composition for delivery to a patient (human subject) diagnosed with a disease or condition for which the device is indicated. Such antigen-binding fragments of therapeutic mAbs include Fab, F, and (ab')2, or scFv (single chain variable fragment) (referred to herein as "antigen-binding fragment" As used herein, "HuP™ Fab" refers to any mAb or other fragment thereof. It may comprise an antigen-binding fragment. In an alternative embodiment, a full-length mAb may be used. Delivery can be via gene therapy, for example, delivery of a therapeutic mAb or antigen-binding fragment thereof (or a viral vector or other DNA encoding the The expression construct is administered to a patient (human subject) diagnosed with a condition for which treatment with a therapeutic mAb is indicated. to induce the production of a HuPTM mAb or an antigen-binding fragment of a therapeutic mAb, e.g., a human mAb. The glycosylated transgene product is then bound to a mAb or antigen-binding fragment thereof to exert its therapeutic effect. Create a permanent depot within a patient's tissue or organ that provides a continuous supply of targeted tissue. This can be advantageously achieved by:

[0005] Transgene-encoded HuPTM mAb or HuPTM antigen-binding The fragments are Nervous system targets, e.g., solanezumab, GSK, indicated for the treatment of Alzheimer's disease 933776, and lecanemab (see Figures 2A-2C). Amyloid beta (Aβ or Aβ) peptide; AL-001 for treating frontotemporal dementia (FTD) (see Figure 3); Sortilin, including but not limited to (see references); for treating tauopathies ABBV-8E12, UCB-0107, and NI-105 (BIIB076) (Figure 4 A-4C), including but not limited to Alzheimer's disease, progressive neurodegenerative disorders, Epiphysial paralysis, frontotemporal dementia, chronic traumatic encephalopathy, Pick's complex, primary age-related tauopathy Tau proteins involved in tauopathies, including Huntington's disease and juvenile Huntington's disease VX15 / 2503 (see Figure 5) for treating leishmaniasis. including, but not limited to, SEMA4D; for treating Parkinson's disease and synucleinopathies Prasinezumab, NI-202 (BIIB054), and MED-1341 (Figure 6A-C) α-synuclein; ALS and Alzheimer's disease; NI-204 (see Figures 7A and 7B) for treating Immersion disease. including, but not limited to, superoxide dismutase-1 (SOD-1); and migraine and eptinezumab, fremanezumab, and galcanezumab for treating cluster headaches. CGRP receptors, including but not limited to (see Figures 8A-C); ·Ocular anti-angiogenic targets, diabetic retinopathy (DR), myopic choroidal neovascularization (mCNV) Sebaciza for treating retinal disorders including age-related macular degeneration (AMD), and macular edema - Patent Application 20090223933 VEGF (vascular endothelial growth factor) inhibitors, including but not limited to, vasculitic acid inhibitors (e.g., vasculitic acid inhibitors), and vasculitic acid inhibitors (e.g., vasculitic acid inhibitors), ... factors), including but not limited to; retinal vein occlusion (RVO), wet AMD, and macular edema, and LKA-651 (see Figures 9B and 9C). erythropoietin receptor; dry AMD solanezumab, GSK933776, or lecanemab to treat lecanema (Figure 2A-2C amyloid precursor protein (APP), including but not limited to, ), amyloid beta (Aβ or Aβ) peptide; a cause of neovascular age-related macular degeneration Including but not limited to ascumarin (see Figure 10A) where treatment is indicated activin receptor-like kinase 1 (ALK1); dry AMD and non-infectious bronchitis Tesidolumab and ravulizumab (see Figures 10B and 10D) are indicated for the treatment of uveitis. Complement component 5 (C5), including but not limited to, due to increased angiogenesis Carotuximab (Figure 10C) is indicated for the treatment of wet AMD and other retinal disorders. ), endoglin (END or CD105 ); ANX-007 (see Figure 11), which is indicated for the treatment of glaucoma. Complement component 1Q (C1Q), including but not limited to: diabetic retinopathy and diabetic macular edema and lanthanum, including but not limited to plasma kallikrein (pKal), for the treatment of Human complement proteins, including but not limited to, delumab (see Figure 19) plasma protein targets such as; Includes ravulizumab, which is indicated for the treatment of myasthenia gravis (see Figure 10D) including but not limited to, complement component 5; Adalim is indicated for the treatment of non-infectious uveitis (see Figures 12A-C). Mab (HUMIRA®), infliximab (REMICADE®) ), and TNF-α, including but not limited to golimumab; including elezanumab (see Figure 13) for treating multiple sclerosis Repulsive guidance molecule-A, including but not limited to; NI-301 and PRX-004 (Fig. 14A and Transthyretin (TTR), including but not limited to (see also Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor (FGF); Indicated for the treatment of fibrotic diseases (e.g., diabetic nephropathy, hepatic fibrosis, idiopathic pulmonary fibrosis) and connective tissue components, including but not limited to pamrevlumab (see Figure 15), which long factor (CTGF); Neuromyelitis optica (NMO) / non-infectious uveitis targets, e.g., NMO, DR, DME , and satralizumab, sarilumab, siltuki, which are indicated for the treatment of non-infectious uveitis. Cimab, clazakizumab, sirukumab, olokizumab, gerilizumab, and tocilizumab The TNF-α targets described above, including but not limited to, TNF-α antibodies (see Figures 16A-H), Targeted antibodies, and interleukin 6 (IL6)- and interleukin 6 receptor (IL6 R)-targeting antibodies; as well as inebilizumab (see Figure 16I) indicated for the treatment of NMO. including, but not limited to, CD19; Immune response targets, e.g., cytokine release syndrome, associated with bacterial or viral infections and administration with immune-modulating agents such as CAR-T and other cell-based therapies are indicated for the treatment of adverse immune responses, such as those indicated for the treatment of steroid-resistant strains, such as satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilimu- zumab, and Interleukin-11b (IL-11b) and tocilizumab (see Figures 16A-H) are examples of interleukin-11b (IL-11b) inhibitors. Interleukin 6 (IL6)- and interleukin 6 receptor (IL6R)-targeting antibodies, and counteract, reduce, or ameliorate the adverse immune responses associated with such therapies. immuno-oncology agents; etrolizumab, which is indicated for the treatment of ulcerative colitis and Crohn's disease (see Figure 17) including but not limited to integrin β7; Romosozumab (EVE) is indicated for the treatment of osteoporosis and abnormal bone loss or bone weakness. and other similar applications, including but not limited to, scrubs, scrubs, and scrubs. Rerostin; Plasma protein targets, e.g., hereditary angioedema, and diabetic retinopathy and diabetes and / or plasma kallikrein for treating ocular indications including chronic macular edema. human complement inhibitors, including but not limited to lanadelumab (see Figure 19) Protein; and Anti-IL and IL-receptor and other targets for autoimmune, respiratory and allergic diseases Antibodies, including but not limited to, for example, benralizumab (see Figure 29A) , interleukin 5 (IL5); reslizumab (see Figure 29B). These include, but are not limited to, interleukin-5 receptor (IL5R); tralokinumab (Figure 29 Interleukin 13 (IL13), including but not limited to, Interleukin-1 (IL-1)-1 (IL-1)-2 (IL-1)-3 (IL-1)-4 (IL-1)-5 (IL-1)-6 (IL-1)-7 (IL-1)-8 (IL-1)-9 (IL-1)-10 (IL-1)-11 (IL-1)-12 (IL-1)-13 (IL-1)-14 (IL-1)-15 (IL-1)-16 (IL IL-31 receptor alpha (IL-31RA); omalizumab (see Figure 29E) including, but not limited to, immunoglobulin E (IgE); and tezepelumab (Figure 29F thymic stromal lymphopoietin (TSLP), including but not limited to thymic stromal lymphopoietin (TSLP), see ) These may include, but are not limited to, full length therapeutic antibodies or antigen-binding fragments thereof that bind to .

[0006] The recombinant vector used to deliver the transgene is a non-replicating recombinant adenovirus. However, lentiviral vectors include recombinant adenovirus vectors ("rAAV"). , vaccinia virus vectors, or non-viral vectors, referred to as "naked DNA" constructs. Other viral vectors may also be used, including but not limited to, viral expression vectors. Transgene expression can be regulated by constitutive or tissue-specific expression control elements. It can be controlled by a control element.

[0007] The gene therapy construct is designed to express both the heavy and light chains. The coding sequence for the light chain produces a heavy chain having a distinct heavy chain polypeptide, and a light chain polypeptide. The heavy and light chains are separated by a cleavable linker or IRES, allowing expression of a single In certain embodiments, the coding sequence can be engineered into a Fab or In certain embodiments, the full-length antibody fragment encodes a F(ab')2 or scFv. In another embodiment, the construct expresses a heavy chain variable domain and a full-length light chain. The scFvs are expressed with the variable domains connected via a flexible, non-cleavable linker. In certain embodiments, the construct comprises, from the N-terminus, NH2-V L -Linker-V H -CO OH or NH2-V H -Linker-V L -COOH is expressed.

[0008] Therapeutic antibodies delivered by gene therapy dissipate over time, resulting in peak exceeding injected or infused therapeutic antibodies, resulting in peak and trough levels It has several advantages: Sustained expression of the antibody ensures that more consistent levels of antibody are present at the site of action. This reduces the risk to the patient and increases convenience because fewer injections are required. Furthermore, antibodies expressed from transgenes contain co- and post-translational components. Due to the different microenvironment, antibodies are post-translationally modified differently than those injected directly. Without being bound by any particular theory, this is because the antibody delivered to the site of action Compared to directly injected antibodies, they have different diffusion characteristics, bioactivity, and are therefore "bio-better." The resulting antibody has the following characteristics: specificity, distribution, affinity, pharmacokinetics, and immunogenicity. and bring about.

[0009] In addition, antibodies expressed from transgenes in vivo can be synthesized by the synthesis of proteins. Degradation products associated with recombinantly produced antibodies, such as aggregation and protein oxidation Aggregation is unlikely to occur due to high protein concentrations, surface interactions with manufacturing equipment and vessels. and associated with protein production and storage due to purification involving certain buffer systems. These conditions that promote aggregation are a problem for transgenes in gene therapy. Oxidation, such as oxidation of methionine, tryptophan, and histidine, is absent in the expression of Also related to protein production and storage are stress conditions in cell culture, metals and air. In vivo, this is caused by contact with the Proteins expressed from transgenes can also be oxidized under stress conditions. However, humans and many other organisms are equipped with antioxidant defense systems. Not only do they reduce oxidation, but in some cases they also repair and / or reverse oxidation. Therefore, proteins produced in vivo are unlikely to be in an oxidized form. Both aggregation and oxidation affect efficacy, pharmacokinetics (clearance), and immunogenicity. It is possible.

[0010] Pharmaceutical compositions suitable for administration to human subjects may contain physiologically compatible aqueous buffers, surfactants, and optional excipients in a formulation buffer.

[0011] The present invention is based in part on the following principles: (i) Currently available mAb therapeutics include IgG1, IgG2, and IgG4. immunoglobulin G (IgG) isotype, which generally have a slower clearance rate It has pharmacokinetic (PK) characteristics such as slow release, extended half-life, and limited tissue distribution. Following administration, the typical serum PK profile of a mAb consists of a rapid distribution phase and a slow elimination phase. and to maintain the dose needed to treat chronic conditions. In addition, the distribution of mAbs is generally limited by their large size. Because of their high molecular weight and hydrophilicity, mAbs are restricted to the intravascular and interstitial spaces. The extent of tissue distribution generally ranges from about 5 to 15%, except in the brain where it is extremely low ( See, e.g., Kamath, 2016, incorporated herein by reference in its entirety. ,Drug Discovery Today:Technologies 21-22 :75-83). The sustained production of TM Fab avoids repeated administration and the short time it takes to achieve efficacy with other methods. The described administration method allows for the use of Fabs with excessive systemic half-lives; Allows direct access to target tissues, such as the brain, where high-dose delivery to the tissue can be achieved. do. (ii) The Fab region of many therapeutic mAbs possesses glycosylation sites. For example, Consensus and non-consensus asparagine residues within the Fab region of a particular therapeutic mAb The glycosylation site is glutamine ("Q"), which is a glycosylation site. ") residues are identified and highlighted in blue and green, respectively, Figures 2A-2C, 3, 4A-4C , 5, 6A~6C, 7A~7B, 8A~8C, 9A~9C, 10A~10D, 11, 12 A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 2 9A-29F (e.g., for identifying N-linked glycosylation sites within antibodies). Valliere-Doug, each of which is incorporated by reference in its entirety. lass et al.,2009,J.Biol.Chem.284:32493-3 2506; and Valliere-Douglass et al., 2010, JB (See Biol. Chem. 285:16012-16022). In addition, Glycosylation is the enzymatic addition of N-acetylgalactosyltransferase to serine or threonine residues. The amino acid residues in the hinge region of the antibody are O-glycosylated. Again, E. coli is a naturally occurring bacterium. However, because they do not contain the machinery equivalent to that used in human O-glycosylation (alternatively In E. coli, O-glycosylation occurs when the bacterium specifically binds to a specific O-glycosylating agent. It has been demonstrated that the mechanism is limited to those modified to contain the Fa rid-Moayer et al.,2007,J.Bacteriol.189:8 (See, e.g., 088-8098), the possibility of O-glycosylation is presented herein. Therapeutic antibodies produced in Escherichia coli (E. coli) are compared to antigen-binding fragments, for example. Furthermore, the Fab antigen can be used to engineer hyperglycosylated variants. The amino acid sequence can be modified (e.g., as shown in Figures 20A and 20B) for therapeutic antibodies. amino acid substitutions that can be made to engineer hyperglycosylated Fab regions of the antibody; as well as full-length antibodies; Description of antibody derivatives with hyperglycosylation on the Fab domain. Courtois et al., which is incorporated herein by reference in its entirety. l., 2016, mAbs8:99-112). (iii) In addition to glycosylation sites, the Fab region contains nucleotides within or near the CDRs. The Fab region of certain therapeutic mAbs may contain lysine ("Y") sulfation sites. Identifying tyrosine-O-sulfation sites, Figures 2A-2C, 3, 4A-4C, 5, and 6A-6C , 7A~7B, 8A~8C, 9A~9C, 10A~10D, 11, 12A~12C, 13 See 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F. (e.g., tyrosine sulfation of proteins) For an analysis of hydroxycarboxylic acids, see Yang et al., which is incorporated by reference in its entirety. l., 2015, Molecules 20:2138-2164 (especially page 2154) (See ). The "rules" can be summarized as follows: Position within +5 to -5 from Y. In this case, the position -1 from Y is a neutral or acid residue. It is a charged amino acid and a basic amino acid, e.g., R, K, or is not H. (iv) Human cells, Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7 B, 8A~8C, 9A~9C, 10A~10D, 11, 12A~12C, 13, 14A~ 14B, 15, 16A-16I, 17, 18, 19, and 29A-29F Glycosylation of the Fab region (see Figure 22 and Table 7), such as glycosylation, Improve the stability, half-life, and reduce undesired aggregation and / or immunogenicity of the gene product. This would result in the addition of glycans that may reduce the For a review of the emerging importance of,Bovenkamp et al.,2016,J. Immunol. 196:1435-1441; and conjugated to HuGlyFab Figure 22 (Bondt et al., 2014, Mol & Cel (See Proteomics 13.1:3029-3039). The Fab and Fc portions of the antibody differ in galactosylation, sialylation, and branching of the Fab glycans ( For example, bisecting GlcNAc) and Fc glycans have a high degree of fucosylation. have been shown to have significantly different glycosylation patterns (e.g., See, e.g., the disclosure of N-glycans associated with Fabs, which is incorporated herein by reference in its entirety. Bondt et al., 2014, Mol. & C ell. Proteomics 13.11:3029-3039). (v) The glycans added to the HuPTM mAb and HuGlyFab of the present invention are It is known that the N-glycans are highly processed complex N-glycans containing 6-sialic acid. Such glycans are (a) therapeutically active compounds produced in Escherichia coli (E. coli). (b) in mAb (totally unglycosylated); ... C lacks the 2,6-sialyltransferase required to add the sialyl acid. in therapeutic antibodies produced in HO cells; or (c) in the predominant human sialic acid, N-sialic acid. It is not cetylneuraminic acid ("Neu5Ac"), which is not naturally occurring in humans (and has potential (which is immunogenic), N-glycosylneuraminic acid ("Neu5Gc" or "Neu Gc") into therapeutic antibodies produced in CHO cell lines or mouse cell lines. For example, the following are incorporated herein by reference in their entireties: Dumont et al.,2015,Crit.Rev.Biotechnol.3 6(6):1110-1122;Huang et al.,2006,Anal.Bi ochem.349:197-207 (NeuGc is a soluble form of SP2 / 0 and NS0 in mice. (Song et al., 2014, An See al. Chem. 86:5661-5666. (vi) Human glycosylation patterns of the HuPTM mAbs and HuGlyFabs of the invention The vaccine should reduce the immunogenicity and improve the efficacy of the transgene product. When the antigen-binding fragment used according to the method described in 2. is expressed in a human target cell , in a prokaryotic host cell (e.g., E. coli), or in a eukaryotic host cell (e.g., In vitro in CHO cells or mouse NS0 or SP2 / 0 cells Importantly, the need for the production of ribosomal proteins is avoided. As a result of the methods used (e.g., the use of human target cells expressing antigen-binding fragments), The N-glycosylation sites of the full-length antibodies and antigen-binding fragments are relevant for human treatment, and For example, (a) CHO cells can be used to decorate certain glycans. The components required for the addition of glycans (e.g., 2,6 sialic acid and branched GlcNAc) (b) CHO cells and mouse cells (NS0 cells and SP2 / 0 cells) lack Neu5 (c) Neu5Gc is added as the sialic acid, which is not typical for humans, instead of Ac; CHO cells react with anti-α-Gal antibodies present in most individuals, and at high concentrations It also produces α-Gal antigen, an immunogenic glycan that can induce anaphylaxis. (e.g., Bosques, 2010, Nat. Biotech. 28:1153- 1156); and (d) E. coli naturally produces N-glucan. This advantage is due to the absence of components required for glycosylation in CHO cells, mouse Utilizing Escherichia coli (E. coli) or Escherichia coli (E. coli) in the production of antibodies / antigen-binding fragments. If the target is met, it will not be achieved. (vii) Figures 2A~2C, 3, 4A~4C, 5, 6A~6C, 7A~7B, 8A~8C , 9A~9C, 10A~10D, 11, 12A~12C, 13, 14A~14B, 15, Tyrosine sulfation (multiple) shown in 16A-16I, 17, 18, 19, and 29A-29F Tyrosine sulfation of the Fab region contributes to their synthesis (a robust post-translational process in many human cells). Resulting in a transgene product with increased avidity for the molecular target In fact, tyrosine sulfation of the Fab of an antibody affects the avidity and It has been shown that ATP dramatically increases the activity of ATP-dependent agonists (e.g., Loos et al., 2014). 15, PNAS112:12675-12680; and Choe et al., 200 3, Cell 114:161-170). Such post-translational modifications are Produced in E. coli (a host lacking the enzymes required for tyrosine sulfation) It is not present on therapeutic antibodies and is present, at most, to a lesser extent in therapeutic mAbs made in CHO cells. CHO cells are not secretory cells and have no posttranslational tyrosine sulfation capacity. Limited (e.g., Mikkelsen & Ezban, 1991, Biochem See the discussion at p. 1537, especially p. 30:1533-1537. stomach).

[0012] For the reasons mentioned above, the generation of HuPTM mAb or HuPTM Fab is a promising approach for gene therapy. For example, a therapeutic mAb, full-length HuPTM mAb, or HuPTM Fab can be synthesized via A viral vector or other DNA expression construct encoding this mAb is used. administered to a patient (human subject) diagnosed with a disease, and the subject is treated with the transduced cells of the subject. A sustained supply of human glycosylated, sulfated transgene products produced by "Bio-better" molecules for the treatment of diseases achieved by creating permanent depots - Patent Application 20070122999 For HuPTM mAb or HuPTM Fab The cDNA constructs are required for proper co-processing and post-translational processing by transduced human cells. Contains a signal peptide that ensures processing (glycosylation and protein sulfation) It should be.

[0013] As an alternative or additional treatment to gene therapy, full-length HuTPM mAb or H uPTM Fab is produced in a human cell line using recombinant DNA technology, and the glycoprotein is delivered to the patient. It can be administered to

[0014] The methods of the invention are useful for delivering full-length HuPTM mAbs or HuPTM Fabs to patients. , including combination therapy with the administration of other available treatments. It may be administered prior to, concurrently with, or subsequent to treatment with a therapy. may include, but is not limited to, combination therapy with therapeutic mAbs.

[0015] Also provided are methods for producing viral vectors, particularly AAV-based viral vectors. In a specific embodiment, a method for producing a recombinant AAV is provided, comprising: R, and the cis expression cassette is expressed by the trans gene in human cells. a gene encoding a therapeutic antibody operably linked to an expression control element that controls the expression of the gene; and an artificial genome containing a transgene; a transgene expression cassette lacking AAV ITRs. In cultured host cells, AAV rep proteins and AAV capsid proteins and driving expression of the rep protein and the ca The AAV rep protein and AAV capsid protein are supplied in trans. and a trans-expression cassette encoding the AAV capsid protein; Adenoviral helper vectors sufficient to allow replication and packaging of the artificial genome. and culturing a host cell containing the artificial genome; and and recovering the encapsidated recombinant AAV.

[0016] The present inventors have also shown that full-length antibodies can be expressed from AAV-based vectors. (See Examples 36 and 37.) The nucleotide sequence can be codon optimized for expression in human cells, and the sequence Therefore, the number of CpG dimers in the full-length heavy chain (Fc and an AAV vector expressing a transgene encoding a light chain (including a domain). Compositions are provided. Methods of administration and manufacture are also provided. 3.1 Exemplary Embodiments composition 1. Alzheimer's disease (AD), frontotemporal dementia (FD), tauopathy, progressive nuclei Epigastric paralysis, chronic traumatic encephalopathy, Pick's complex, and primary age-related tauopathy, Huntington's disease Huntington's disease, juvenile Huntington's disease, Parkinson's disease, synucleinopathy, ALS, migraine, or Alzheimer's disease (AD), frontal lobectomy in a human subject in need of treatment for cluster headache. Temporal dementia (FD), tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, Pick's complex , and primary age-related tauopathies, Huntington's disease, juvenile Huntington's disease, Parkinson's disease Pharmaceutical compositions for treating Son's disease, synucleinopathy, ALS, migraine, or cluster headache A composition comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrh10 capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid or a virus that is at least 95% identical to the amino acid sequence of the AAVcy5 capsid Ruscapsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; transgenes in human CNS cells, human liver cells, and / or human muscle cells. an anti-amyloid gene operably linked to one or more regulatory sequences that control gene expression; β (anti-Aβ), anti-sortilin, anti-tau protein (anti-tau), anti-semaphorin 4D (anti-S EMA4D), anti-α-synuclein (anti-SNCA), anti-superoxide dismutase -1 (anti-SOD1) or anti-calcitonin gene-related peptide receptor (anti-CGRPR) monoclonal antibodies A monoclonal antibody (mAb), or an antigen-binding fragment thereof, substantially full-length or full-length mAb. the artificial genome encoding b; an adeno-associated virus (AAV) vector having The AAV vector is formulated for administration to the subject, and optionally, administration is by intrathecal administration. The pharmaceutical composition is administered intravenously, intravenously, subcutaneously, intranasally, or intramuscularly. 2.The anti-Aβ mAb is solanezumab, lecanemab, or GSK933776. the anti-sortilin mAb is AL-001; the anti-tau mAb is ABBV-8E12; UCB-0107, or NI-105 (BIIB076); anti-SEMA4D m Ab is VX15 / 2503; anti-SNCA mAb is prasinezumab, NI-2 02 (BIIB054), or MED-1341; anti-SOD1 mAb is NI -2041.10D12 or NI-204.12G7; and anti-CGRPR mA b is eptinezumab, fremanezumab, or galcanezumab. Pharmaceutical compositions. 3. The antigen-binding fragment is a Fab, F(ab')2, or single-chain variable domain (sc 3. The pharmaceutical composition according to item 1 or 2, wherein the IgG1A-binding domain is Fv). 4. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 1, and optionally 290, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 290, and a light chain having the amino acid sequence of SEQ ID NO:2; or the amino acid sequence of SEQ ID NO:3, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:291, and an amino acid sequence of SEQ ID NO:4; a light chain having the amino acid sequence of SEQ ID NO: 360; or a light chain having the amino acid sequence of SEQ ID NO: 3 a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 361; a light chain having the amino acid sequence of SEQ ID NO: 5, and optionally an IgG1 isoform a heavy chain having an Fc polypeptide of the type (e.g., the amino acid sequence of SEQ ID NO: 283), and and a light chain having the amino acid sequence of SEQ ID NO: 6; or the amino acid sequence of SEQ ID NO: 7, and optionally and an Fc polypeptide of the IgG4 isotype (e.g., the amino acid sequence of SEQ ID NO: 285). a heavy chain having the amino acid sequence of SEQ ID NO: 8, and a light chain having the amino acid sequence of SEQ ID NO: 9; and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 292. a heavy chain having the amino acid sequence of SEQ ID NO: 10, and a light chain having the amino acid sequence of SEQ ID NO: 11; sequence, and optionally, of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283). a heavy chain having an Fc polypeptide and a light chain having the amino acid sequence of SEQ ID NO: 12; or The amino acid sequence of SEQ ID NO: 13, and optionally an IgG4 isotype (e.g., SEQ ID NO: 2 a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 14; a light chain having the amino acid sequence of SEQ ID NO: 15, and optionally, the amino acid sequence of SEQ ID NO: 293; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 16; or a light chain having the amino acid sequence of SEQ ID NO: 17, and optionally an IgG1 isotype ( For example, a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 283, and a light chain having the amino acid sequence of SEQ ID NO: 18; or the amino acid sequence of SEQ ID NO: 19, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 294, and a light chain having the amino acid sequence of SEQ ID NO: 21; or the amino acid sequence of SEQ ID NO: 22, and optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 295, and a light chain having the amino acid sequence of SEQ ID NO: 23, and optionally, an IgG1 a heavy chain having an Fc polypeptide of the isotype (e.g., the amino acid sequence of SEQ ID NO: 283); a light chain having the amino acid sequence of SEQ ID NO: 24; or a light chain having the amino acid sequence of SEQ ID NO: 25 and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 296; and a light chain having the amino acid sequence of SEQ ID NO: 26; or the amino acid sequence of SEQ ID NO: 27, and and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 297; and a light chain having the amino acid sequence of SEQ ID NO: 28; or the amino acid sequence of SEQ ID NO: 29, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 298, and the sequence 4. The pharmaceutical composition according to any one of items 1 to 3, comprising a light chain having the amino acid sequence of No. 30. thing. 5. The transgene encodes a heavy chain comprising the nucleotide sequence of SEQ ID NO: 71, and the nucleotide sequence of SEQ ID NO: 72 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 73 encoding the heavy chain 73, and the nucleotide sequence encoding the light chain, SEQ ID NO: 74 or the nucleotide sequence of SEQ ID NO: 376 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 376 encoding the light chain nucleotide sequence of SEQ ID NO: 377; or the nucleotide sequence of SEQ ID NO: 75 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 76, encoding the nucleotide sequence of the light chain; or SEQ ID NO: 77 and a light chain having the nucleotide sequence of SEQ ID NO: 78. a heavy chain having the nucleotide sequence of SEQ ID NO: 79, and a nucleotide sequence of SEQ ID NO: 80 a light chain having the nucleotide sequence of SEQ ID NO: 81; or a heavy chain having the nucleotide sequence of SEQ ID NO: 8 a light chain having the nucleotide sequence of SEQ ID NO:2; or a heavy chain having the nucleotide sequence of SEQ ID NO:83. a light chain having the nucleotide sequence of SEQ ID NO: 84; or a light chain having the nucleotide sequence of SEQ ID NO: 85 a heavy chain having the nucleotide sequence of SEQ ID NO: 86, and a light chain having the nucleotide sequence of SEQ ID NO: 87; or a heavy chain having the nucleotide sequence of SEQ ID NO: 87, and a or a heavy chain having the nucleotide sequence of SEQ ID NO: 89, and a light chain having the nucleotide sequence of SEQ ID NO: 90. a light chain having the nucleotide sequence of SEQ ID NO: 91; or a heavy chain having the nucleotide sequence of SEQ ID NO: 92; a light chain having the nucleotide sequence of SEQ ID NO: 92; or the nucleotide sequence of SEQ ID NO: 93 and a light chain having the nucleotide sequence of SEQ ID NO: 94; or SEQ ID NO: 95 a heavy chain having the nucleotide sequence of SEQ ID NO: 96; and a light chain having the nucleotide sequence of SEQ ID NO: 97; or a heavy chain having the nucleotide sequence of SEQ ID NO: 97 and a nucleotide sequence of SEQ ID NO: 98 a light chain having the nucleotide sequence of SEQ ID NO: 99; or a heavy chain having the nucleotide sequence of SEQ ID NO: 5. The pharmaceutical composition of item 4, comprising a light chain having a nucleotide sequence of 100. 6. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, and Item 1 to 5, wherein the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 5. A pharmaceutical composition according to any one of claims 4 to 4. 7. The transgene is capable of secreting and expressing the transgene in the human CNS cells, muscle cells, or hepatic cells. and signaling genes at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-translational modification. 7. The pharmaceutical composition according to any one of items 1 to 6, wherein the pharmaceutical composition encodes a nucleotide sequence. 8. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 14 6), or a signal sequence according to Table 2. 9. The method according to any one of items 1 to 8, wherein the AAV capsid is AAV8 or AAV9. The pharmaceutical composition described above. 10. Diabetic retinopathy, myopic choroidal neovascularization (mCNV), macular degeneration (e.g. neovascular (wet) or dry age-related macular degeneration (nAMD)), macular edema (e.g., Macular edema after retinal vein occlusion (RVO) or diabetic macular edema (DME), retinal veins ocular obstruction, diabetic retinopathy (DR), non-infectious uveitis, or glaucoma, or retinal abnormalities diabetic retinopathy in a human subject in need of treatment for a retinal disorder involving abnormal angiogenesis; Myopic choroidal neovascularization (mCNV), macular degeneration (e.g., neovascular (wet) or vascular degeneration) Ley age-related macular degeneration (nAMD), macular edema (e.g., retinal vein occlusion (RVO) or macular edema after diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy ( DR), non-infectious uveitis, or glaucoma, or abnormal retinal neovascularization, including A pharmaceutical composition for treating a disorder, comprising: (a) AAV2.7m8 capsid (SEQ ID NO: 142), AAV8 capsid (SEQ ID NO: 1 43), AAV9 capsid (SEQ ID NO: 144); or AAVrh10 capsid (SEQ ID NO: No. 145); and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; The transgene controls one or more regulatory factors that regulate the expression of the transgene in human retinal cells. anti-vascular endothelial growth factor (anti-VEGF), anti-erythropoietin, operably linked to a cleavage sequence anti-EPOR, anti-Aβ, anti-activin receptor-like kinase 1 (anti-ALK1), anti Complement component 5 (anti-C5), anti-endoglin (anti-ENG), anti-complement component 1Q (anti-CC1Q), or an anti-pKal mAb, or a substantially full-length or full-length mAb of an antigen-binding fragment thereof. Encoding an artificial genome; an AAV vector comprising the AAV vector is administered subretinal, intravitreal, intranasal, or suprachoroidally to the subject The pharmaceutical composition is formulated for the following purpose: 11. The anti-VEGF mAb is sevacizumab; and the anti-EPOR mAb is LK A-651 (NSV2) or LKA-651 (NSV3); anti-Aβ mAb , solanezumab, lecanemab, or GSK933776; anti-ALK1 mAb and the anti-C5 mAb is tesidolumab or ravulizumab. The anti-ENG mAb is carotuximab; the anti-CC1Q mAb is ANX-00 7; and the anti-pKal mAb is lanadelumab. thing. 12. The antigen-binding fragment is Fab, F(ab')2, or scFv. 12. The pharmaceutical composition according to claim 10 or 11. 13. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 1, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 290, and a light chain having the amino acid sequence of SEQ ID NO: 2; or the amino acid sequence of SEQ ID NO: 360, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 392, and a light chain having the amino acid sequence of SEQ ID NO: 61; or the amino acid sequence of SEQ ID NO: 31, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 299, and or the amino acid sequence of SEQ ID NO: 33, and optionally, an IgG having an Fc polypeptide of one isotype (e.g., the amino acid sequence of SEQ ID NO: 283) a heavy chain and a light chain having the amino acid sequence of SEQ ID NO: 34; or the amino acid sequence of SEQ ID NO: 35 sequence, and optionally, F of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283). a heavy chain having the c polypeptide, and a light chain having the amino acid sequence of SEQ ID NO: 36; or an Fc polypeptide having the amino acid sequence of SEQ ID NO: 3, and optionally the amino acid sequence of SEQ ID NO: 291; a heavy chain having a peptide and a light chain having the amino acid sequence of SEQ ID NO: 4; or SEQ ID NO: 3 7, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 300. a heavy chain having the amino acid sequence of SEQ ID NO: 38, and a light chain having the amino acid sequence of SEQ ID NO: 39; and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 301. a heavy chain having the amino acid sequence of SEQ ID NO: 40, and a light chain having the amino acid sequence of SEQ ID NO: 362; and optionally, an Fc polypeptide having the amino acid sequence of SEQ ID NO: 393. a heavy chain having the amino acid sequence of SEQ ID NO: 363; or a light chain having the amino acid sequence of SEQ ID NO: 41; and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 302. a heavy chain having the amino acid sequence of SEQ ID NO: 42; or a light chain having the amino acid sequence of SEQ ID NO: 43 sequence, and optionally, of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283). a heavy chain having an Fc polypeptide and a light chain having the amino acid sequence of SEQ ID NO: 44; or Fc having the amino acid sequence of SEQ ID NO: 69 and, optionally, the amino acid sequence of SEQ ID NO: 314 a heavy chain having a polypeptide and a light chain having the amino acid sequence of SEQ ID NO: 70. 13. A pharmaceutical composition according to any one of 10 to 12. 14. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 71. and the nucleotide sequence of SEQ ID NO: 72 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 73 encoding the heavy chain. The nucleotide sequence of SEQ ID NO: 376, which encodes the light chain, and the nucleotide sequence of SEQ ID NO: 377, which encodes the light chain or the nucleotide sequence of SEQ ID NO: 101 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 102 encoding the light chain the nucleotide sequence of SEQ ID NO: 102 encoding the heavy chain; or the nucleotide sequence of SEQ ID NO: 103 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 104 encoding the light chain; The nucleotide sequence of SEQ ID NO: 105 encodes the heavy chain, and the sequence of SEQ ID NO: 106 encodes the light chain. nucleotide sequence of SEQ ID NO: 106; or the heavy chain encoding nucleotide sequence of SEQ ID NO: 73 the nucleotide sequence of SEQ ID NO: 74 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 75 encoding the heavy chain. The nucleotide sequence of SEQ ID NO: 107 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 108 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 109 encoding the heavy chain, and the light chain or the heavy chain, encoding the nucleotide sequence of SEQ ID NO: 110; 378, and the nucleotide sequence encoding the light chain, SEQ ID NO: 379 or the nucleotide sequence of SEQ ID NO: 111 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 112 encoding the light chain , the nucleotide sequence of SEQ ID NO: 112; or the nucleotide sequence of SEQ ID NO: 113 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 114, encoding the nucleotide sequence of the light chain; or the heavy chain The nucleotide sequence of SEQ ID NO: 139 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 1 40 nucleotide sequences; or SEQ ID NOs: 141, 286, 287, or 435-44 14. The pharmaceutical composition according to item 13, comprising the nucleotide sequence of 3. 15. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 14. A pharmaceutical composition according to any one of claims 1 to 13. 16. The transgene directs secretion and post-translational modifications in the human retinal cells. and encoding signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment. A pharmaceutical composition according to any one of items 10 to 15. 17. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 2, Table 3 or Table 4. composition. 18. The medicament according to any one of items 10 to 17, wherein the AAV capsid is AAV8. composition. 19. Treatment of non-infectious uveitis in a human subject in need of treatment for non-infectious uveitis A pharmaceutical composition for treating (a) AAV2.7m8 (SEQ ID NO: 142), AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or AAVrh10 capsid (SEQ ID NO: 145 a viral capsid that is at least 95% identical to the amino acid sequence of (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; The transgene controls one or more regulatory factors that regulate the expression of the transgene in human retinal cells. a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-TNF) operably linked to a cleavage sequence; α) mAb or antigen-binding fragment thereof, substantially full-length or full-length anti-complement component 5 (C5) mAb or antigen-binding fragment thereof, substantially full-length or full-length anti-interleukin-6 ( IL-6) mAb or antigen-binding fragment thereof, or substantially full-length or full-length anti-IL-6 mAb A human antibody encoding an IL-6 receptor (IL-6R) mAb or an antigen-binding fragment thereof Engineering Genomics; an AAV vector comprising the AAV vector is administered subretinal, intravitreal, intranasal, or suprachoroidally to the subject The pharmaceutical composition is formulated for the following purpose: 20. The anti-TNFα mAb is adalimumab, infliximab, or golimumab. the anti-C5 mAb is tesidolumab or ravulizumab; the anti-IL-6 mAb is b is siltuximab, clazakimuzumab, sirukumab, olokizumab, or gerilimuzumab or the anti-IL-6R mAb is satralizumab, sarilumab, or tosirilumab 20. The pharmaceutical composition of item 19, which is izumab. 21. The antigen-binding fragment is Fab, F(ab')2, or scFv. 21. The pharmaceutical composition according to claim 19 or 20. 22. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 45, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 303, and SEQ ID NO: a light chain having the amino acid sequence of 46, or SEQ ID NO: 451, 452 or 453; or Fc having the amino acid sequence of SEQ ID NO: 47 and, optionally, the amino acid sequence of SEQ ID NO: 304 a heavy chain having a polypeptide and a light chain having the amino acid sequence of SEQ ID NO: 48; or the sequence 49, and optionally, an Fc polypeptide having the amino acid sequence of SEQ ID NO: 305. a heavy chain having a peptide and a light chain having the amino acid sequence of SEQ ID NO: 50; and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 301. a heavy chain having the amino acid sequence of SEQ ID NO: 40; and a light chain having the amino acid sequence of SEQ ID NO: 362. and optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 393. a light chain having the amino acid sequence of SEQ ID NO: 363; and a light chain having the amino acid sequence of SEQ ID NO: 331; and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 355, and a light chain having the amino acid sequence of SEQ ID NO: 332; a light chain having the amino acid sequence of SEQ ID NO: 333; Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 356, and the sequence a light chain having the amino acid sequence of SEQ ID NO: 334; an amino acid sequence of SEQ ID NO: 335, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 357, and a light chain having the amino acid sequence of SEQ ID NO: 36; an amino acid sequence of SEQ ID NO: 337; and optionally an amino acid sequence of SEQ ID NO: a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 358, and a a light chain having the amino acid sequence of SEQ ID NO: 339 and the amino acid sequence of SEQ ID NO: 340; a light chain having the amino acid sequence of SEQ ID NO: 59, and optionally the amino acid sequence of SEQ ID NO: 309; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 60; a light chain having the amino acid sequence of SEQ ID NO: 61, and optionally the amino acid sequence of SEQ ID NO: 310; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 62; and the amino acid sequence of SEQ ID NO: 341, and optionally the amino acid sequence of SEQ ID NO: 359. and a light chain having the amino acid sequence of SEQ ID NO: 342. 22. The pharmaceutical composition according to any one of items 19 to 21. 23. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 115, and the nucleotide sequence of SEQ ID NO: 116 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 117 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 117, which encodes the light chain, and the nucleotide sequence of SEQ ID NO: 118, which encodes the light chain the nucleotide sequence of SEQ ID NO: 119 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 119 encoding the light chain the nucleotide sequence of SEQ ID NO: 120; the nucleotide sequence of SEQ ID NO: 109 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 110 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 111 encoding the light chain; The nucleotide sequence of SEQ ID NO: 378 encoding the light chain and the nucleotide sequence of SEQ ID NO: 379 encoding the light chain nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 344 encoding the light chain the nucleotide sequence of SEQ ID NO: 344 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 345 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 346 encoding the light chain; the nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain; The nucleotide sequence of SEQ ID NO: 347 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 34 nucleotide sequence of SEQ ID NO: 349, encoding the heavy chain; and nucleotide sequence of SEQ ID NO: 350, encoding the light chain. the nucleotide sequence of SEQ ID NO: 350 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 35 encoding the heavy chain nucleotide sequence of SEQ ID NO: 352 encoding the light chain; The nucleotide sequence of SEQ ID NO: 129 encoding the light chain and the nucleotide sequence of SEQ ID NO: 130 encoding the light chain. the nucleotide sequence of SEQ ID NO: 130 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 132 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 133 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 341, which encodes the light chain, and the nucleotide sequence of SEQ ID NO: 342, which encodes the light chain 23. The pharmaceutical composition according to item 22, comprising a nucleotide sequence. 24. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 23. A pharmaceutical composition according to any one of claims 1 to 22. 25. The transgene directs secretion and post-translational modifications in the human retinal cells. and encoding signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment. A pharmaceutical composition according to any one of items 19 to 24. 26. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146 26. The pharmaceutical composition according to item 25, wherein the signal sequence is a signal sequence according to Table 2, Table 3 or Table 4. thing. 27. The medicament according to any one of items 19 to 26, wherein the AAV capsid is AAV8. composition. 28. For treating multiple sclerosis in a human subject in need thereof 1. A pharmaceutical composition comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrh10 capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid or a virus that is at least 95% identical to the amino acid sequence of the AAVcy5 capsid Ruscapsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; transgenes in human CNS cells, human liver cells, and / or human muscle cells. A substantially full-length gene operably linked to one or more regulatory sequences that control the expression of the gene. or full-length anti-repulsive guidance molecule-A (anti-RGMa) mAb, or its antigen-binding the artificial genome encoding the fragment; an AAV vector comprising The AAV vector is formulated for administration to the subject, and optionally, administration is by intrathecal administration. The pharmaceutical composition is administered intravenously, intravenously, subcutaneously, intranasally, or intramuscularly. 29. The pharmaceutical composition according to item 28, wherein the anti-RGMa mAb is elezanumab. . 30. The antigen-binding fragment is Fab, F(ab')2, or scFv. 29. The pharmaceutical composition according to claim 28 or 29. 31. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 51, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 306, and SEQ ID NO: 31. The pharmaceutical composition according to any of items 28 to 30, comprising a light chain having an amino acid sequence of 52. thing. 32. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 121. 32. The method according to claim 31, comprising the nucleotide sequence of SEQ ID NO: 122 encoding the nucleotide sequence of SEQ ID NO: 123, Pharmaceutical compositions. 33. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant or 28 to 3, wherein the Fc polypeptide of the Ab is glycosylated or non-glycosylated. 1. A pharmaceutical composition according to any one of claims 1 to 10. 34. The transgene directs secretion and post-translational modification in the human CNS cells. and encoding signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment. 34. The pharmaceutical composition according to any of items 28 to 33. 35. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 2, Table 3 or Table 4. composition. 36. The medicament according to any one of items 28 to 35, wherein the AAV capsid is AAV9. composition. 37. Amyloidosis (ATTR), familial amyloid cardiomyopathy (FAC), or familial amyloidosis In a human subject in need of treatment for family amyloid polyneuropathy (FAP), Myloidosis (ATTR), Familial Amyloid Cardiomyopathy (FAC), or Familial Amyloidosis A pharmaceutical composition for treating false adenomatous polyneuropathy (FAP), comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), At least 95% identical to the amino acid sequence of the AAVrh10 capsid (SEQ ID NO: 145). viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or a substantially full-length or full-length anti-transgenic mouse operably linked to a plurality of regulatory sequences. an artificial genome encoding an Iretin (anti-TTR) mAb, or an antigen-binding fragment thereof; an AAV vector comprising The AAV vector is formulated for subcutaneous, intramuscular, or intravenous administration to a subject. The pharmaceutical composition. 38. Item 37, wherein the anti-TTR mAb is NI-301 or PRX-004. The pharmaceutical composition described in 39. The antigen-binding fragment is Fab, F(ab')2, or scFv. 39. The pharmaceutical composition according to claim 37 or 38. 40. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 53, and optionally , an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283) a heavy chain having the amino acid sequence of SEQ ID NO: 54; or a light chain having the amino acid sequence of SEQ ID NO: 55 and optionally, an Fc polypeptide having the amino acid sequence of SEQ ID NO: 307. 39. Any of items 37 to 39, comprising a heavy chain having the amino acid sequence of SEQ ID NO: 56 and a light chain having the amino acid sequence of SEQ ID NO: 56. The pharmaceutical composition according to any one of the preceding claims. 41. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 123. and the nucleotide sequence of SEQ ID NO: 124 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 124 encoding the heavy chain , the nucleotide sequence of SEQ ID NO: 125, and the nucleotide sequence of SEQ ID NO: 126 encoding the light chain. 41. The pharmaceutical composition according to item 40, comprising a nucleotide sequence. 42. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or 37 to 39, wherein the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 41. A pharmaceutical composition according to any one of claims 1 to 41. 43. The transgene is secreted and translated into the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct the modification 43. A pharmaceutical composition according to any of items 37 to 42, encoding 44. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 3 or Table 4, . 45. The medicament according to any one of items 37 to 44, wherein the AAV capsid is AAV8. composition. 46. Fibrotic disorders, pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver Cirrhosis, atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction, arthrofibrosis, Crohn's disease, ulcer colitis, mediastinal fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive In a human subject in need of treatment for peritoneal fibrosis (PMF) and retroperitoneal fibrosis (RPF), Fibrotic disorders, pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, cardiac Atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, ulcerative colitis , mediastinal fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis ( A pharmaceutical composition for treating PMF and retroperitoneal fibrosis (RPF), comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or at least 95% identical to the amino acid sequence of AAVrh10 (SEQ ID NO: 145) viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or a substantially full-length or full-length anti-connective tissue augmenting antibody operably linked to a plurality of regulatory sequences. an artificial genome encoding an anti-CTGF mAb or an antigen-binding fragment thereof; an AAV vector comprising The AAV vector is formulated for subcutaneous, intramuscular, or intravenous administration to a subject. The pharmaceutical composition. 47. The pharmaceutical composition according to item 46, wherein the anti-CTGF mAb is pamrevlumab. 48. The antigen-binding fragment is Fab, F(ab')2, or scFv. 48. The pharmaceutical composition according to claim 46 or 47. 49. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 57, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 308, and the sequence 49. The medicament according to any one of items 46 to 48, comprising a light chain having the amino acid sequence of No. 58. composition. 50. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 127. 49. The method according to claim 48, comprising the nucleotide sequence of SEQ ID NO: 128 encoding the nucleotide sequence of SEQ ID NO: 128, which encodes the nucleotide sequence of the light chain of the nucleotide sequence of SEQ ID NO: 128. Pharmaceutical compositions. 51. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 51. A pharmaceutical composition according to any one of claims 1 to 50. 52. The transgene is secreted and translated into the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct the modification 52. A pharmaceutical composition according to any of items 44 to 51, encoding 53. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 3 or Table 4, . 54. The medicament according to any one of items 44 to 53, wherein the AAV capsid is AAV8. composition. 55. Non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR), and non-infectious uveal edema in human subjects requiring treatment for diabetic macular edema (DME) retinal inflammation, neuromyelitis optica (NMO), diabetic retinopathy (DR), or diabetic macular edema (DM) E) A pharmaceutical composition for treating (a) AAV8 capsid (SEQ ID NO: 143), AAV2.7m8 capsid (SEQ ID NO: 1 42), AAV9 capsid (SEQ ID NO: 144), or AAVrh10 capsid (SEQ ID NO: No. 145); and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; The transgene controls one or more regulatory factors that regulate the expression of the transgene in human retinal cells. anti-interleukin-6 receptor (anti-IL6R), anti-interleukin-6 receptor (anti-IL6R), operably linked to a cleavage sequence Interleukin-6 (IL6), or anti-cluster of differentiation 19 (anti-CD19) mAb, an artificial genome encoding a substantially full-length or full-length mAb of an antigen-binding fragment thereof; an AAV vector comprising the AAV vector is administered subretinal, intravitreal, intranasal, or suprachoroidally to the subject The pharmaceutical composition is formulated for the following purpose: 56. The anti-IL6R mAb is satralizumab, sarilumab, or tocilizumab. or anti-IL6 mAb, such as siltuximab, clazakizumab, sirukumab, oroxacin. or the anti-CD19 mAb is inebilizumab Item 56. The pharmaceutical composition according to Item 55. 57. Item 55, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. Or the pharmaceutical composition described in 56. 58. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 59, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 309, and the sequence a light chain having the amino acid sequence of SEQ ID NO: 60; or the amino acid sequence of SEQ ID NO: 61, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 310, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 62; or the amino acid sequence of SEQ ID NO: 331, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 355, and a a light chain having the amino acid sequence of SEQ ID NO: 32; or the amino acid sequence of SEQ ID NO: 333, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 356, and a a light chain having the amino acid sequence of SEQ ID NO: 34; or the amino acid sequence of SEQ ID NO: 335, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 357, and a light chain having the amino acid sequence of SEQ ID NO: 36; or the amino acid sequence of SEQ ID NO: 337, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 358, and a a light chain having the amino acid sequence of SEQ ID NO: 38; or the amino acid sequence of SEQ ID NO: 339, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 283, and a a light chain having the amino acid sequence of SEQ ID NO: 40; or the amino acid sequence of SEQ ID NO: 341, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and a a light chain having the amino acid sequence of SEQ ID NO: 42; an amino acid sequence of SEQ ID NO: 63; and optionally an amino acid sequence of SEQ ID NO: a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 64; 58. The pharmaceutical composition of any of items 55 to 57, comprising a light chain having the amino acid sequence 59. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 129. and the nucleotide sequence of SEQ ID NO: 130 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 130 encoding the heavy chain , the nucleotide sequence of SEQ ID NO: 131, and the nucleotide sequence of SEQ ID NO: 132 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 344 encoding the light chain the heavy chain encoding the nucleotide sequence of SEQ ID NO: 344; or the heavy chain encoding the nucleotide sequence of SEQ ID NO: 3 45 nucleotide sequence, and the nucleotide sequence of SEQ ID NO: 346 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 348 encoding the light chain the nucleotide sequence of SEQ ID NO: 348; or the nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 350 encoding the heavy chain; The nucleotide sequence of SEQ ID NO: 351 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 35 2; or the nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 354 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 354 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 133 and the nucleotide sequence of SEQ ID NO: 134 encoding the light chain 59. The pharmaceutical composition of item 58, comprising a nucleotide sequence. 60. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or 55 to 59, wherein the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 59. A pharmaceutical composition according to any one of 59. 61. The transgene directs secretion and post-translational modifications in the human retinal cells. and encoding signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment. 61. A pharmaceutical composition according to any one of items 55 to 60. 62. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 2, Table 3 or Table 4, composition. 63. The medicament according to any one of items 55 to 62, wherein the AAV capsid is AAV8. composition. In a human subject in need of treatment for inflammatory bowel disease (IBD), including 64.C and CD 1. A pharmaceutical composition for treating inflammatory bowel disease (IBD), including UC and CD, comprising: A viral capsid AAV8 capsid that is at least 95% identical to the amino acid sequence of (a) AAV9 capsid (SEQ ID NO: 144); or AAVrh10 Capsid (SEQ ID NO: 145); and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette, wherein the expression cassette is expressed in human hepatocytes or human liver cells; operably linked to one or more regulatory sequences that control expression of the transgene in the mouse muscle cells. Conjugated, substantially full-length or full-length anti-integrin β7 subunit (anti-ITGB7 ) the artificial genome comprising a mAb or an antigen-binding fragment thereof; an AAV vector comprising The AAV vector is formulated for subcutaneous, intramuscular, or intravenous administration to the subject. The pharmaceutical composition. 65. The pharmaceutical composition according to item 64, wherein the anti-ITGB7 mAb is etrolizumab. Finished product. 66. The antigen-binding fragment is Fab, F(ab')2, or scFv. 66. The pharmaceutical composition according to claim 64 or 65. 67. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 65, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 312, and the sequence 67. The medicament according to any one of items 64 to 66, comprising a light chain having the amino acid sequence of item 66. composition. 68. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 135. 68. The method according to item 67, comprising the nucleotide sequence of SEQ ID NO: 136 encoding the nucleotide sequence of SEQ ID NO: 136, which encodes the nucleotide sequence of the light chain of the nucleotide sequence of SEQ ID NO: 136. Pharmaceutical compositions. 69. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or 64 to 66, wherein the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 68. A pharmaceutical composition according to any one of claims 68 to 68. 70. The transgene is secreted and translated into the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct the modification 70. A pharmaceutical composition according to any of items 64 to 69, encoding 71. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 3 or Table 4. . 72. The medicament according to any one of items 64 to 71, wherein the AAV capsid is AAV8. composition. 73. Treating osteoporosis or abnormal bone loss or bone weakness (e.g., bone giant cells) Treating cancer-related tumors, Treating treatment-induced bone loss, Bone loss in breast and prostate cancer patients slowing bone loss (or increasing bone mass), preventing skeletal-related events caused by bone metastases, 2. Therapeutic use of osteoporosis in human subjects in need of inhibiting or attenuating bone resorption and bone turnover. Treating osteoporosis or abnormal bone loss or bone weakness (e.g., treating giant cell tumor of bone) Treating treatment-induced bone loss; Slowing bone loss in breast and prostate cancer patients increase bone mass (or bone mass), prevent skeletal events caused by bone metastasis, and A pharmaceutical composition for reducing bone resorption and bone turnover, comprising: (a) AAV8 capsid (SEQ ID NO: 143); AAVrh10 capsid (SEQ ID NO: 14 5); or a sequence at least 95% identical to the amino acid sequence of the AAV9 capsid (SEQ ID NO: 144). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or a substantially full-length or full-length anti-sclerosing antibody operably linked to multiple regulatory sequences. an artificial genome encoding the Tschin (anti-SOST) mAb or its antigen-binding fragment; an AAV vector comprising The AAV vector is formulated for intravenous, intramuscular, or subcutaneous administration to the subject. The pharmaceutical composition. 74. The pharmaceutical composition according to item 73, wherein the anti-SOST mAb is romosozumab. . 75. The antigen-binding fragment is Fab, F(ab')2, or scFv. 75. The pharmaceutical composition according to claim 73 or 74. 76. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 67, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 313, and SEQ ID NO: 76. A pharmaceutical composition according to any of items 73 to 75, comprising a light chain having an amino acid sequence of 68. thing. 77. The nucleotide sequence of SEQ ID NO: 137, wherein the transgene encodes a heavy chain. 77. The method according to item 76, comprising the nucleotide sequence of SEQ ID NO: 138 encoding the nucleotide sequence of SEQ ID NO: 138, which encodes the nucleotide sequence of the light chain of the nucleotide sequence of SEQ ID NO: 138. Pharmaceutical compositions. 78. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or 73 to 75, wherein the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 77. A pharmaceutical composition according to any one of claims 77 to 77. 79. The transgene is secreted and translated into the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct the modification 79. A pharmaceutical composition according to any of items 73 to 78, encoding 80. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 3 or Table 4, . 81. The medicament according to any one of items 73 to 80, wherein the AAV capsid is AAV8. composition. 82. A method for treating angioedema, including hereditary angioedema, in a human subject in need of treatment. 1. A pharmaceutical composition for treating angioedema, including vasoconstrictive angioedema, comprising: A viral capsid AAV8 capsid that is at least 95% identical to the amino acid sequence of (a) AAVrh10 capsid (SEQ ID NO: 143); AAVrh10 capsid (SEQ ID NO: 145); or AAV9 Capsid (SEQ ID NO: 144); and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or a substantially full-length or full-length anti-kallikrein antibody operably linked to multiple regulatory sequences. the artificial genome encoding an anti-pKal mAb or an antigen-binding fragment thereof; an AAV vector comprising The AAV vector is formulated for intravenous, intramuscular, or subcutaneous administration to the subject. The pharmaceutical composition. 83. The pharmaceutical composition according to item 82, wherein the anti-pKal mAb is lanadelumab. . 84. The antigen-binding fragment is Fab, F(ab')2, or scFv. 82. The pharmaceutical composition according to claim 83. 85. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 69, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 314, and the sequence 85. The medicament according to any one of items 82 to 84, comprising a light chain having the amino acid sequence of No. 70. composition. 86. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 139. nucleotide sequence of SEQ ID NO: 140, encoding the light chain; or SEQ ID NO: 141, 86, 287, or 435 to 443 of the nucleotide sequence of Item 85. Pharmaceutical composition. 87. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or 82 to 84, wherein the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 85. A pharmaceutical composition according to any one of claims 85 to 85. 88. The transgene directs secretion and post-translational modifications in the human retinal cells. and encoding signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment. 88. A pharmaceutical composition according to any one of items 82 to 87. 89. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 1 46), or a signal sequence according to Table 3 or Table 4, . 90. The medicament according to any one of items 82 to 89, wherein the AAV capsid is AAV8. composition. Treatment 91. Alzheimer's disease (AD), frontotemporal dementia (FD), tauopathy, progressive Supranuclear palsy, chronic traumatic encephalopathy, Pick's complex, and primary age-related tauopathy, huntingtin syndrome Tony's disease, juvenile Huntington's disease, Parkinson's disease, synucleinopathy, ALS, migraine or Alzheimer's disease (AD), frontal lobectomy in a human subject in need of treatment for cluster headache. Temporal dementia (FD), tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, Pick's complex , and primary age-related tauopathies, Huntington's disease, juvenile Huntington's disease, Parkinson's disease 1. A method for treating Son's disease, synucleinopathy, ALS, migraine or cluster headache, comprising: a human CSF gene expressed from a transgene and present in the cerebrospinal fluid (CSF) of the human subject; A therapeutically effective amount of anti-amyloid beta (anti-Aβ), anti-sortilin, anti- Tau protein (anti-tau), anti-semaphorin 4D (anti-SEMA4D), anti-α-synuclein anti-SNCA, anti-superoxide dismutase-1 (anti-SOD1), or anti-calcium Cytokinin gene-related peptide receptor (anti-CGRPR) mAb or its antigen-binding fragment The method comprises delivering a substantially full-length or full-length mAb of the invention. 92. Alzheimer's disease, frontotemporal dementia (FD), tauopathy, progressive supranuclear palsy Neuropathy, chronic traumatic encephalopathy, Pick's complex, and primary age-related tauopathies, Huntington's disease, Juvenile Huntington's disease, Parkinson's disease, synucleinopathy, ALS, migraine or cluster Alzheimer's disease, frontotemporal dementia (FMD) in human subjects in need of headache treatment D), tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, Pick's complex, and primary age Related tauopathies, Huntington's disease, juvenile Huntington's disease, Parkinson's disease, synuclein 1. A method for treating inotropic steroids, ALS, migraine, or cluster headaches, comprising: Depots that release human post-translationally modified (HuPTM) forms of mAbs or their antigen-binding fragments one or more genes that control the expression of a transgene in human CNS cells so that a anti-amyloid beta (anti-Aβ), anti-sortilin, anti-tandem repeat inhibitors operably linked to a number of regulatory sequences Anti-tau protein (anti-tau), anti-semaphorin 4D (anti-SEMA4D), anti-α-synuclein (anti-SNCA), anti-superoxide dismutase-1 (anti-SOD1) or anti-calcium CGRPR mAb or its antigen-binding fragment A therapeutically effective amount of a recombinant human mAb containing a transgene encoding a substantially full-length or full-length mAb. administering to said subject a nucleotide expression vector. 93. The anti-Aβ mAb is solanezumab, lecanemab, or GSK933776. The anti-sortilin mAb is AL-001; the anti-tau mAb is ABBV-8E12 , UCB-0107, or NI-105 (BIIB076); anti-SEMA4D The mAb is VX15 / 2503; the anti-SNCA mAb is prasinezumab, NI- 202 (BIIB054), or MED-1341; anti-SOD1 mAb is N I-2041.10D12 or NI-204.12G7; and anti-CGRPR mAb , eptinezumab, fremanezumab, or galcanezumab, item 91 or 92 The method described below. 94. The antigen-binding fragment is Fab, F(ab')2, or scFv. 94. A method according to any one of claims 91 to 93. 95. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 1, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 290, and a light chain having the amino acid sequence of SEQ ID NO: 2; or the amino acid sequence of SEQ ID NO: 3, and optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 292, and an Fc polypeptide having the amino acid sequence of SEQ ID NO: 4; a light chain having the amino acid sequence of SEQ ID NO: 360; or the amino acid sequence of SEQ ID NO: 361; and optionally, a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 392, and an Fc polypeptide having an amino acid sequence of SEQ ID NO: 361; a light chain having the amino acid sequence of SEQ ID NO: 5, and optionally an IgG1 amino acid sequence; a heavy chain having an Fc polypeptide of the same type (e.g., the amino acid sequence of SEQ ID NO: 283); and a light chain having the amino acid sequence of SEQ ID NO: 6; or the amino acid sequence of SEQ ID NO: 7, and any Optionally, an Fc polypeptide of the IgG4 isotype (e.g., the amino acid sequence of SEQ ID NO: 285) a heavy chain having the amino acid sequence of SEQ ID NO: 8, and a light chain having the amino acid sequence of SEQ ID NO: 9; and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 292. a heavy chain having the amino acid sequence of SEQ ID NO: 10; or a light chain having the amino acid sequence of SEQ ID NO: 11; amino acid sequence, and optionally, IgG1 isotype (e.g., amino acid sequence of SEQ ID NO: 283) a heavy chain having an Fc polypeptide of SEQ ID NO: 12 and a light chain having the amino acid sequence of SEQ ID NO: 13; is the amino acid sequence of SEQ ID NO: 13, and optionally an IgG4 isotype (e.g., SEQ ID NO: a heavy chain having an Fc polypeptide of amino acid sequence SEQ ID NO: 14; a light chain having the amino acid sequence of SEQ ID NO: 15, and optionally, the amino acid sequence of SEQ ID NO: 293; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 16; or a light chain having the amino acid sequence of SEQ ID NO: 17, and optionally an IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283), and a heavy chain having an Fc polypeptide of the sequence a light chain having the amino acid sequence of SEQ ID NO: 18; or the amino acid sequence of SEQ ID NO: 19, and optionally 294, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 295, and a light chain having the amino acid sequence of SEQ ID NO: 20; or the amino acid sequence of SEQ ID NO: 21, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 295, and or the amino acid sequence of SEQ ID NO: 23, and optionally, an IgG having an Fc polypeptide of one isotype (e.g., the amino acid sequence of SEQ ID NO: 283) a heavy chain and a light chain having the amino acid sequence of SEQ ID NO: 24; or the amino acid sequence of SEQ ID NO: 25 and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 296. and a light chain having the amino acid sequence of SEQ ID NO: 26; or the amino acid sequence of SEQ ID NO: 27, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 297, and and a light chain having the amino acid sequence of SEQ ID NO: 28; or the amino acid sequence of SEQ ID NO: 29, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 298, and 95. The method according to any one of items 91 to 94, comprising a light chain having the amino acid sequence of SEQ ID NO: 30. Law. 96. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 71. and the nucleotide sequence of SEQ ID NO: 72 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 73 encoding the heavy chain. The nucleotide sequence of SEQ ID NO: 73, which encodes the light chain, and the nucleotide sequence of SEQ ID NO: 74, which encodes the light chain or the nucleotide sequence of SEQ ID NO: 376 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 377 encoding the light chain or the nucleotide sequence of SEQ ID NO: 75 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 76, encoding the nucleotide sequence of the base chain and the light chain; or SEQ ID NO: a heavy chain having the nucleotide sequence of SEQ ID NO: 77, and a heavy chain having the nucleotide sequence of SEQ ID NO: 78 a light chain having the nucleotide sequence of SEQ ID NO: 79; and a heavy chain having the nucleotide sequence of SEQ ID NO: 80. a light chain having the nucleotide sequence of SEQ ID NO: 81; or a heavy chain having the nucleotide sequence of SEQ ID NO: a light chain having the nucleotide sequence of SEQ ID NO: 82; or a light chain having the nucleotide sequence of SEQ ID NO: 83 a heavy chain and a light chain having the nucleotide sequence of SEQ ID NO: 84; or a nucleotide sequence of SEQ ID NO: 85 a heavy chain having the nucleotide sequence of SEQ ID NO: 86, and a light chain having the nucleotide sequence of SEQ ID NO: 86; or a heavy chain having the nucleotide sequence of SEQ ID NO: 87, and a or a heavy chain having the nucleotide sequence of SEQ ID NO: 89, and a light chain having the nucleotide sequence of SEQ ID NO: 90. a light chain having the nucleotide sequence of SEQ ID NO: 91; or a heavy chain having the nucleotide sequence of SEQ ID NO: 92; and a light chain having the nucleotide sequence of SEQ ID NO: 92; or a light chain having the nucleotide sequence of SEQ ID NO: 93 a heavy chain having the nucleotide sequence of SEQ ID NO: 94, and a light chain having the nucleotide sequence of SEQ ID NO: 9 a heavy chain having the nucleotide sequence of SEQ ID NO:5, and a light chain having the nucleotide sequence of SEQ ID NO:96 or a heavy chain having the nucleotide sequence of SEQ ID NO:97 and a heavy chain having the nucleotide sequence of SEQ ID NO:98 a light chain having the nucleotide sequence of SEQ ID NO: 99; or a heavy chain having the nucleotide sequence of SEQ ID NO: 100; 96. The method of item 95, comprising a light chain having the nucleotide sequence of item 100. 97. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant, or Item 91. The Fc polypeptide of the mAb or mAb is glycosylated or non-glycosylated. 95. A method according to any one of claims 1 to 95. 98. The mAb or antigen-binding fragment thereof comprises an α2,6-sialylated glycan. 98. The method of any of items 91 to 97, comprising: 99. The mAb or antigen-binding fragment thereof is glycosylated but detectably 91 to 98, which does not contain NeuGc and / or α-Gal How to do it. 100. Item 9, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 10. A method according to any one of 1 to 99. 101. The method according to any one of items 92 to 100, wherein the recombinant expression vector is AAV9. How to post. 102. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, wherein the antibody is confirmed by expressing the antibody according to any one of items 92 to 101. The method according to any one of the preceding claims. 103. Diabetic retinopathy, myopic choroidal neovascularization (mCNV), macular degeneration (e.g., neovascular (wet) or dry age-related macular degeneration (nAMD)), macular edema (e.g. , macular edema after retinal vein occlusion (RVO) or diabetic macular edema (DME), RVO , diabetic retinopathy (DR), non-infectious uveitis, glaucoma, or abnormal retinal neovascularization and diabetic retinopathy, myopic choroidal neovascularization (mCN) in human subjects in need of treatment. V), macular degeneration (e.g., neovascular (wet) or dry age-related macular degeneration (nA MD), macular edema (e.g., retinal vein occlusion (RVO) or diabetic macular edema (DM) E) macular edema), RVO, diabetic retinopathy (DR), non-infectious uveitis, glaucoma, Or a method for treating abnormal retinal neovascularization, comprising: in the retina of said human subject, expressed from a transgene and produced by human retinal cells. a therapeutically effective amount of an anti-vascular endothelial growth factor (anti-VEGF), anti-erythropoietin receptor (anti-EPOR), anti-Aβ, anti-activin receptor-like kinase 1 (anti-ALK1), anti-complement component 5 (anti-C5), anti-endoglin (anti-ENG), anti-complement component 1Q (anti-CC1Q)), or Delivering substantially full-length or full-length anti-pKal mAb, or antigen-binding fragment thereof The method comprising: 104. Diabetic retinopathy, myopic choroidal neovascularization (mCNV), macular degeneration (e.g., neovascular (wet) or dry age-related macular degeneration (nAMD)), macular edema (e.g. , macular edema after retinal vein occlusion (RVO) or diabetic macular edema (DME), RVO , diabetic retinopathy (DR), non-infectious uveitis, glaucoma or abnormal retinal neovascularization Diabetic retinopathy, myopic choroidal neovascularization (mCNV) in a human subject in need of treatment ), macular degeneration (e.g., neovascular (wet) or dry age-related macular degeneration (nAM) D)), macular edema (e.g., retinal vein occlusion (RVO) or diabetic macular edema (DME) ) macular edema after ocular edema), RVO, diabetic retinopathy (DR), non-infectious uveitis, glaucoma, or A method for treating abnormal retinal neovascularization, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. and injecting into the retina of said human subject one or more transgenes that control expression of a transgene in human retinal cells. anti-vascular endothelial growth factor (anti-VEGF), anti-erythropoietin, operably linked to multiple regulatory sequences Anti-epileptic steroid receptor (anti-EPOR), anti-Aβ, anti-activin receptor-like kinase 1 (anti-ALK) 1), anti-complement component 5 (anti-C5), anti-endoglin (anti-ENG), anti-complement component 1Q (anti-CC 1Q), or substantially full-length or full-length anti-pKal mAb, or antigen-binding fragment thereof A therapeutically effective amount of a recombinant nucleotide expression vector containing a transgene encoding a long mAb. The method further comprises delivering a steroid to the subject. 105. The anti-VEGF mAb is sevacizumab; the anti-EPOR mAb is LKA -651 (NSV2) or LKA-651 (NSV3); and anti-Aβ mAb ranezumab, lecanemab, or GSK933776; anti-ALK1 mAb the anti-C5 mAb is tesidolumab or ravulizumab; The anti-ENG mAb is carotuximab; the anti-CC1Q mAb is ANX-007; and the anti-pKal mAb is lanadelumab. . 106. The antigen-binding fragment is Fab, F(ab')2, or scFv. 106. A method according to any one of items 103 to 105. 107. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 1, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 290, and the sequence a light chain having the amino acid sequence of SEQ ID NO: 2; or the amino acid sequence of SEQ ID NO: 360, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 392, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 361; or the amino acid sequence of SEQ ID NO: 31, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 299, and a a light chain having the amino acid sequence of SEQ ID NO: 2; or the amino acid sequence of SEQ ID NO: 33, and optionally an Ig having an Fc polypeptide of the G1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283); a heavy chain having the amino acid sequence of SEQ ID NO: 34; or a light chain having the amino acid sequence of SEQ ID NO: 35 sequence, and optionally, of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283). a heavy chain having an Fc polypeptide and a light chain having the amino acid sequence of SEQ ID NO: 36; or an Fc polypeptide having the amino acid sequence of SEQ ID NO: 3 and, optionally, the amino acid sequence of SEQ ID NO: 291; a heavy chain having the polypeptide of SEQ ID NO: 4, and a light chain having the amino acid sequence of SEQ ID NO: 4; or SEQ ID NO: 37, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 300. a heavy chain having the amino acid sequence of SEQ ID NO: 38; or a light chain having the amino acid sequence of SEQ ID NO: 39 and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 301. and a light chain having the amino acid sequence of SEQ ID NO: 40; or and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 393. a heavy chain having the amino acid sequence of SEQ ID NO: 363; or a light chain having the amino acid sequence of SEQ ID NO: 41 and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 302. a heavy chain having the amino acid sequence of SEQ ID NO: 42; or a light chain having the amino acid sequence of SEQ ID NO: 43 amino acid sequence, and optionally, IgG1 isotype (e.g., amino acid sequence of SEQ ID NO: 283) a heavy chain having an Fc polypeptide of SEQ ID NO: 43 and a light chain having the amino acid sequence of SEQ ID NO: 44; F having the amino acid sequence of SEQ ID NO: 69, and optionally the amino acid sequence of SEQ ID NO: 314 c) a heavy chain having a polypeptide of formula (I) and a light chain having the amino acid sequence of SEQ ID NO: 70; 107. A method according to any one of items 103 to 106. 108. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 71. and the nucleotide sequence of SEQ ID NO: 72 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 73 encoding the heavy chain. The nucleotide sequence of SEQ ID NO: 376, which encodes the light chain, and the nucleotide sequence of SEQ ID NO: 377, which encodes the light chain or the nucleotide sequence of SEQ ID NO: 101 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 102 encoding the light chain the nucleotide sequence of SEQ ID NO: 102 encoding the heavy chain; or the nucleotide sequence of SEQ ID NO: 103 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 104 encoding the light chain; The nucleotide sequence of SEQ ID NO: 105 encodes the heavy chain, and the sequence of SEQ ID NO: 106 encodes the light chain. nucleotide sequence of SEQ ID NO: 106; or the heavy chain encoding nucleotide sequence of SEQ ID NO: 73 the nucleotide sequence of SEQ ID NO: 74 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 75 encoding the heavy chain. The nucleotide sequence of SEQ ID NO: 107 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 108 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 109 encoding the heavy chain, and the light chain or the heavy chain, encoding the nucleotide sequence of SEQ ID NO: 110; 378, and the nucleotide sequence encoding the light chain, SEQ ID NO: 379 or the nucleotide sequence of SEQ ID NO: 111 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 112 encoding the light chain , the nucleotide sequence of SEQ ID NO: 112; or the nucleotide sequence of SEQ ID NO: 113 encoding the heavy chain nucleotide sequence of SEQ ID NO: 114, or the sequence encoding the nucleotide sequence of SEQ ID NO: 114, which encodes the nucleotide sequence of the light chain; Item 1, including the nucleotide sequence of numbers 141, 286, 287, or 435 to 443 The method described in 07. 109. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 03 to 105. 110. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 109. The method of any of items 103 to 109, comprising: 111. The mAb or antigen-binding fragment thereof is glycosylated but detectably 103 to 110, which does not contain NeuGc or α-Gal, How to do it. 112. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 03 to 111. 113. The recombinant expression vector is AAV2.7m8, AAV8, or AAV9. 113. The method according to any of items 104 to 112. 114. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human retinal cells in culture to express the mAb or 114. The method according to any one of items 104 to 113, wherein the antibody is confirmed by expressing the antibody or an antigen-binding fragment thereof. The method according to any one of the preceding claims. 115. Non-infectious uveitis in a human subject in need of treatment for non-infectious uveitis. A method of treating in the retina of said human subject, expressed from a transgene and produced by human retinal cells. a therapeutically effective amount of a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-TNFα) mAb administered b or an antigen-binding fragment thereof. 116. A method for treating non-infectious uveitis in a human subject in need thereof, comprising: The pre-treatment step is carried out to form a depot that releases the HuPTM form of the mAb or antigen-binding fragment. The retina of the human subject is provided with one or more genes that control expression of a transgene in human retinal cells. a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-T) operably linked to a regulatory sequence of NFα) mAb, or an antigen-binding fragment thereof, substantially full-length or full-length anti-complement component 5( C5) mAb or antigen-binding fragment thereof, substantially full-length or full-length anti-interleukin -6 (IL-6) mAb or antigen-binding fragment thereof, substantially full-length or full-length anti-interleukin-6 (IL-6) mAb or antigen-binding fragment thereof A vector encoding an IL-6 receptor (IL-6R) mAb or its antigen-binding fragment and administering a therapeutically effective amount of a recombinant nucleotide expression vector containing a gene encoding the nucleotide sequence of the present invention. Hmm, the above method. 117. Anti-TNFα mAb is adalimumab, infliximab, or golimumab. and the anti-C5 mAb is tesidolumab or ravulizumab; and the anti-IL-6 mAb is However, siltuximab, clazakimuzumab, sirukumab, olokizumab, or gerilimus or the anti-IL-6R mAb is satralizumab, sarilumab, or tocilizumab. 117. The method of item 115 or 116, wherein the antibody is a mab. 118. The antigen-binding fragment is Fab, F(ab')2, or scFv. 118. A method according to any one of items 115 to 117. 119. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 45, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 303, and a light chain having the amino acid sequence of SEQ ID NO: 46; or the amino acid sequence of SEQ ID NO: 47, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 304, and a light chain having the amino acid sequence of SEQ ID NO: 48; or the amino acid sequence of SEQ ID NO: 49, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 305; and an Fc polypeptide having the amino acid sequence of SEQ ID NO: 50 a light chain having the amino acid sequence of SEQ ID NO: 39, and optionally the amino acid sequence of SEQ ID NO: 301; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 40; a light chain comprising the amino acid sequence of SEQ ID NO: 362, and optionally the amino acid sequence of SEQ ID NO: 393; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 363; and a light chain having the amino acid sequence of SEQ ID NO: 363. having the amino acid sequence of SEQ ID NO: 331, and optionally the amino acid sequence of SEQ ID NO: 355; a heavy chain having an Fc polypeptide and a light chain having the amino acid sequence of SEQ ID NO: 332; 333, and optionally, an Fc polypeptide having the amino acid sequence of SEQ ID NO: 356. a heavy chain having the polypeptide of SEQ ID NO: 334; and a light chain having the amino acid sequence of SEQ ID NO: 3 35, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 357. a heavy chain having the amino acid sequence of SEQ ID NO: 336; a light chain having the amino acid sequence of SEQ ID NO: 337; and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 358. a heavy chain having the amino acid sequence of SEQ ID NO: 338; and a light chain having the amino acid sequence of SEQ ID NO: 339. a light chain having the amino acid sequence of SEQ ID NO: 340; and a light chain having the amino acid sequence of SEQ ID NO: 59; and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 309, and a light chain having the amino acid sequence of SEQ ID NO: 60; an amino acid sequence of SEQ ID NO: 61, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 310, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 62; and a heavy chain with the amino acid sequence of SEQ ID NO: 341, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and and a light chain having the amino acid sequence of SEQ ID NO: 342. The method described below. 120. The transgene comprises the nucleotide sequence of SEQ ID NO: 115, encoding the heavy chain. the nucleotide sequence of SEQ ID NO: 116 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 117 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 117 encoding the light chain and the nucleotide sequence of SEQ ID NO: 118 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 119 encoding the heavy chain, and the light chain the nucleotide sequence of SEQ ID NO: 120 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 109 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 110 encoding the light chain; The nucleotide sequence of SEQ ID NO: 378 encodes the heavy chain, and the sequence of SEQ ID NO: 379 encodes the light chain. the nucleotide sequence of SEQ ID NO: 379 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain nucleotide sequence of SEQ ID NO: 344 encoding the light chain; and nucleotide sequence of SEQ ID NO: 345 encoding the heavy chain. The nucleotide sequence of SEQ ID NO: 345 and the nucleotide sequence of SEQ ID NO: 346 encoding the light chain the nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 348 encoding the light chain the nucleotide sequence of SEQ ID NO: 348; the nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 350 encoding the light chain; the nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain; The nucleotide sequence of SEQ ID NO: 351 and the nucleotide sequence of SEQ ID NO: 352 encoding the light chain the nucleotide sequence of SEQ ID NO: 129 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 130 encoding the light chain the nucleotide sequence of SEQ ID NO: 130 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain; the nucleotide sequence of SEQ ID NO: 132 encoding the heavy chain; The nucleotide sequence of SEQ ID NO: 341 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 342 encoding the light chain Item 120. The method of item 119, comprising the nucleotide sequence of 121. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant, or Item 11. The Fc polypeptide of the mAb is glycosylated or non-glycosylated. 119. The method of any one of claims 5 to 118. 122. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 122. The method of any of items 115 to 121, comprising: 123. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, which can be used for the treatment of ulcerative colitis. How to do it. 124. The mAb or antigen-binding fragment thereof, comprising tyrosine sulfation. 15 to 123. 125. The recombinant expression vector is AAV2.7m8, AAV8, or AAV9; 125. The method according to any one of items 116 to 124. 126. Production of a HuPTM form of the mAb or antigen-binding fragment thereof is carried out by the recombinant The nucleotide expression vector is transfected into human retinal cells in culture to express the mAb or 126. Any of items 116 to 125, characterized by expressing an antigen-binding fragment thereof. The method described above. 127. A method for treating multiple sclerosis in a human subject in need thereof. There was, a human CSF gene expressed from a transgene and present in the cerebrospinal fluid (CSF) of the human subject; A therapeutically effective amount of substantially full-length or full-length anti-repellent guidance produced by S cells. the method comprising delivering Molecule-A (anti-RGMa) mAb or an antigen-binding fragment thereof. Law. 128. A method for treating multiple sclerosis in a human subject in need thereof. There was, The pre-treatment step is carried out to form a depot that releases the HuPTM form of the mAb or antigen-binding fragment. a human subject's CNS containing one or more transgenes that control expression of the transgene in human CNS cells; Substantially full-length or full-length anti-repulsive guidance operably linked to multiple regulatory sequences A transgene encoding Molecule-A (anti-RGMa) mAb or its antigen-binding fragment is 20. A method comprising administering a therapeutically effective amount of a recombinant nucleotide expression vector comprising: 129. The method according to item 127 or 128, wherein the anti-RGMa mAb is elezanumab. How to do it. 130. The antigen-binding fragment is Fab, F(ab')2, or scFv. 129. A method according to any one of items 127 to 129. 131. The full-length mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 51, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 306, and 131. Any of items 127 to 130, comprising a light chain having the amino acid sequence of sequence number 52. How to do it. 132. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 121. Item 131, which includes the nucleotide sequence of SEQ ID NO: 122 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 123, which encodes the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 124, and the nucleotide sequence of the light chain of the nucleotides of SEQ ID NO: 125. How to post. 133. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 127-131. A method according to any one of claims 127-131. 134. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 134. The method of any of items 127 to 133, comprising: 135. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, which can be used for the treatment of ulcerative colitis. How to do it. 136. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 27 to 135. 137. Any of items 128 to 136, wherein the recombinant expression vector is AAV9. The method described. 138. Production of a HuPTM form of the mAb or antigen-binding fragment thereof is carried out by the recombinant The nucleotide expression vector is transfected into human CNS cells in culture to express the mAb or any of items 128 to 136, wherein the antigen-binding fragment is confirmed by expressing the antigen-binding fragment. The method described above. 139. Amyloidosis (ATTR), familial amyloidotic cardiomyopathy (FAC), or In a human subject in need of treatment for familial amyloidotic polyneuropathy (FAP), amyloidosis (ATTR), familial amyloid cardiomyopathy (FAC), or familial amyloidosis 1. A method for treating fibroid polyneuropathy (FAP), comprising introducing into the circulation of said human subject a transmembrane protein (TTP) containing TTP. A therapeutically active compound expressed from a human liver cell or human muscle cell and a therapeutically effective amount of a substantially full-length or full-length anti-transthyretin (anti-TTR) mAb or delivering an antigen-binding fragment. 140. A method for treating asthma in a human subject in need thereof, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. a transgene in the human liver cells or human muscle cells of said human subject; substantially full-length or operably linked to one or more regulatory sequences that control expression of the gene or a full-length anti-transthyretin (anti-TTR) mAb or an antigen-binding fragment thereof. administering a therapeutically effective amount of a recombinant nucleotide expression vector containing a transgene that The method comprising: 141. Item 139, where the anti-TTR mAb is NI-301 or PRX-004. Or the method described in 140. 142. Item 1, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. 39 to 141. 143. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 53, and Optionally, an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283). a heavy chain having the peptide of SEQ ID NO: 54, and a light chain having the amino acid sequence of SEQ ID NO: 5; or 5, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 307. 139 to 140, comprising a heavy chain having the amino acid sequence of SEQ ID NO: 56 and a light chain having the amino acid sequence of SEQ ID NO: 57. 142. A method according to any one of claims 142 to 142. 144. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 123. the nucleotide sequence of SEQ ID NO: 124 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 125 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 125 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 126 encoding the light chain. 144. The method of claim 143, comprising a nucleic acid sequence. 145. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant, or Item 13. The Fc polypeptide of the mAb is glycosylated or non-glycosylated. 9 to 143. 146. The mAb or its antigen-binding fragment contains α2,6-sialylated glycans. 146. The method according to any one of items 139 to 145. 147. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, which can be used for the treatment of ulcerative colitis. How to do it. 148. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 39 to 147. 149. Items 140 to 14, wherein the recombinant expression vector is AAV8 or AAV9. 8. A method according to any one of claims 7 to 8. 150. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vectors were transduced into human hepatocytes or human muscle cells in culture. Item 140, wherein the antibody is confirmed by expressing the mAb or antigen-binding fragment thereof. 149. A method according to any one of claims 1 to 149. 151. Pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrium Fibrosis, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, mediastinal fibrosis, bone Myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and pulmonary fibrosis in a human subject in need of treatment for a fibrotic disorder, including peritoneal fibrosis (RPF). Disease, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrial fibrosis, endocardial Myofibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, mediastinal fibrosis, myelofibrosis (MF) , nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and retroperitoneal fibrosis (RP) F) a method for treating a fibrotic disorder, comprising: a human subject having a circulating antibody expressed from a transgene and administered to human liver cells or human muscle cells; a therapeutically effective amount of substantially full-length or full-length anti-connective tissue growth factor ( A method comprising delivering an anti-CTGF mAb or antigen-binding fragment thereof. 152. Pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrium Fibrosis, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, mediastinal fibrosis, bone Myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and pulmonary fibrosis in a human subject in need of treatment for a fibrotic disorder, including peritoneal fibrosis (RPF). Disease, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrial fibrosis, endocardial Myofibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, mediastinal fibrosis, myelofibrosis (MF) , nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and retroperitoneal fibrosis (RP) F) a method for treating a fibrotic disorder, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. a transgene in the human liver cells or human muscle cells of said human subject; operably linked to one or more regulatory sequences that control expression of the gene, A substantially full-length or full-length anti-connective tissue growth factor (anti-CTGF) mAb, or its antigen binding a therapeutically effective amount of a recombinant nucleotide expression vector containing a transgene encoding a recombinant fragment. The method comprises administering a steroid. 153. The anti-CTGF mAb is pamrevlumab. How to post. 154. Item 15, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. 154. A method according to any one of claims 1 to 153. 155. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 57, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 308, and 154. A light chain having the amino acid sequence of SEQ ID NO: 58. How to do it. 156. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 127. Item 155, which includes the nucleotide sequence of SEQ ID NO: 128 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 128, which encodes the nucleotide sequence of the nucleotides of the nucleotides of the nucleotides of SEQ ID NO: 128, which encodes the light chain ... How to post. 157. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 51 to 155. 158. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 158. The method of any of items 151 to 157, comprising: 159. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 151 to 158 How to do it. 160. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 51 to 159. 161. Items 152 to 16, wherein the recombinant expression vector is AAV8 or AAV9. 10. A method according to any one of claims 1 to 9. 162. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vectors were transduced into human hepatocytes or human muscle cells in culture. Item 152, wherein the antibody is confirmed by expressing the mAb or antigen-binding fragment thereof. 161. A method according to any one of claims 1 to 161. 163. Non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR) or non-infectious uveal edema in human subjects requiring treatment for diabetic macular edema (DME) inflammation, neuromyelitis optica (NMO), diabetic retinopathy (DR) or diabetic macular edema (DME) ) a method for treating in the retina of said human subject, expressed from a transgene and produced by human retinal cells. a therapeutically effective amount of an anti-interleukin-6 receptor (anti-IL6R) mAb, an anti-interleukin-6 receptor (anti-IL6R) mAb, an anti-IL6R ... -Leukin-6 (IL6) mAb, or anti-cluster of differentiation 19 (anti-CD19) mAb, or an antigen-binding fragment thereof, comprising delivering a substantially full-length or full-length mAb. method. 164. Non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR) or non-infectious uveal edema in human subjects requiring treatment for diabetic macular edema (DME) inflammation, neuromyelitis optica (NMO), diabetic retinopathy (DR) or diabetic macular edema (DME) ) a method for treating to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. and injecting into the retina of said human subject one or more transgenes that control expression of a transgene in human retinal cells. Anti-interleukin-6 receptor (anti-IL6R) operably linked to multiple regulatory sequences mAb, anti-interleukin-6 (IL6) mAb, or anti-cluster of differentiation 19 (anti-C D19) A mAb, or an antigen-binding fragment thereof, encoding a substantially full-length or full-length mAb and administering a therapeutically effective amount of a recombinant nucleotide expression vector containing a transgene that The method comprising: 165. The anti-IL6R is satralizumab, sarilumab, or tocilizumab, or or anti-IL6 mAb, such as siltuximab, clazakizumab, sirukumab, and olokizumab. or gerilizumab, or the anti-CD19 mAb is inebilizumab; Item 165. The method according to item 163 or 164. 166. Item 1, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. 63 to 165. 167. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 59, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 309, and a light chain having the amino acid sequence of SEQ ID NO: 60; or the amino acid sequence of SEQ ID NO: 61, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 310, and a light chain having the amino acid sequence of SEQ ID NO: 62; or the amino acid sequence of SEQ ID NO: 341, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 342; or the amino acid sequence of SEQ ID NO: 331, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 355, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 332; or the amino acid sequence of SEQ ID NO: 333, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 356, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 334; or the amino acid sequence of SEQ ID NO: 335, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 357, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 336; or the amino acid sequence of SEQ ID NO: 337, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 358, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 338; or the amino acid sequence of SEQ ID NO: 339, and optionally a heavy chain having an Fc polypeptide having the IgG1 amino acid sequence of SEQ ID NO: 283, and a light chain having the amino acid sequence of SEQ ID NO: 340; or the amino acid sequence of SEQ ID NO: 341; and and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and a light chain having the amino acid sequence of SEQ ID NO: 342; an amino acid sequence of SEQ ID NO: 63; and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 311, and SEQ ID NO: 167. The method according to any of items 163 to 166, comprising a light chain having an amino acid sequence of 64. . 168. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 129. the nucleotide sequence of SEQ ID NO: 130 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 131 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 132 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain, and the light chain or the heavy chain encoding the nucleotide sequence of SEQ ID NO: 344; 345, and the nucleotide sequence encoding the light chain, SEQ ID NO: 346 or the nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 348 encoding the light chain , the nucleotide sequence of SEQ ID NO: 348; or the nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 350 encoding the nucleotide sequence of the light chain; or the heavy chain the nucleotide sequence of SEQ ID NO: 351 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 3 or the nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain. and the nucleotide sequence of SEQ ID NO: 354 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 354 encoding the heavy chain , the nucleotide sequence of SEQ ID NO: 133, and the nucleotide sequence of SEQ ID NO: 134 encoding the light chain. Item 168. The method of item 167, comprising a nucleotide sequence. 169. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 63 to 167. 170. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 169. The method of any of items 163 to 168, comprising: 171. The mAb or antigen-binding fragment thereof is glycosylated but not detectably glycosylated. does not contain NeuGc or α-Gal, as described in any of items 163 to 169 How to do it. 172. The mAb or antigen-binding fragment thereof, comprising tyrosine sulfation. 63 to 170. 173. The recombinant expression vector is AAV8, AAV2.7m8, or AAV9; 172. The method according to any one of items 164 to 171. 174. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human retinal cells in culture to express the mAb or 172. The method of claim 164, wherein the antibody or antigen-binding fragment thereof is identified by expressing the antibody or antigen-binding fragment thereof. The method according to any one of the preceding claims. 175. In a human subject in need of treatment for inflammatory bowel disease (IBD), including UC and CD. 1. A method for treating inflammatory bowel disease (IBD), including UC and CD, in a human subject, comprising administering to said subject Into circulation, expressed from a transgene and produced by human liver cells or human muscle cells. a therapeutically effective amount of a substantially full-length or full-length anti-integrin β7 subunit (anti-I The method comprises delivering a TGB7 mAb or an antigen-binding fragment thereof. 176. In a human subject in need of treatment for inflammatory bowel disease (IBD), including UC and CD. 1. A method for treating inflammatory bowel disease (IBD), including UC and CD, comprising administering to a subject a subject in need thereof a therapeutically effective amount of steroids, the method comprising administering to a subject ... to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. a transgene in the human liver cells or human muscle cells of said human subject; substantially full-length or operably linked to one or more regulatory sequences that control expression of the gene or full-length anti-integrin β7 subunit (anti-ITGB7) mAb or its antigen binding a therapeutically effective amount of a recombinant nucleotide expression vector containing a transgene encoding a functional fragment of The method comprises administering a 177. The anti-ITGB7 mAb is etrolizumab. The method described. 178. Item 1, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. 75 to 177. 179. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 65, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 312, and 179. A light chain comprising the amino acid sequence of SEQ ID NO: 66. How to do it. 180. The transgene comprises the nucleotide sequence of SEQ ID NO: 135, encoding the heavy chain. Item 179, which includes the nucleotide sequence of SEQ ID NO: 136 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 136, which encodes the nucleotide sequence of the nucleotides of the nucleotides of the nucleotides of SEQ ID NO: 136, which encodes the light chain ... How to post. 181. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 75 to 179. 182. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 182. The method of any of items 175 to 181, comprising: 183. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 175 to 182 How to do it. 184. The mAb or antigen-binding fragment thereof, comprising tyrosine sulfation. 75 to 183. 185. Items 176 to 18, wherein the recombinant expression vector is AAV8 or AAV9. 5. A method according to any one of claims 4 to 4. 186. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vectors were transduced into human hepatocytes or human muscle cells in culture. Item 176, wherein the antibody is confirmed by expressing the mAb or antigen-binding fragment thereof. 185. A method according to any one of claims 1 to 185. 187. Treating systemic osteoporosis or abnormal bone loss or bone weakness (e.g., bone Treating giant cell tumors, Treating treatment-induced bone loss, In patients with breast cancer and prostate cancer slowing bone loss (or increasing bone mass) in patients with skeletal events due to bone metastases; Systemic osteoporosis in human subjects requiring prevention of bone resorption and bone turnover or reduction of bone resorption to treat bone disease or abnormal bone loss or weakness (e.g., to treat giant cell tumor of bone) Treating Treatment-Induced Bone Loss and Slowing Bone Loss in Breast and Prostate Cancer Patients (or increase bone mass), prevent skeletal-related events caused by bone metastasis, or 1. A method for reducing bone resorption and turnover, comprising: a human subject having a circulating antibody expressed from a transgene and administered to human liver cells or human muscle cells; A therapeutically effective amount of substantially full-length or full-length anti-sclerostin (anti- The method comprises delivering an anti-SOST (anti-SOST) mAb or an antigen-binding fragment thereof. 188. Treating osteoporosis or abnormal bone loss or bone weakness (e.g., bone hypertrophy) Treating cystic tumors, treating treatment-induced bone loss, in breast cancer and prostate cancer patients Slow bone loss (or increase bone mass), and prevent skeletal events caused by bone metastases Osteoporosis or osteoporosis in a human subject in need of inhibiting or reducing bone resorption and bone turnover. Treating abnormal bone loss or bone weakness (e.g., treating giant cell tumor of bone, treating Treating induced bone loss, slowing bone loss in breast and prostate cancer patients or increase bone mass), inhibit skeletal-related events caused by bone metastasis or bone resorption and 1. A method of reducing bone turnover, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. Injecting the subject's liver cells or muscle cells with the transgene in human liver cells or human muscle cells. Substantially full-length or operably linked to one or more regulatory sequences that control expression A transcript encoding a full-length anti-sclerostin (anti-SOST) mAb or its antigen-binding fragment administering a therapeutically effective amount of a recombinant nucleotide expression vector containing a transgene. The method comprising: 189. The anti-SOST mAb is romosozumab, as described in item 187 or 188. How to do it. 190. Item 1, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. 87 to 189. 191. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 67, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 313, and 190. A light chain having the amino acid sequence of SEQ ID NO: 68. How to do it. 192. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 137. Item 191, which includes the nucleotide sequence of SEQ ID NO: 138 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 138, which encodes the nucleotide sequence of the nucleotides of the nucleotides of the nucleotides of SEQ ID NO: 138, which encodes the light chain ... How to post. 193. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 87 to 191. 194. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 194. The method of any of items 187 to 193, comprising: 195. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 187 to 194 How to do it. 196. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 87 to 195. 197. Items 188 to 19, wherein the recombinant expression vector is AAV8 or AAV9. 7. A method according to any one of 6. 198. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vectors were transduced into human hepatocytes or human muscle cells in culture. Item 188, wherein the antibody is confirmed by expressing the mAb or antigen-binding fragment thereof. 196. A method according to any one of claims 1 to 196. 199. A method for treating angioedema in a human subject in need thereof. hand, the human subject expresses from the transgene into the circulation and delivers to human muscle cells or human liver cells. A therapeutically effective amount of substantially full-length or full-length antikallikrein (anti-p The method further comprises delivering a Kal) mAb or an antigen-binding fragment thereof. 200. A method for treating angioedema in a human subject in need thereof. hand, to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. Injecting the muscle cells or liver cells of the subject with the transgene in human muscle cells or human liver cells. Substantially full-length or operably linked to one or more regulatory sequences that control expression A vector encoding a full-length anti-kallikrein (anti-pKal) mAb or its antigen-binding fragment and administering a therapeutically effective amount of a recombinant nucleotide expression vector containing a gene encoding the nucleotide sequence of the present invention. Hmm, the above method. 201. The method according to item 199 or 200, wherein the anti-pKal mAb is lanadelumab. method. 202. The antigen-binding fragment is Fab, F(ab')2, or scFv. 199-201. A method according to any one of claims 199-201. 203. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 69, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 314, and 202. A light chain comprising the amino acid sequence of SEQ ID NO: 70. How to do it. 204. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 139. Item 203, which includes the nucleotide sequence of SEQ ID NO: 140 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 140, which encodes the nucleotide sequence of the nucleotides of the nucleotides of the nucleotides of SEQ ID NO: 140, which encodes the light chain ... How to post. 205. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 99 to 203. 206. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 206. The method of any of items 199 to 205, comprising: 207. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 199 to 206 How to do it. 208. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 99 to 207. 209. Items 200 to 20, wherein the recombinant expression vector is AAV8 or AAV9. 8. A method according to any one of claims 7 to 8. 210. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vectors were transduced into human hepatocytes or human muscle cells in culture. Item 200, wherein the antibody is confirmed by expressing the mAb or antigen-binding fragment thereof. 209. A method according to any one of claims 1 to 209. Manufacturing method 211. A method for producing recombinant AAV, comprising: (a)(i) A cis expression cassette flanked by AAV ITRs, wherein the cis expression cassette operably linked to an expression control element that controls expression of the transgene in a human cell. an artificial genome comprising a transgene encoding a therapeutic antibody; (ii) a trans-expression cassette lacking AAV ITRs, which is expressed in host cells in culture; , an expression control gene that drives the expression of AAV rep protein and AAV capsid protein. AAV rep protein and AAV capsid protein operably linked to the element The protein is encoded by a trans-transferase that supplies the rep and cap proteins. with an expression cassette; (iii) Replication and packaging of the artificial genome by AAV capsid proteins Adenoviral helper functions sufficient to allow Culturing a host cell containing (b) recovering recombinant AAVs encapsidating the artificial genome from the cell culture; and The method comprising: 212. The transgene is selected from the group consisting of solanezumab, lecanemab, GSK933776, A L-001, ABBV-8E12, UCB-0107, NI-105(BIIB076) , VX15 / 2503, prasinezumab, NI-202 (BIIB054), MED-1 341, NI-2041.10D12, NI-204.12G7, eptinezumab, fre comprising the heavy and light chain variable domains of manezumab, galcanezumab, or elezanumab; 212. The method of claim 211, encoding a substantially full-length or full-length mAb or antigen-binding fragment. method. 213. The AAV capsid protein is AAV9, AAVrh10, or AAVrh2. 212, which is an AAVrh39 or AAVcy5 capsid protein. How to do it. 214. The transgene is selected from the group consisting of sevacizumab, LKA-651 (NSV2), and LKA -651(NSV3), GSK933776, solanezumab, lecanemab, ascrib Coumab, tesidolumab, ravulizumab, carotuximab, ANX-007, lanadelumab , adalimumab, infliximab, golimumab, satralizumab, sarilumab, tosiri Ibuprofen, siltuximab, clazakizumab, sirukumab, olokizumab, gerilimuzumab or a substantially full-length or full-length mV polypeptide comprising the heavy and light chain variable domains of inebilizumab. 212. The method of claim 211, encoding an Ab or antigen-binding fragment. 215. The AAV capsid protein is AAV2.7m8, AAV8, or AA 215. The method of claim 214, wherein the V9 capsid protein is a V9 capsid protein. 216. The transgene is selected from the group consisting of NI-301, PRX-004, pamrevlumab, and comprising the heavy and light chain variable domains of trolizumab, romosozumab, or lanadelumab, 212. The method of claim 211, encoding a substantially full-length or full-length mAb or antigen-binding fragment. method. 217. The AAV capsid protein is AAV8, AAV9, or AAVrh1. 217. The method of claim 216, wherein the IgG1A1 / IgG2A1 capsid protein is IgG1A1 / IgG2A1 / ... 218. Item 2, wherein the transgene encodes a substantially full-length or full-length mAb. 11. The method according to claim 11. Autoimmune, respiratory, and allergic diseases Material composition 219. Treating atopic dermatitis in a human subject in need thereof. A pharmaceutical composition for placing (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or a sequence at least 95% identical to the amino acid sequence of the AAVrh10 capsid (SEQ ID NO: 145). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or an anti-IL13 mAb or an anti-IL31R mAb operably linked to multiple regulatory sequences. A, or an antigen-binding fragment thereof, encoding an artificial genome; an AAV vector comprising The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition. 220. Anti-IL13 or IL31RA is tralokinumab or nemolizumab 219. The pharmaceutical composition according to item 219. 221. The antigen-binding fragment is Fab, F(ab')2, or scFv. 219. A pharmaceutical composition according to item 219 or 220. 222. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 368, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 396, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 369; or the antigen-binding fragment comprises a light chain having the amino acid sequence of SEQ ID NO: 370; and optionally a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 397; 222. Any of items 219 to 221, comprising a light chain having the amino acid sequence of SEQ ID NO: 371. The pharmaceutical composition described. 223. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 384. the nucleotide sequence of SEQ ID NO: 385 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 385 encoding the nucleotides of ... SEQ The nucleotide sequence of SEQ ID NO: 386 encodes the heavy chain, and the nucleotide sequence of SEQ ID NO: 387 encodes the light chain. Item 223. The pharmaceutical composition according to item 222, comprising the nucleotide sequence of sequence number 387. 224. Item 224, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant. 222. A pharmaceutical composition according to any one of claims 219 to 221. 225. The transgene is secreted and translated in the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-modification 225. The pharmaceutical composition according to any of items 219 to 224, encoding 226. Item 22, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 5. The pharmaceutical composition described in 5. 227. Any of items 219 to 226, wherein the AAV capsid is AAV8. The pharmaceutical composition described. 228. A method for treating eosinophilic asthma in a human subject in need thereof. A pharmaceutical composition for (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or a sequence at least 95% identical to the amino acid sequence of the AAVrh10 capsid (SEQ ID NO: 145). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or an anti-IL5R mAb or an anti-IgE m mAb operably linked to multiple regulatory sequences. an artificial genome encoding an Ab or an antigen-binding fragment thereof; an AAV vector comprising The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition. 229. If the anti-IL5R or anti-IgE mAb is reslizumab or omalizumab, Item 229. The pharmaceutical composition according to Item 228. 230. Item 2, wherein the antigen-binding fragment is Fab, F(ab')2, or scFv. 28 or 229. The pharmaceutical composition according to claim 28 or 229. 231. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 364, and optionally the amino acid sequence of SEQ ID NO: 3 a heavy chain having an Fc polypeptide of amino acid sequence 94, and an Fc polypeptide of amino acid sequence 365; a light chain having the amino acid sequence of SEQ ID NO: 372, and optionally the amino acid sequence of SEQ ID NO: 398; a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 373; 231. The pharmaceutical composition according to any of items 228 to 230, comprising a light chain which is 232. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 380 the nucleotide sequence of SEQ ID NO: 381 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 382 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 388 encoding the light chain and the nucleotide sequence of SEQ ID NO: 389 encoding the light chain. 232. The pharmaceutical composition according to item 231, comprising a leutide sequence. 233. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant, item 2 232. A pharmaceutical composition according to any one of claims 28 to 231. 234. The transgene is secreted and translated in the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-modification 234. The pharmaceutical composition according to any of items 228 to 233, encoding 235. Item 23, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 4. The pharmaceutical composition according to claim 4. 236. Any of items 228 to 235, wherein the AAV capsid is AAV8. The pharmaceutical composition described. 237. In human subjects requiring treatment for asthma or chronic obstructive pulmonary disease (COPD), 1. A pharmaceutical composition for treating asthma or chronic obstructive pulmonary disease (COPD), comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or a sequence at least 95% identical to the amino acid sequence of the AAVrh10 capsid (SEQ ID NO: 145). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or anti-IL5, anti-IL-5R, anti-IgE, or or an anti-TSLP mAb, or an antigen-binding fragment thereof; an AAV vector comprising The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition. 238. Anti-IL-5, anti-IL5R, anti-IgE, or anti-TSLP mAb was used in Benrali 238. The method according to item 237, wherein the compound is izumab, reslizumab, omalizumab, or tezepelumab. Pharmaceutical compositions. 239. The antigen-binding fragment is Fab, F(ab')2, or scFv. 239. A pharmaceutical composition according to item 237 or 238. 240. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 364, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 394, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 365; a light chain having the amino acid sequence of SEQ ID NO: 366, and optionally, the amino acid sequence of SEQ ID NO: 395; a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 367; a light chain having the amino acid sequence of SEQ ID NO: 372 and a light chain having the amino acid sequence of SEQ ID NO: 373 or the amino acid sequence of SEQ ID NO: 374, and optionally the amino acid sequence of SEQ ID NO: 284 an IgG2 Fc polypeptide, and a light chain having the amino acid sequence of SEQ ID NO: 375; 239. A pharmaceutical composition according to any of items 237 to 239. 241. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 380. the nucleotide sequence of SEQ ID NO: 381 encoding the heavy chain; The nucleotide sequence of SEQ ID NO: 382, which encodes the light chain, and the nucleotide sequence of SEQ ID NO: 383, which encodes the light chain the nucleotide sequence of SEQ ID NO: 388 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 389 encoding the light chain the nucleotide sequence of SEQ ID NO: 389; the nucleotide sequence of SEQ ID NO: 390 encoding the heavy chain; Item 240, comprising the nucleotide sequence of SEQ ID NO: 391 encoding the light chain and the light chain. The pharmaceutical composition described in 242. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant, item 2 37 to 240. A pharmaceutical composition according to any one of claims 37 to 240. 243. The transgene is secreted and translated in the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-modification 243. The pharmaceutical composition according to any of items 237 to 242, encoding 244. The signal sequence is selected from the signal sequences of Tables 2 or 3. 3. The pharmaceutical composition according to claim 3. 245. Any of items 237 to 244, wherein the AAV capsid is AAV8. The pharmaceutical composition described. 246. Treatment of chronic idiopathic urticaria in a human subject in need thereof. A pharmaceutical composition for placing (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or a sequence at least 95% identical to the amino acid sequence of the AAVrh10 capsid (SEQ ID NO: 145). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or an anti-IgE mAb or its antigen-binding activity operably linked to a plurality of regulatory sequences. Encoding fragments, artificial genomes; an AAV vector comprising The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition. 247. The pharmaceutical composition according to item 246, wherein the anti-IgE mAb is omalizumab. 248. The antigen-binding fragment is Fab, F(ab')2, or scFv. 248. A pharmaceutical composition according to item 246 or 247. 249. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 372, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 373; 249. The pharmaceutical composition according to any of items 246 to 248, comprising a light chain having the sequence AGA ... 250. The transgene comprises the nucleotide sequence of SEQ ID NO: 388, encoding the heavy chain. Item 249, which includes the nucleotide sequence of SEQ ID NO: 389 encoding the nucleotide sequence of the nucleotides ... SEQ ID NO: 389 encoding the light chain. The pharmaceutical composition described above. 251. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant, item 2 46 to 249. A pharmaceutical composition according to any one of claims 46 to 249. 252. The transgene is secreted and translated in the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-modification 252. The pharmaceutical composition according to any of items 246 to 251, encoding 253. The signal sequence is selected from the signal sequences of Table 2 or 3. 2. The pharmaceutical composition according to claim 2. 254. The medicament according to any one of items 246 to 253, wherein the AAV capsid is AAV8. composition. Treatment 254. Treatment of atopic dermatitis in a human subject in need thereof. A method of placing a device, comprising: a therapeutically effective amount of a compound produced by human liver cells or human muscle cells into the circulation of said human subject; and delivering anti-IL13 or anti-IL31RA mAb or antigen-binding fragment thereof. The method comprising: 255. Treatment of atopic dermatitis in a human subject in need thereof. A method of placing a device, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. , Injecting the subject's liver cells or muscle cells with the transgene in human liver cells or human muscle cells. anti-IL13 or anti-IL13, operably linked to one or more regulatory sequences that control expression A therapeutic agent comprising a transgene encoding the IL31RA mAb or an antigen-binding fragment thereof. The method comprises administering a therapeutically effective amount of a recombinant nucleotide expression vector. 256. Anti-IL13 or anti-IL31RA mAb is used in combination with tralokinumab or Nemoris 256. The method of item 254 or 255, wherein the antibody is a mab. 257. The antigen-binding fragment is Fab, F(ab')2, or scFv. 257. A method according to any one of items 254 to 256. 258. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 368, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 396, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 369; a light chain having the amino acid sequence of SEQ ID NO: 370, and optionally, the amino acid sequence of SEQ ID NO: 39 a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 7, and an amino acid sequence of SEQ ID NO: 371; 258. The method of any of items 254 to 257, comprising a light chain having the following structure: 259. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 384. the nucleotide sequence of SEQ ID NO: 385 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 386 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 386 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 387 encoding the light chain. 259. The method of claim 258, comprising a nucleic acid sequence. 260. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 259. The method according to any one of items 254 to 258. 261. The mAb or its antigen-binding fragment contains α2,6-sialylated glycans. 261. The method according to any one of items 254 to 260. 262. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 254 to 261 How to do it. 263. Item 2, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 54 to 262. 264. Items 254 to 26, where the recombinant expression vector is AAV8 or AAV9. 3. A method according to any one of the preceding claims. 265. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, Any of the methods described above. 266. A method for treating eosinophilic asthma in a human subject in need thereof. There was, a therapeutically effective amount of a compound produced by human liver cells or human muscle cells into the circulation of said human subject; , comprising delivering an anti-IL5R or anti-IgE mAb or an antigen-binding fragment thereof; The method. 267. A method for treating eosinophilic asthma in a human subject in need thereof. There was, to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. Injecting the subject's liver cells or muscle cells with the transgene in human liver cells or human muscle cells. operably linked to one or more regulatory sequences that control expression of an anti-IL5R or anti-IL5R polypeptide; Therapeutic agents containing transgenes encoding IgE mAbs, or antigen-binding fragments thereof The method comprises administering an effective amount of a recombinant nucleotide expression vector. 268. If the anti-IL5R or anti-IgE mAb is reslizumab or omalizumab, 268. The method according to item 266 or 267, 269. The antigen-binding fragment is Fab, F(ab')2, or scFv. 269. A method according to any one of items 266 to 268. 270. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 366, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 395, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 367; a light chain having the amino acid sequence of SEQ ID NO: 372, and optionally, the amino acid sequence of SEQ ID NO: 39 a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 373; 269. The method of any of items 266 to 269, comprising a light chain having the following structure: 271. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 382. the nucleotide sequence of SEQ ID NO: 383 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 384 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 388 encoding the light chain and the nucleotide sequence of SEQ ID NO: 389 encoding the light chain. 271. The method of claim 270, comprising a nucleic acid sequence. 272. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 271. The method according to any of items 266 to 270. 273. The mAb or antigen-binding fragment thereof binds to α2,6-sialylated glycans. 273. The method of any of items 266 to 272, comprising 274. The mAb or antigen-binding fragment thereof is glycosylated but not detectably glycosylated. does not contain NeuGc or α-Gal, as described in any of items 266 to 273 How to do it. 275. Item 2, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 66 to 274. 276. Items 266 to 27, where the recombinant expression vector is AAV8 or AAV9. 6. A method according to any one of 5. 277. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, Any of the methods described above. 278. Asthma or COPD in a human subject in need of treatment for asthma or COPD. A method of treating a therapeutically effective amount of a compound produced by human liver cells or human muscle cells into the circulation of said human subject; , anti-IL5, anti-IL5R, anti-IgE, or anti-TSLP mAb or antigen-binding fragment thereof delivering the piece. 279. A method for treating eosinophilic asthma in a human subject in need thereof. There was, to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. Injecting the subject's liver cells or muscle cells with the transgene in human liver cells or human muscle cells. anti-IL5R, anti-IL, operably linked to one or more regulatory sequences that control expression 5. Transgenic vectors encoding anti-IgE or anti-TSLP mAbs, or antigen-binding fragments thereof and administering a therapeutically effective amount of a recombinant nucleotide expression vector containing a gene encoding the nucleotide sequence of the present invention. Hmm, the above method. 280. Anti-IL5R, anti-IL5, anti-IgE, or anti-TSLP mAb is used in Benraliz tezepellumab, reslizumab, omalizumab, or tezepelumab, items 278 or 27 9. The method according to claim 9. 281. The antigen-binding fragment is Fab, F(ab')2, or scFv. 278-280. A method according to any one of claims 278-280. 282. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 364, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 394, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 365; a light chain having the amino acid sequence of SEQ ID NO: 366, and optionally, the amino acid sequence of SEQ ID NO: 39 a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 5, and an amino acid sequence of SEQ ID NO: 367; a light chain having the amino acid sequence of SEQ ID NO: 372, and optionally the amino acid sequence of SEQ ID NO: 398; a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 373; or a light chain having the amino acid sequence of SEQ ID NO: 374, and optionally the amino acid sequence of SEQ ID NO: 284 and a light chain having the amino acid sequence of SEQ ID NO: 375. 282. The method of any of items 278 to 281, comprising: 283. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 380. the nucleotide sequence of SEQ ID NO: 381 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 382 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 383 encoding the light chain, or the nucleotide sequence of SEQ ID NO: 388 encoding the heavy chain, and the light chain or the heavy chain, encoding the nucleotide sequence of SEQ ID NO: 389; 390, and the nucleotide sequence of SEQ ID NO: 391, encoding the light chain 283. The method of claim 282, comprising: 284. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 284. The method according to any one of items 278 to 283. 285. The mAb or antigen-binding fragment thereof binds α2,6-sialylated glycans. 285. The method of any of items 278 to 284, comprising 286. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 278 to 285 How to do it. 287. Item 2, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 78 to 286. 288. Items 278 to 28, where the recombinant expression vector is AAV8 or AAV9. 7. A method according to any one of claims 7 to 7. 289. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, Any of the methods described above. 290. Treatment of chronic spontaneous urticaria in a human subject in need thereof. A method of placing a device, comprising: a therapeutically effective amount of a compound produced by human liver cells or human muscle cells into the circulation of said human subject; The method comprises delivering an anti-IgE mAb or an antigen-binding fragment thereof. 291. A method for treating eosinophilic asthma in a human subject in need thereof, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. Injecting the subject's liver cells or muscle cells with the transgene in human liver cells or human muscle cells. an anti-IgE mAb or a mAb operably linked to one or more regulatory sequences that control its expression; a therapeutically effective amount of a recombinant nucleic acid comprising a transgene encoding the antibody or an antigen-binding fragment thereof; administering a leutidine expression vector. 292. The method according to item 290 or 291, wherein the anti-IgE mAb is omalizumab. method. 293. The antigen-binding fragment is Fab, F(ab')2, or scFv. 290-292. A method according to any one of claims 290-292. 294. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 372, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 373; 294. The method of any of items 290 to 293, comprising a light chain having the sequence 295. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 388. Item 294, which includes the nucleotide sequence of SEQ ID NO: 389 encoding the nucleotide sequence of the nucleotides of the nucleotides of SEQ ID NO: 389, encoding the light chain of the nucleotides of the nucleotides of SEQ ID NO: 389, How to post. 296. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 296. The method according to any one of items 290 to 295. 297. The mAb or antigen-binding fragment thereof binds to α2,6-sialylated glycans. 297. The method of any of items 290 to 296, comprising: 298. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, as described in any of items 290 to 297 How to do it. 299. Item 2, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 90 to 298. 300. Items 290 to 29, where the recombinant expression vector is AAV8 or AAV9. 9. A method according to any one of claims 1 to 9. 301. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, Any of the methods described above. Manufacturing method 302. The transgene is selected from the group consisting of benralizumab, reslizumab, tralokinumab, and nephrotoxicosis. A compound comprising the heavy and light chain variable domains of molizumab, omalizumab, or tezepelumab. 212. The method of claim 211, encoding a full-length or full-length mAb or antigen-binding fragment. Law. 303. The AAV capsid protein is AAV8, AAV9, or AAVrh1. 303. The method of claim 302, wherein the IgG1A1 / IgG2A1 capsid protein is IgG1A1 / IgG2A1 / IgG1B ... myasthenia gravis Material composition 304. A method for treating myasthenia gravis in a human subject in need thereof. A pharmaceutical composition for (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or a sequence at least 95% identical to the amino acid sequence of the AAVrh10 capsid (SEQ ID NO: 145). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; A transgene controls the expression of a transgene in human liver cells or human muscle cells. or an anti-C5 mAb or antigen-binding fragment thereof operably linked to multiple regulatory sequences. Encoding pieces, artificial genomes; an AAV vector comprising The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition. 305. The pharmaceutical composition according to item 304, wherein the anti-C5 is ravulizumab. 306. The antigen-binding fragment is Fab, F(ab')2, or scFv. A pharmaceutical composition according to item 304 or 305. 307. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 362, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 393, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 363; 307. The pharmaceutical composition according to any of items 304 to 306, comprising a light chain having the sequence AGA ...G. 308. The transgene encodes a heavy chain, the nucleotide sequence of SEQ ID NO: 378. Item 307, which includes the nucleotide sequence of SEQ ID NO: 379, encoding the nucleotide sequence of the nucleotides ... SEQ ID NO: 379, encoding the light chain. The pharmaceutical composition described above. 309. The antibody or antigen-binding fragment thereof is a hyperglycosylated mutant, item 3 04 to 308. A pharmaceutical composition according to any one of claims 04 to 308. 310. The transgene is secreted and translated in the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-modification 311. The pharmaceutical composition according to any of items 304 to 310, encoding 311. Item 31, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 10. The pharmaceutical composition according to claim 0. 312. Any of items 304 to 311, wherein the AAV capsid is AAV8. The pharmaceutical composition described. Treatment 313. A method for treating myasthenia gravis in a human subject in need thereof. There was, a therapeutically effective amount of a compound produced by human liver cells or human muscle cells into the circulation of said human subject; The method comprises delivering an anti-C5 mAb or an antigen-binding fragment thereof. 314. A method for treating myasthenia gravis in a human subject in need thereof. There was, to form a depot that releases the HuPTM form of the mAb or antigen-binding fragment thereof. The subject's liver cells or muscle cells are then transduced with a transgene for expression in human liver cells or human muscle cells. an anti-C5 mAb or an anti-C5 mAb operably linked to one or more regulatory sequences controlling expression a therapeutically effective amount of a recombinant nucleoside containing a transgene encoding the antigen-binding fragment thereof; The method further comprises administering a tide expression vector. 315. The method according to item 313 or 314, wherein the anti-C5 is ravulizumab. 316. The antigen-binding fragment is Fab, F(ab')2, or scFv. 316. A method according to any one of items 313 to 315. 317. The antigen-binding fragment has the amino acid sequence of SEQ ID NO: 362, and optionally, SEQ ID NO: a heavy chain having an Fc polypeptide of the amino acid sequence of SEQ ID NO: 393, and an Fc polypeptide of the amino acid sequence of SEQ ID NO: 363; 317. The method of any of items 313 to 316, comprising a light chain having the sequence 318. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 378 Item 260, which includes the nucleotide sequence of SEQ ID NO: 379, encoding the nucleotide sequence of the nucleotides ... SEQ ID NO: 379, encoding the light chain. How to post. 319. The mAb or its antigen-binding fragment is a hyperglycosylated mutant. 9. The method according to any one of items 313 to 318. 320. The mAb or its antigen-binding fragment contains α2,6-sialylated glycans. 319. The method according to any one of items 313 to 319. 321. The mAb or antigen-binding fragment thereof is glycosylated but detectably does not contain NeuGc or α-Gal, which can be used for the treatment of ulcerative colitis. How to do it. 322. The mAb or antigen-binding fragment thereof contains tyrosine sulfation. 321. A method according to any one of claims 3 to 321. 323. Items 313 to 32, where the recombinant expression vector is AAV8 or AAV9. 2. A method according to any one of claims 1 to 11. 324. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, Any of the methods described above. Manufacturing method 325. The transgene encodes the heavy and light chain variable domains of ravulizumab. Item 21, encoding a substantially full-length or full-length mAb or antigen-binding fragment, including The method described in 1. 326. The AAV capsid protein is AAV8, AAV9, or AAVrh1. 305. The method of claim 304, wherein the IgG1A1 / IgG2A1 capsid protein is IgG1A1 / IgG2A1 / IgG1B1 / IgG2A1 / IgG2A1 / IgG3A1 / IgG4A ... Compositions and methods for inhibiting immune responses 327. In human subjects in need of reducing, inhibiting, or ameliorating a deleterious immune response 1. A pharmaceutical composition for reducing, inhibiting, or ameliorating a deleterious immune response in a mammal, comprising: A viral capsid AAV8 capsid that is at least 95% identical to the amino acid sequence of (a) AAV9 capsid (SEQ ID NO: 144), AAVrh10 capsid (SEQ ID NO: 145), AAV10 capsid (SEQ ID NO: 146), AAV11 capsid (SEQ ID NO: 147), AAV12 capsid (SEQ ID NO: 148), AAV13 capsid (SEQ ID NO: 149), AAV14 capsid (SEQ ID NO: 150), A Do (SEQ ID NO: 145); and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; an artificial genome anti-interacting antibody, wherein the transgene encodes a substantially full-length or full-length mAb of anti-IL6 receptor (anti-IL6R) or anti-interleukin-6 (IL6), or the antigen-binding fragment, to one or more regulatory sequences controlling expression of the transgene within operably linked human liver cells or muscle cells; an AAV vector comprising The AAV vector is formulated for subcutaneous, intramuscular, intravenous, or pulmonary administration to a subject. The pharmaceutical composition. 328. The anti-IL6R mAb is satralizumab, sarilumab, or tocilizumab. or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, 328. The pharmaceutical composition according to item 327, which is olokizumab or gerilimu- zumab. 329. The antigen-binding fragment is Fab, F(ab')2, or scFv. 327 or 328. A pharmaceutical composition according to item 327 or 328. 330. The full-length mAb or antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 59, and Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 309, and a light chain having the amino acid sequence of SEQ ID NO: 60; or the amino acid sequence of SEQ ID NO: 61, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 310, and a light chain having the amino acid sequence of SEQ ID NO: 62; or the amino acid sequence of SEQ ID NO: 331, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 355, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 332; or the amino acid sequence of SEQ ID NO: 333, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 356, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 334; or the amino acid sequence of SEQ ID NO: 335, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 357, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 336; or the amino acid sequence of SEQ ID NO: 337, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 358, and SEQ ID NO: a light chain having the amino acid sequence of SEQ ID NO: 338; or the amino acid sequence of SEQ ID NO: 339, and optionally 283, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 284, and a light chain having the amino acid sequence of SEQ ID NO: 340; or the amino acid sequence of SEQ ID NO: 341, and optionally , a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and SEQ ID NO: 320. The method of any of items 327 to 329, comprising administering to a subject a method for treating a subject ... a light chain having an amino acid sequence of 342. Pharmaceutical composition. 331. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 129 the nucleotide sequence of SEQ ID NO: 130 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 131 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 132 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain, and the light chain or the heavy chain encoding the nucleotide sequence of SEQ ID NO: 344; 345, and the nucleotide sequence encoding the light chain, SEQ ID NO: 346 or the nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 348 encoding the light chain , the nucleotide sequence of SEQ ID NO: 348; or the nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 350 encoding the nucleotide sequence of the light chain; or the heavy chain the nucleotide sequence of SEQ ID NO: 351 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 3 or the nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain. 330, comprising the nucleotide sequence of SEQ ID NO: 354 encoding the light chain, A pharmaceutical composition comprising: 332. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 27 to 331. A pharmaceutical composition according to any one of claims 27 to 331. 333. The transgene is secreted and translated in the human liver cells or human muscle cells. signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct post-modification 332. The pharmaceutical composition according to any of items 327 to 331, encoding 334. The signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 3 or Table 4. Finished product. 335. Any of items 327 to 334, wherein the AAV capsid is AAV8. The pharmaceutical composition described. 336. In human subjects in need of reducing, inhibiting, or ameliorating a deleterious immune response 1. A pharmaceutical composition for reducing, inhibiting, or ameliorating a deleterious immune response in a mammal, comprising: a transgene expressed in the circulation or tissues that are targets of the immune response of said human subject; and a therapeutically effective amount of an anti-interleukin produced by human muscle cells or liver cells. -6 receptor (anti-IL6R) mAb, anti-interleukin-6 (IL6) mAb, or The method comprises delivering a substantially full-length or full-length mAb of an antigen-binding fragment of the antibody. 337. In human subjects in need of reducing, inhibiting, or ameliorating a deleterious immune response 1. A pharmaceutical composition for reducing, inhibiting, or ameliorating a deleterious immune response in a mammal, comprising: to form a depot that releases the HuPTM form of the mAb or its antigen-binding fragment. inducing into muscle cells or liver cells of said human subject, the expression of a transgene in the human muscle cells or liver cells. an anti-interleukin operably linked to one or more regulatory sequences that control its expression; -6 receptor (anti-IL6R) mAb, anti-interleukin-6 (IL6) mAb, or a transgene encoding a substantially full-length or full-length mAb of an antigen-binding fragment of The method comprises administering a therapeutically effective amount of a recombinant nucleotide expression vector. 338. The anti-IL6R is satralizumab, sarilumab, or tocilizumab. , or anti-IL6 mAb, such as siltuximab, clazakizumab, sirukumab, oroxazolidin. 338. The method of claim 336 or 337, wherein the antibody is ribozyme, ribozyme inhibitor, or gerilimuzumab. 339. The antigen-binding fragment is Fab, F(ab')2, or scFv. 336. A method according to any one of items 336 to 338. 340. The mAb or antigen-binding fragment has the amino acid sequence of SEQ ID NO: 59, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 309, and a light chain having the amino acid sequence of SEQ ID NO: 60; or the amino acid sequence of SEQ ID NO: 61, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 310, and a a light chain having the amino acid sequence of SEQ ID NO: 341; or a light chain having the amino acid sequence of SEQ ID NO: 342, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and a light chain having the amino acid sequence of SEQ ID NO: 331; or a light chain having the amino acid sequence of SEQ ID NO: 332, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 355, and a light chain having the amino acid sequence of SEQ ID NO: 333; or a light chain having the amino acid sequence of SEQ ID NO: 334; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 356, and a light chain having the amino acid sequence of SEQ ID NO: 4; or the amino acid sequence of SEQ ID NO: 335, and optionally a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 357, and a light chain having the amino acid sequence of SEQ ID NO: 337; or a light chain having the amino acid sequence of SEQ ID NO: 338; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 358, and a light chain having the amino acid sequence of SEQ ID NO: 339; or a light chain having the amino acid sequence of SEQ ID NO: 340; a heavy chain having an Fc polypeptide having the IgG1 amino acid sequence of sequence number 283, and the sequence a light chain having the amino acid sequence of SEQ ID NO: 340; or the amino acid sequence of SEQ ID NO: 341, and any Optionally, a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and the sequence 339. The method according to any one of items 336 to 339, comprising administering to a subject a light chain having the amino acid sequence of item 342. How to do it. 341. The transgene encodes the heavy chain, the nucleotide sequence of SEQ ID NO: 129. the nucleotide sequence of SEQ ID NO: 130 encoding the heavy chain and the light chain; or the nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain The nucleotide sequence of SEQ ID NO: 131 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 132 encoding the light chain. or the nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain, and the light chain or the heavy chain encoding the nucleotide sequence of SEQ ID NO: 344; 345, and the nucleotide sequence encoding the light chain, SEQ ID NO: 346 or the nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain, and the nucleotide sequence of SEQ ID NO: 348 encoding the light chain , the nucleotide sequence of SEQ ID NO: 348; or the nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain the nucleotide sequence of SEQ ID NO: 350 encoding the nucleotide sequence of the light chain; or the heavy chain the nucleotide sequence of SEQ ID NO: 351 encoding the light chain, and the nucleotide sequence of SEQ ID NO: 3 or the nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain. 340, comprising the nucleotide sequence of SEQ ID NO: 354 encoding the light chain, How to do it. 342. The mAb or antigen-binding fragment thereof is a hyperglycosylated mutant; or the Fc polypeptide of the mAb is glycosylated or non-glycosylated, 36 to 339. 343. The mAb or antigen-binding fragment thereof binds to α2,6-sialylated glycans. 343. The method of any of items 336 to 342, comprising: 344. The mAb or antigen-binding fragment thereof is glycosylated but not detectably glycosylated. does not contain NeuGc or α-Gal, as described in any of items 336 to 343 How to do it. 345. Item 3, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 36 to 344. 346. Items 336 to 34, where the recombinant expression vector is AAV8 or AAV9. 6. A method according to any one of 5. 347. The production of the HuPTM form of the mAb or antigen-binding fragment thereof is The recombinant nucleotide expression vector is transfected into human CNS cells in culture, and the mAb or an antigen-binding fragment thereof, Any of the methods described above. AAV embodiments encoding full-length mAb compositions 348. A composition comprising an adeno-associated virus (AAV) vector, Adeno-associated virus (AAV) vectors a. AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), A AVrh10 capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid or optionally at least 95% identical to the amino acid sequence of the AAVcy5 capsid. the viral AAV capsid; and b.AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette, the expression cassette comprising a transgene, The transgene contains one or more regulatory sequences that control the expression of the transgene in human cells. an artificial genome encoding a substantially full-length or full-length mAb operably linked to and c. A transgene directing the secretion and post-translational modification of the mAb. The composition encodes signal sequences at the N-terminus of the main and light chains. 349. The mAb comprises a heavy chain having an Fc polypeptide, and 1, 40, 49, 58, 67, 76, 85, 95, 107, 119, 131, 143, 1 55, 167, 179, 191, 203, 222, 231, 240, 249, 258, 2 Any one of the sequence combinations designated as 70, 282, 294, 307, and 317 349. The composition of item 348, comprising a light chain having the following structure: 350. The composition according to items 348 to 349, wherein the mAb is full-length lanadelumab. thing. 351. The transgene comprises a nucleotide sequence encoding the heavy and light chains of the mAb. 351. The composition of item 350, comprising a Furin / T2A linker between the sequences. 352. The combination according to items 350 to 351, wherein the regulatory sequence comprises a regulatory sequence from Table 1. Finished product. 353. The regulatory sequence is selected from the group consisting of LMTP6 promoter, ApoE, hAAT regulatory sequence, C AG promoter, CK8 regulatory sequence, or TBG promoter, as described in Item 352. The composition described above. 354. The transgene is selected from the group consisting of SEQ ID NOs: 141, 286, 287, and 435-4 44. The composition according to items 350 to 353, comprising a nucleotide sequence of 44. 355. The viral capsid is an AAV8 viral capsid. 54. The composition according to claim 54. 356. Delivering lanadelumab to the bloodstream to treat hereditary angioedema in humans. A pharmaceutical composition for delivering lanadelumab to the bloodstream to treat hereditary angioedema in elephants. There was, The composition comprises one or more molecules that regulate the expression of a transgene in muscle cells and / or liver cells. a transgene encoding lanadelumab operably linked to one or more regulatory sequences; a recombinant AAV comprising The recombinant AAV is administered to the subject at a concentration of at least 5 μg / ml to at least 35 μg / ml The human subject is administered a lanadelumab plasma level of 100 mg / ml of lanadelumab. and human subjects at a dose sufficient to result in expression and secretion of lanadelumab from the transgene. The pharmaceutical composition is administered into the bloodstream. 357. Treatment of hereditary angioedema in a human subject in need thereof. A method of placing a device, comprising: The subject is provided with one or more transgenes that control expression of the transgene in muscle cells and / or liver cells. The method comprises administering to a subject the method of claim 1, further comprising administering to said subject a transgene encoding lanadelumab operably linked to a number of regulatory sequences. The dose of the composition comprising the recombinant AAV is administered to the subject at a concentration of at least 5 μg / ml to less than 5 μg / ml. To produce lanadelumab plasma levels of at least 35 μg / ml of lanadelumab, and administering the compound in an amount sufficient to result in expression from the lanadelumab gene and secretion of lanadelumab. The method comprising: 358. The transgene is selected from the group consisting of SEQ ID NOs: 141, 286, 287, and 435-4 358. The method or composition of item 356 or 357, comprising the nucleotide sequence of 44. 359. Lanadelumab plasma levels are between 20 μg / ml and 35 μg / ml. 56-358. 360. Lanadelumab plasma levels are maintained for at least 3 months, as determined by items 356 to 359. A method or composition according to claim 359. 361. Lanadelumab antibodies secreted into plasma were detected by kinetic enzyme function assay. At least 40%, 45%, 50%, 55%, 60% of pKal activity as measured 360. The method or composition according to any one of claims 356 to 360, wherein the method or composition exhibits a reduction of more than 65% or 70%. thing. 362. The activity of lanadelumab antibody was evaluated at 2, 3, 4, 5, and 6 weeks after administration. Measure at week 1, 7, 8, 9, 10, 11 or 12, item 36 1. The method or composition according to claim 1. 363. A method for determining human anti-pKal antibody activity in a sample, comprising: a. Incubating the sample with activated human pKal; b. The sample incubated with activated human pKal was then subjected to ELISA using the synthetic substrate Pro-P incubating with he-Arg-AMC; c. Measuring the release of AMC over a 3 hour period compared to a control sample The method comprising: Further embodiments 364. An antibody or antigen-binding fragment thereof is delivered to the bloodstream of a human subject in need thereof. , a pharmaceutical composition for delivering an antibody or antigen-binding fragment thereof, comprising: (a) AAV viral capsids that infect hepatocytes and / or muscle cells; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; The Lance gene is operable with a chimeric promoter that directs expression in muscle cells and liver cells. an artificial genome encoding a full-length antibody or an antigen-binding fragment thereof linked to an AAV vector comprising The pharmaceutical composition, wherein the AAV vector is formulated for intramuscular administration. 365. The chimeric promoter is selected from the group consisting of LMTP6 (SEQ ID NO: 320), LMTP13 ( SEQ ID NO: 321), LMTP14 (SEQ ID NO: 322), LMTP15 (SEQ ID NO: 323) , LMTP18 (SEQ ID NO: 324), LMTP19 (SEQ ID NO: 325), or LMTP 20 (SEQ ID NO: 326). 366. Item 36, wherein the chimeric promoter is LMPT6 (SEQ ID NO: 320). 5. The pharmaceutical composition described in 5. 367. The AAV viral capsid is an AAV8 capsid (SEQ ID NO: 143), AA Amino acid sequence of V9 capsid (SEQ ID NO: 144), AAVrh10 capsid (SEQ ID NO: 145) 367. The method of claim 366, wherein the nucleic acid sequence is at least 95% identical to the nucleic acid sequence of Pharmaceutical composition. 368. The antibody is sevacizumab, LKA-651, ravulizumab, adalimumab, Infliximab, golimumab, elezanumab, NI-301, PRX-004, Pamule Blumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilimusma satralizumab, sarilumab, tocilizumab, inebilizumab, etrolizumab, Mosozumab, lanadelumab, benralizumab, reslizumab, tralokinumab, nemoris umab, omalizumab, or tezepelumab, in any of items 364 to 3673 The pharmaceutical composition described. 369. Item 364, wherein the transgene comprises the nucleotide sequence SEQ ID NO: 443. 366. A pharmaceutical composition according to any one of claims 1 to 366. [Brief explanation of the drawings]

[0017] 4. Brief description of the drawings [Figure 1] FIG. 1 is a schematic diagram of an rAAV vector genome construct containing expression cassettes encoding the heavy and light chains of the Fab region of a therapeutic mAb, controlled by expression elements and flanked by AAV ITRs. [Figure 2A]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against amyloid β peptide: solanezumab Fab (Figure 2A), GSK933776 (Figure 2B), and lecanemab (Figure 2C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 2B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against amyloid β peptide: solanezumab Fab (Figure 2A), GSK933776 (Figure 2B), and lecanemab (Figure 2C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 2C] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against amyloid β peptide: solanezumab Fab (Figure 2A), GSK933776 (Figure 2B), and lecanemab (Figure 2C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 3] Amino acid sequence of the transgene construct for the Fab region of a therapeutic antibody against sortilin: AL-001 (Figure 3). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 4A]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against tau: ABBV-8E12 (Figure 4A), UCB-0107 (Figure 4B), and NI-105 (Figure 4C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 4B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against tau: ABBV-8E12 (Figure 4A), UCB-0107 (Figure 4B), and NI-105 (Figure 4C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 4C] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against tau: ABBV-8E12 (Figure 4A), UCB-0107 (Figure 4B), and NI-105 (Figure 4C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 5] Amino acid sequence of the transgene construct for the Fab region of a therapeutic antibody against SEMA4D: VX15 / 2503 (Figure 5). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 6A]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against α-synuclein: prasinezumab (FIG. 6A), NI-202 (FIG. 6B), and MEDI-1341 (FIG. 6C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 6B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against α-synuclein: prasinezumab (FIG. 6A), NI-202 (FIG. 6B), and MEDI-1341 (FIG. 6C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 6C] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against α-synuclein: prasinezumab (FIG. 6A), NI-202 (FIG. 6B), and MEDI-1341 (FIG. 6C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 7A] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies against superoxide dismutase 1 (SOD1): NI-205.10D12 (FIG. 7A); and NI-205.12G7 (FIG. 7B). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 7B] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies against superoxide dismutase 1 (SOD1): NI-205.10D12 (FIG. 7A); and NI-205.12G7 (FIG. 7B). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 8A] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against CGRPR: eptinezumab (FIG. 8A), fremanezumab (FIG. 8B), and galcanezumab (FIG. 8C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 8B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against CGRPR: eptinezumab (FIG. 8A), fremanezumab (FIG. 8B), and galcanezumab (FIG. 8C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 8C]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against CGRPR: eptinezumab (FIG. 8A), fremanezumab (FIG. 8B), and galcanezumab (FIG. 8C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 9A] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-VEGF, sevacizumab (Figure 9A); anti-EpoR, LKA-651.NVS2 (Figure 9B), and LKA-651.NVS3 (Figure 9C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 9B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-VEGF, sevacizumab (Figure 9A); anti-EpoR, LKA-651.NVS2 (Figure 9B), and LKA-651.NVS3 (Figure 9C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 9C]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-VEGF, sevacizumab (Figure 9A); anti-EpoR, LKA-651.NVS2 (Figure 9B), and LKA-651.NVS3 (Figure 9C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 10A] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological agents: anti-ALK1, asclinbacumab (FIG. 10A); anti-C5, tesidolumab (FIG. 10B) and ravulizumab (FIG. 10D); and anti-endoglin, carotuximab (FIG. 10C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 10B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological agents: anti-ALK1, asclinbacumab (FIG. 10A); anti-C5, tesidolumab (FIG. 10B) and ravulizumab (FIG. 10D); and anti-endoglin, carotuximab (FIG. 10C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 10C]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological agents: anti-ALK1, asclinbacumab (FIG. 10A); anti-C5, tesidolumab (FIG. 10B) and ravulizumab (FIG. 10D); and anti-endoglin, carotuximab (FIG. 10C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 10D] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological agents: anti-ALK1, asclinbacumab (FIG. 10A); anti-C5, tesidolumab (FIG. 10B) and ravulizumab (FIG. 10D); and anti-endoglin, carotuximab (FIG. 10C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 11] Amino acid sequence of the transgene construct for the Fab region of ANX-007, a therapeutic antibody against CC1Q. Glycosylation sites are in bold. Glutamic acid glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. The hinge region is highlighted in gray. [Figure 12A]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against TNF-α: adalimumab (FIG. 12A), infliximab (FIG. 12B), and golimumab (FIG. 12C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 12B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against TNF-α: adalimumab (FIG. 12A), infliximab (FIG. 12B), and golimumab (FIG. 12C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 12C] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against TNF-α: adalimumab (FIG. 12A), infliximab (FIG. 12B), and golimumab (FIG. 12C). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The heavy chain hinge region is highlighted in gray. [Figure 13] Amino acid sequence of the transgene construct for the Fab region of elezanumab, a therapeutic antibody against RGMa. Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 14A]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against transthyretin (TTR): NI-301 (FIG. 14A) and PRX-004 (FIG. 14B). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 14B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against transthyretin (TTR): NI-301 (FIG. 14A) and PRX-004 (FIG. 14B). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 15] Figure 1 shows the amino acid sequence of the transgene construct for the Fab region of pamrevlumab, a therapeutic antibody against CTGF. Glycosylation sites are in bold. Glutamic acid glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 16A]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16C]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16D] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16E]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16F] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16G]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16H] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 16I]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), and tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), and gerilimu- zumab (Figure 16G); and anti-CD19, inebilizumab (Figure 16I). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in grey. [Figure 17] Figure 1 shows the amino acid sequence of the transgene construct for the Fab region of etrolizumab, a therapeutic antibody against ITGB7. Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 18] Figure 1 shows the amino acid sequence of the transgene construct for the Fab region of romosozumab, a therapeutic antibody against sclerostin. Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 19] Figure 1 shows the amino acid sequence of the transgene construct for the Fab region of lanadelumab, a therapeutic antibody against plasma kallikrein (pKal). Glycosylation sites are in bold. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 20A]Heavy chain Fab portions ( FIG. 20A ) of therapeutic antibodies disclosed herein (respectively, in order of appearance, residues 1-220 of SEQ ID NO:1, residues 1-223 of SEQ ID NO:3, residues 1-237 of SEQ ID NO:5, residues 1-220 of SEQ ID NO:7, residues 1-223 of SEQ ID NO:9, residues 1-232 of SEQ ID NO:11, residues 1-228 of SEQ ID NO:13, residues 1-224 of SEQ ID NO:15, residues 1-232 of SEQ ID NO:17, residues 1-230 of SEQ ID NO:19, residues 1-234 of SEQ ID NO:21, residues 1-231 of SEQ ID NO:23, residues 1-219 of SEQ ID NO:25, residues 1-227 of SEQ ID NO:27, residues 1-234 of SEQ ID NO:28, residues 1-231 of SEQ ID NO:29, residues 1-234 of SEQ ID NO:30, residues 1-231 of SEQ ID NO:31, residues 1-219 of SEQ ID NO:32, residues 1-227 of SEQ ID NO:33, residues 1-227 of SEQ ID NO:34, residues 1-234 of SEQ ID NO:35, residues 1-231 of SEQ ID NO:36, residues 1-237 of SEQ ID NO:37, residues 1-234 of SEQ ID NO:38, residues 1-231 of SEQ ID NO:39, residues 1-234 of SEQ ID NO:40, residues 1-231 of SEQ ID NO:41, residues 1-237 of S Residues 1 to 224 of SEQ ID NO:29, Residues 1 to 230 of SEQ ID NO:31, Residues 1 to 225 of SEQ ID NO:33, Residues 1 to 235 of SEQ ID NO:35, Residues 1 to 223 of SEQ ID NO:37, Residues 1 to 224 of SEQ ID NO:39, Residues 1 to 226 of SEQ ID NO:41, Residues 1 to 229 of SEQ ID NO:43, Residues 1 to 229 of SEQ ID NO:45, Residues 1 to 228 of SEQ ID NO:47, Residues 1 to 237 of SEQ ID NO:49, Residues 1 to 228 of SEQ ID NO:51, Residues 1 to 228 of SEQ ID NO:53, Residues 1 to 225 of SEQ ID NO:55, Residues 1 to 224 of SEQ ID NO:57, Residues 1 to 224 of SEQ ID NO:59, Residues 1 to 2 24, residues 1 to 229 of SEQ ID NO:63, residues 1 to 225 of SEQ ID NO:65, residues 1 to 228 of SEQ ID NO:67, residues 1 to 230 of SEQ ID NO:69, residues 1 to 227 of SEQ ID NO:331, residues 1 to 228 of SEQ ID NO:333, residues 1 to 227 of SEQ ID NO:335, residues 1 to 224 of SEQ ID NO:337, residues 1 to 230 of SEQ ID NO:339, residues 1 to 228 of SEQ ID NO:341, residues 1 to 232 of SEQ ID NO:360, residues 1 to 227 of SEQ ID NO:362, residues 1 to 229 of SEQ ID NO:364, residues 1 to 221 of SEQ ID NO:366, residues 1 to 226 of SEQ ID NO:368, residues 1 to 226 of SEQ ID NO:370 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 448, 450, 451, 452, 453, 454, 455, 456, 458, 459, 460, 461, 462, 463, 464, 465, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487,Positions that can be substituted to create hyperglycosylated variants of the Fab region are highlighted. Four substitutions (one in the heavy chain and three in the light chain) that would result in hyperglycosylation of the Fab region by human cells are noted above the amino acid residue position. (For engineering mAbs or antigen-binding fragments to contain additional glycosylation sites on the Fab domain, see, e.g., Courtois et al., 2016, mAbs 8:99-112, for a description of antibody derivatives with hyperglycosylation on the Fab domain of the full-length antibody.) [Figure 20B]Heavy chain Fab portions ( FIG. 20A ) of therapeutic antibodies disclosed herein (respectively, in order of appearance, residues 1-220 of SEQ ID NO:1, residues 1-223 of SEQ ID NO:3, residues 1-237 of SEQ ID NO:5, residues 1-220 of SEQ ID NO:7, residues 1-223 of SEQ ID NO:9, residues 1-232 of SEQ ID NO:11, residues 1-228 of SEQ ID NO:13, residues 1-224 of SEQ ID NO:15, residues 1-232 of SEQ ID NO:17, residues 1-230 of SEQ ID NO:19, residues 1-234 of SEQ ID NO:21, residues 1-231 of SEQ ID NO:23, residues 1-219 of SEQ ID NO:25, residues 1-227 of SEQ ID NO:27, residues 1-234 of SEQ ID NO:28, residues 1-231 of SEQ ID NO:29, residues 1-234 of SEQ ID NO:30, residues 1-231 of SEQ ID NO:31, residues 1-219 of SEQ ID NO:32, residues 1-227 of SEQ ID NO:33, residues 1-227 of SEQ ID NO:34, residues 1-234 of SEQ ID NO:35, residues 1-231 of SEQ ID NO:36, residues 1-237 of SEQ ID NO:37, residues 1-234 of SEQ ID NO:38, residues 1-231 of SEQ ID NO:39, residues 1-234 of SEQ ID NO:40, residues 1-231 of SEQ ID NO:41, residues 1-237 of S Residues 1 to 224 of SEQ ID NO:29, Residues 1 to 230 of SEQ ID NO:31, Residues 1 to 225 of SEQ ID NO:33, Residues 1 to 235 of SEQ ID NO:35, Residues 1 to 223 of SEQ ID NO:37, Residues 1 to 224 of SEQ ID NO:39, Residues 1 to 226 of SEQ ID NO:41, Residues 1 to 229 of SEQ ID NO:43, Residues 1 to 229 of SEQ ID NO:45, Residues 1 to 228 of SEQ ID NO:47, Residues 1 to 237 of SEQ ID NO:49, Residues 1 to 228 of SEQ ID NO:51, Residues 1 to 228 of SEQ ID NO:53, Residues 1 to 225 of SEQ ID NO:55, Residues 1 to 224 of SEQ ID NO:57, Residues 1 to 224 of SEQ ID NO:59, Residues 1 to 2 24, residues 1 to 229 of SEQ ID NO:63, residues 1 to 225 of SEQ ID NO:65, residues 1 to 228 of SEQ ID NO:67, residues 1 to 230 of SEQ ID NO:69, residues 1 to 227 of SEQ ID NO:331, residues 1 to 228 of SEQ ID NO:333, residues 1 to 227 of SEQ ID NO:335, residues 1 to 224 of SEQ ID NO:337, residues 1 to 230 of SEQ ID NO:339, residues 1 to 228 of SEQ ID NO:341, residues 1 to 232 of SEQ ID NO:360, residues 1 to 227 of SEQ ID NO:362, residues 1 to 229 of SEQ ID NO:364, residues 1 to 221 of SEQ ID NO:366, residues 1 to 226 of SEQ ID NO:368, residues 1 to 226 of SEQ ID NO:370 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 448, 450, 451, 452, 453, 454, 455, 456, 458, 459, 460, 461, 462, 463, 464, 465, 466, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487,Positions that can be substituted to create hyperglycosylated variants of the Fab region are highlighted. Four substitutions (one in the heavy chain and three in the light chain) that would result in hyperglycosylation of the Fab region by human cells are noted above the amino acid residue position. (For engineering mAbs or antigen-binding fragments to contain additional glycosylation sites on the Fab domain, see, e.g., Courtois et al., 2016, mAbs 8:99-112, for a description of antibody derivatives with hyperglycosylation on the Fab domain of the full-length antibody.) [Figure 21] Clustal multiple sequence alignment of AAV capsids 1-9. Amino acid substitutions (shown in bold in the lower row) can be made to AAV9 and AAV8 capsids by "recruiting" amino acid residues from corresponding positions in other aligned AAV capsids. Sequences shown in gray = hypervariable regions. The amino acid sequences of AAV capsids are assigned SEQ ID NOs as follows: AAV1 is SEQ ID NO: 274; AAV2 is SEQ ID NO: 275; AAV3-3 is SEQ ID NO: 276; AAV4-4 is SEQ ID NO: 277; AAV5 is SEQ ID NO: 278; AAV6 is SEQ ID NO: 279; AAV7 is SEQ ID NO: 280; AAV8 is SEQ ID NO: 143; AAV9 is SEQ ID NO: 144; AAVrh10 is SEQ ID NO: 145; hu31 is SEQ ID NO: 281; and hu32 is SEQ ID NO: 282. [Figure 22] FIG. 1 shows glycans that can be conjugated to the HuGlyFab region of a full-length mAb or antigen-binding domain (reprinted from Bondt et al., 2014, Mol&Cell Proteomics 13.1:3029-3039). [Figure 23] Figure 1 shows a Clustal multiple sequence alignment of the constant heavy chain regions (CH2 and CH3) of IgG1 (SEQ ID NO: 283), IgG2 (SEQ ID NO: 284), and IgG4 (SEQ ID NO: 285). The hinge region of the heavy chain from residues 219 to 230 is shown in italics. Amino acid numbering is in EU format. [Figure 24A] Schematic diagram showing the genomic organization of AAV8 and AAV9. The expression cassettes utilize a CAG promoter (SEQ ID NO: 411) to drive expression of, for example, plasma kallikrein (pKal) or a human antibody that binds and inhibits TNFα. A mutant IL2 leader (mIL2, SEQ ID NO: 146) targets the heavy and light chains for secretion, and a furin-F2A sequence (SEQ ID NO: 231) drives cleavage of the polyprotein into heavy and light chain components. [Figure 24B] Transfection titration comparing CAG.L01 (SEQ ID NO: 435; containing lanadelumab sequence L01 (SEQ ID NO: 141)) and CAG.L02 (SEQ ID NO: 437; containing lanadelumab sequence L02 (SEQ ID NO: 286)) proviral plasmid constructs. The top panel shows reporter transgene (eGFP) expression after transfection of different plasmid amounts (4 μg to untransfected). The bottom left panel shows lanadelumab expression in cell lysates, while the bottom right panel detects the plasmid that expressed lanadelumab secreted into the cell supernatant. [Figure 24C] Transfection titration comparing CAG.L02 and CAG.L03 proviral plasmid constructs. The panels show different exposure lengths (30 or 60 seconds) of expressed lanadelumab from CAG.L02 or CAG.L03 constructs secreted into the cell supernatant. [Figure 24D] Transfection titration comparing lanadelumab Fab proviral plasmid constructs. The figure shows the levels of lanadelumab Fab after transfection of different plasmid amounts. The L01 construct (CAG.L01: SEQ ID NO: 435) is driven by the CB promoter, while L02 (CAG.L02: SEQ ID NO: 437) is driven by the CAG promoter (SEQ ID NO: 411). [Figure 25]The indicated AAV9 and AAV8 vectors (n=5 / group) were administered to NGS mice via either intravenous (IV) or intramuscular (IM) routes. IV administration was into the tail vein, and IM administration was into both gastrocnemius muscles. Mice injected with vehicle were included as controls. Seven weeks after administration, mice were sacrificed, and serum human antibody levels were determined by ELISA. [Figure 26] Figure 1 shows the time course of antibody development (lanadelumab serum levels) in NSG mice (n=5 / group) after AAV9 administration. AAV9 vector (2e11 gc) was injected either IV or IM, and serum antibody levels were determined by ELISA on days 7 (D7), 21 (D21), 35 (D35), and 49 (D49). [Figure 27] Figure 1 shows the expression of the monoclonal antibody lanadelumab (Mab1) in C2C12 muscle cells upon transduction of the cells with different cis-plasmids expressing lanadelumab under the control of different regulatory elements: CAG (SEQ ID NO: 411), LMTP6 (SEQ ID NO: 320), and ApoE.hAAT (SEQ ID NO: 412). For detection of antibody protein, cells were treated with FITC-conjugated anti-Fc (IgG) antibody after transduction. DAPI staining is shown to confirm cell confluency and viability under all conditions tested. [Figure 28A]Table 1 shows the serum expression levels (μg / ml) of lanadelumab upon intravenous injection of 2.5×10 vg / kg of AAV8 vectors encoding lanadelumab regulated by different liver-specific, liver tandem, and liver muscle regulatory elements into C / 57BL6 mice (see Table 1). The CAG (SEQ ID NO: 411) and TBG (SEQ ID NO: 423) promoters were used as controls. Data are shown from blood draws 1, 3, 5, and 7 weeks after injection. LSPX1, liver-specific promoter 1 (SEQ ID NO: 315); LSXP2, liver-specific promoter 2 (SEQ ID NO: 316); LTP1, liver-specific tandem promoter 1 (SEQ ID NO: 317); LMTP6, liver and muscle dual-specific tandem promoter 6 (SEQ ID NO: 320). Protein expression levels were quantified by ELISA from biweekly serum collections. N=5 mice / vector. Numbers on the x-axis represent weeks after vector administration. Data represent mean + SEM. 8B. Quantification of viral genomes in the liver. C57B1 / 6 mice were intravenously administered AAV8 vectors driven by different liver-specific promoters at equivalent doses (2.5 x 10 vg / kg). N = 5 mice per group. Vector DNA was analyzed by ddPCR in mouse liver samples collected 49 days after vector administration. Data represent the mean + SEM. [Figure 28B]Table 1 shows the serum expression levels (μg / ml) of lanadelumab upon intravenous injection of 2.5×10 vg / kg of AAV8 vectors encoding lanadelumab regulated by different liver-specific, liver tandem, and liver muscle regulatory elements into C / 57BL6 mice (see Table 1). The CAG (SEQ ID NO: 411) and TBG (SEQ ID NO: 423) promoters were used as controls. Data are shown from blood draws 1, 3, 5, and 7 weeks after injection. LSPX1, liver-specific promoter 1 (SEQ ID NO: 315); LSXP2, liver-specific promoter 2 (SEQ ID NO: 316); LTP1, liver-specific tandem promoter 1 (SEQ ID NO: 317); LMTP6, liver and muscle dual-specific tandem promoter 6 (SEQ ID NO: 320). Protein expression levels were quantified by ELISA from biweekly serum collections. N=5 mice / vector. Numbers on the x-axis represent weeks after vector administration. Data represent mean + SEM. 8B. Quantification of viral genomes in the liver. C57B1 / 6 mice were intravenously administered AAV8 vectors driven by different liver-specific promoters at equivalent doses (2.5 x 10 vg / kg). N = 5 mice per group. Vector DNA was analyzed by ddPCR in mouse liver samples collected 49 days after vector administration. Data represent the mean + SEM. [Figure 29A] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL5, benralizumab (A); anti-IL5R, reslizumab (B); anti-IL13, tralokinumab (C); anti-IL31R, nemolizumab (D); anti-IgE, omalizumab (E); and anti-TSLP, tezepelumab (F). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 29B]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL5, benralizumab (A); anti-IL5R, reslizumab (B); anti-IL13, tralokinumab (C); anti-IL31R, nemolizumab (D); anti-IgE, omalizumab (E); and anti-TSLP, tezepelumab (F). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 29C] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL5, benralizumab (A); anti-IL5R, reslizumab (B); anti-IL13, tralokinumab (C); anti-IL31R, nemolizumab (D); anti-IgE, omalizumab (E); and anti-TSLP, tezepelumab (F). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 29D] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL5, benralizumab (A); anti-IL5R, reslizumab (B); anti-IL13, tralokinumab (C); anti-IL31R, nemolizumab (D); anti-IgE, omalizumab (E); and anti-TSLP, tezepelumab (F). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 29E]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL5, benralizumab (A); anti-IL5R, reslizumab (B); anti-IL13, tralokinumab (C); anti-IL31R, nemolizumab (D); anti-IgE, omalizumab (E); and anti-TSLP, tezepelumab (F). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 29F] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-IL5, benralizumab (A); anti-IL5R, reslizumab (B); anti-IL13, tralokinumab (C); anti-IL31R, nemolizumab (D); anti-IgE, omalizumab (E); and anti-TSLP, tezepelumab (F). Glycosylation sites are in bold. Glutamic acid glycosylation sites, asparagine (N) glycosylation sites, non-consensus asparagine (N) glycosylation sites, and tyrosine-O-sulfation sites (italics) are indicated in the legend. Complementarity-determining regions (CDRs) are underlined. The hinge region is highlighted in gray. [Figure 30A] Route of administration and dose selection in Wistar rats. AAV8 vectors encoding vectorized lanadelumab driven by a CAG promoter were injected intramuscularly into SD rats at 1 x 10 vg / kg body weight or intravenously at 1 x 10 vg / kg and 1 x 10 vg / kg. Protein expression was quantified by ELISA from serum collected every 3 to 7 days. N = 3 rats / vector. Data represent mean + SEM. * indicates p<0.05 by Welch's t-test, and ** indicates p<0.01 by Welch's t-test. [Figure 30B]AAV8 vectors encoding vectored lanadelumab driven by the CAG (SEQ ID NO: 411) or ApoE.hAAT (SEQ ID NO: 412) promoter were injected intravenously at 5x1013 vg / kg into Wistar and SD rats. Protein expression was quantified by ELISA from weekly serum collections. N=3 rats / vector. Data represent mean + SEM. P-values: *, p<0.05; **, p<0.01. Serum antibody concentrations (mean and SEM) in animals from each group at each time point are presented in the table. [Figure 31A] Serum anti-kallikrein (pKal) (lanadelumab) antibody concentrations after AAV8 delivery. Animals received bilateral injections of 5x1010 vg / kg into the GA muscle. Serum was collected biweekly and vectored antibody concentrations were quantified by ELISA. [Figure 31B] Vector genome quantification from relevant tissues by digital droplet PCR (ddPCR). [Figure 31C] Comparison of vector gene expression from liver. Data represent relative gene expression levels as quantified by the ΔΔCT method. [Figure 31D] Comparison of AAV transgene expression from tissues using digital droplet PCR (ddPCR). Anti-pKal antibody mRNA copies were normalized to GAPDH mRNA copies across tissues. Data are presented as mean ± SEM. Statistical significance was determined using one-way ANOVA with Tukey's HSD post-hoc test. *P<0.05, **P<0.01. [Figure 32] Antibody concentrations in the serum of wild-type mice treated with AAV8.lanadelumab vectors produced in different BV / Sf9 production systems compared to the HEK system. C57BL / 6 mice were injected intravenously with the vector at a dose of 2.5 x 10 vg / kg. [Figure 33A] The pKal titration curve and signal-to-noise ratio for the indicated pKal concentrations are shown. [Figure 33B] The pKal titration curve and signal-to-noise ratio for the indicated pKal concentrations are shown. [Figure 33C]Two pKal concentrations (6.25 nM and 12.5 nM) were used to measure the extent of lanadelumab inhibition (compared to a nonspecific human IgG control antibody) in the antibody-dose response. C57BL / 6 mice (n=5) were intravenously administered 5x1010 vector genomes (vg) (2.5x1012 vg / kg) of ApoE.hAAT.L02.AAV8 per mouse. [Figure 33D] The percent reduction in editing enzyme activity and pKal activity in both mouse groups D and E is shown. Specific pKal enzyme activity was calculated using the slope of the enzyme progressive activity curve and the AMC standard, and significantly lower activity was recorded on day 49 compared to day -7. [Figure 33E] The percent reduction in editing enzyme activity and pKal activity in both mouse groups D and E is shown. Specific pKal enzyme activity was calculated using the slope of the enzyme progressive activity curve and the AMC standard, and significantly lower activity was recorded on day 49 compared to day -7. [Figure 33F] The rate of decrease in enzyme activity was calculated by dividing the activity on day 49 by the activity on day -7. IgG containing vectored anti-pKal antibody significantly decreased pKal activity. All results are from 2-5 mice per group. Student's t-test (paired, two-tailed) was used to determine significance. *p<0.05, **p<0.01, ***p<0.001. [Figure 34A] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34B]Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34C] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34D] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34E] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34F] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34G]Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34H] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34I] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34J] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34K] Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 34L]Quantification of mouse paw volume and paw swelling in mice with carrageenan-induced paw edema treated with the test article. Bar graphs show paw volumes (A, C, E, G, I, and K) measured at 2 (A), 4 (C), 6 (E), 8 (G), 24 (I), and 48 (K) hours after carrageenan injection in C57BL / 6 mice. Differences in paw swelling (B, D, F, H, J, and L) were assessed by calculating the difference between paw volumes measured at each time point and baseline. N = 10 mice per group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.D.E.M. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Figure 35] A and B: Time course of mouse paw volume measured in mice with carrageenan-induced paw edema treated with test article. Mouse paw volume was measured before carrageenan injection (baseline) and at various time points after injection of 0.7% (A) or 1% (B) carrageenan. N=10 mice / group. Data represent mean ± SEM. [Figure 36] A and B: Characterization of vectored adalimumab IgG and Fab cis-plasmid expression. (A) Western blot showing expression of adalimumab IgG and Fab from cell supernatants of 293T cells transfected with each cis-plasmid. (B) Human TNFα binding ELISA from cells transfected with the cis-plasmid. pAAV.CAG.lanadelumab.IgG was used as a nonspecific antibody (mAb) control. Data are presented as mean ± SEM. [Figure 37] A-C. Characterization of AAV8-expressed adalimumab IgG expression and activity. (A) Quantification of AAV8-expressed adalimumab at two multiplicities of infection (MOI) after transduction of 293T.AAVR cells. (B) Western blot showing expression of adalimumab IgG heavy and light chain components at two different MOIs. (C) Human TNFα-binding ELISA of adalimumab IgG derived from cell culture supernatants. Data are presented as mean ± SEM. [Figure 38]Comparison of self-complementary AAV cis-plasmids encoding vectorized adalimumab Fab. Negative controls include cell supernatants from non-transfected cells. Data are presented as mean ± SEM. [Figure 39] Binding of TNFα across model species (mouse, rat, and human) by vectorized adalimumab IgG and Fab. Negative controls included supernatant from non-transfected cells. Vectored lanadelumab (pAAV.CAG.lanadelumab.IgG) served as a nonspecific antibody control. Data are presented as mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0018] 5. Detailed Description of the Invention Fully human post-translationally modified (HuPTM) therapeutic monoclonal antibodies (mAbs), or therapeutic HuPTM antigen-binding fragments of therapeutic mAbs (e.g., fully human glycosylated F of therapeutic mAbs) ab(HuGlyFab)) as a disease or condition for which treatment with a therapeutic mAb is indicated. Compositions and methods are described for delivery to diagnosed patients (human subjects). can be delivered via gene therapy, for example, a therapeutic mAb or antigen-binding fragment thereof (or any a viral vector or other DNA expression construct encoding the nucleotide sequence of ... The construct is administered to a patient (human subject) diagnosed with a condition for which treatment with a therapeutic mAb is indicated. and antigen-binding fragments of HuPTM mAbs or therapeutic mAbs, e.g., human glycosyltransferases. The mAb or its antigen-binding fragment exerts its therapeutic effect by binding the lysed transgene product to the target cell. By creating a permanent depot within a patient's tissue or organ that continuously supplies the target tissue. It would be advantageous to achieve more.

[0019] Transgene-encoded HuPTM mAb or HuPTM antigen-binding The fragments are Amyloid β (Aβ or Abeta) peptide, sortilin, tau protein, SE Nervous system targets, including MA4D, alpha-synuclein, and CGRP receptors Contains VEGF, EpoR, ALK1, endoglin, complement component 5, and complement component 1Q Hmm, eye target, Repulsive Guidance Molecule-A Transthyretin Connective tissue growth factor Optic nerve spinal cord, including interleukin 6 receptor, interleukin 6, and CD19 NMO / non-infectious uveitis targets and immune response targets Integrin β7 Sclerostin TNF-α, and Plasma protein targets such as human complement proteins, including plasma kallikrein, IL5, IL5R, IL13, and IL31RA, immunoglobulin E, and thymic stroma Autoimmune diseases such as interleukins and interleukin receptors, including lymphopoietins , respiratory, and allergic disease targets on a full length therapeutic antibody or antigen-binding fragment thereof, or on the Fab domain, which binds to , such mAbs or antigens engineered to contain additional glycosylation sites Binding fragments (e.g., antibody derivatives with hyperglycosylation on the Fab domain of a full-length antibody) the description of which is incorporated herein by reference in its entirety. (See Courtois et al., 2016, mAb8:99-112) The heavy and light chain amino acid sequences of the antigen-binding fragments described above may include, but are not limited to: The sequences are presented in Table 5 below, and include the codon sequences encoding the heavy and light chains of the antigen-binding fragments. The nucleotide sequences, including the optimized versions, are presented in Table 6.

[0020] The recombinant vector used to deliver the transgene is a non-replicating recombinant adenovirus. rAAVs are particularly attractive for a number of reasons. rAAV is a novel vector that can transduce non-replicating cells and therefore It can be used to deliver transgenes to tissues where cell division occurs at a low level, such as the CNS. rAAV can be used to preferentially target selected specific organs. to obtain desired tissue specificity and / or to provide protection against some AAVs. There are hundreds of capsid serotypes to choose from to avoid neutralization by pre-existing patient antibodies. Such rAAVs include AAV1, AAV2, AAV2.m78, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV containing capsid components derived from one or more of AAVrh10, rh10, or AAVrh20 In certain embodiments, the present invention provides vectors that are useful for the treatment of cancer, including, but not limited to, AAV-based vectors. The AAV-based vectors presented herein include AAV8, AAV9, AAV10, AA Derived from one or more of the following serotypes: V11, AAVrh10, or AAVrh20 It contains a capsid that

[0021] However, lentiviral vectors, vaccinia virus vectors, or "Neisseria gonorrhoeae" vectors These include, but are not limited to, non-viral expression vectors, referred to as "kid DNA" constructs. Other viral vectors can also be used. Transgene expression can be constitutive. It can be controlled by current control elements or tissue-specific expression control elements.

[0022] The gene therapy construct is designed to express both the heavy and light chains. Ideally, the heavy and light chains should be expressed in approximately equal amounts. and are expressed in a heavy chain to light chain ratio of about 1:1. The coding sequences for the heavy and light chains are and a heavy chain having separate heavy chain polypeptides, and a light chain polypeptide. The high and light chains are engineered into a single construct, separated by a cleavable linker or IRES. In certain embodiments, the coding sequence can be Fab or F(ab')2 or or scFv.

[0023] In certain embodiments, the nucleic acids (e.g., polynucleotides) and The nucleic acid sequence may be codon optimized, for example, via any codon optimization method known to those of skill in the art. (e.g., Quax et al., 2015, Mol Cell 59:149- 161) and can be optimized to reduce CpG dimers. Codon-optimized nucleotide sequences of heavy and light chain variable domains of therapeutic antibodies The sequences are disclosed in Table 6. Each heavy and light chain has a leader that is required for proper post-translational processing. and to ensure secretion (only the N-terminal strand requires a leader sequence, s As used herein, the heavy and Leader sequences useful for expressing the light chain in human cells are disclosed. The current construct is shown in Figure 1 and Figure 24A.

[0024] To generate HuPTM mAb or HuPTM Fab (including HuPTM scFv), For example, therapeutic mAbs, full-length or HuPTM Fabs, or full-length HuPTM mAb or HuPTM Fab or other antigen-binding fragments, such as scFv or scFv. A viral vector or other DNA expression construct encoding the recombinant fragment of this mAb is then inserted into the administered to a patient (human subject) diagnosed with an applicable disease, to induce the desired trait in the subject; sustainably delivers human glycosylated, sulfated transgene products produced by transfected cells. "Bio-benefit" for the treatment of diseases achieved by creating permanent depots that supply The result should be a "target" molecule. The cDNA constructs for the HuPTM scFv were transduced into human cells. Proper co-processing and post-translational processing (glycosylation and protein sulfation) The nucleic acid sequence should contain a signal peptide that ensures transcription.

[0025] Pharmaceutical compositions suitable for administration to human subjects may contain physiologically compatible aqueous buffers, surfactants, and optional excipients in a formulation buffer. Such formulation buffers may contain one or more of the following: polysaccharides, surfactants, polymers, or oils. It can be seen.

[0026] As an alternative or additional treatment to gene therapy, full-length HuPTM mAb or H uPTM Fab or these other antigen-binding fragments can be expressed in human cell lines using recombinant DNA technology. The glycoprotein may be produced by the method of the present invention and administered to a patient. Human cell lines that can be used for this purpose include human embryonic kidney 293 cells (HEK29), to name a few. 3) in fibrosarcoma HT-1080, HKB-11, CAP, HuH-7, and retinal cell lines These include, but are not limited to, PER.C6 or RPE (e.g., recombinantly produced Hu PTM Fab products or HuPTM scFv products, e.g., HuPTM Fab glycoproteins. For a review of human cell lines that can be used for protein synthesis, see, e.g., J. Immunol. Incorporated into Dumont et al., 2015, Crit. Rev. Biot (See Chem. 36(6):1110-1122). α-2,6-sialylated α-2,6-sialyltransferases were used to ensure sialylation and tyrosine sulfation. transferase (or α-2,3-sialyltransferase and α-2,6-sialyltransferase) aryltransferases), and / or tyrosine-O-sulfation in human cells. Host cells are engineered to co-express the TPST-1 and TPST-2 enzymes, which contribute to By doing so, the cell line used for production can be enhanced.

[0027] Any molecule produced in a gene or protein therapy approach can be fully It is not essential that the glycosylation and sulfate of the glycoprotein be carried out. The protein population was glycosylated (including 2,6-sialylation) sufficiently to support efficacy. The goal of the gene therapy treatment of the present invention is to slow the progression of the disease. The goal is to slow or stop the flow.

[0028] The methods of the invention involve the use of full-length HuPTM mAb or HuPTM Fab or its antigen-binding fragment. Combination therapy involves the delivery of a synthetic fragment to a patient, along with the delivery of other available treatments. The additional treatment may be prior to, concurrent with, or subsequent to the gene therapy treatment. Such further treatment may include co-therapy with a therapeutic mAb. Not limited to these.

[0029] Also provided are methods for producing viral vectors, particularly AAV-based viral vectors. In a specific embodiment, a method for producing a recombinant AAV is provided, comprising: R, and the cis expression cassette is expressed by the trans gene in human cells. a gene encoding a therapeutic antibody operably linked to an expression control element that controls the expression of the gene; and an artificial genome containing a transgene; a transgene expression cassette lacking AAV ITRs. In cultured host cells, AAV rep proteins and AAV capsid proteins an AAV rep protein operably linked to an expression control element that drives expression of It encodes the protein and AAV capsid proteins, and the rep protein and cap protein. , with a trans-expression cassette supplied in trans; and AAV capsid proteins; Adenoviral helper sufficient to allow replication and packaging of the adenovirus genome and culturing a host cell containing the artificial genome; and culturing an artificial genome derived from the cell culture. and recovering the encapsidated recombinant AAV.

[0030] 5.1 Construction As used herein, HuPTMmAb or antigen-binding fragment thereof, particularly HuGlyFab or a virus encoding a hyperglycosylated derivative of the antigen-binding fragment of HuPTM mAb. Viral vectors or other DNA expression constructs are provided herein. Vectors and other DNA expression constructs are suitable for delivering transgenes to target cells. The means for delivering the transgene include viral vectors, liposomes, , other lipid-containing complexes, other macromolecular complexes, synthetic modified mRNA, unmodified mRNA, small molecules , non-biologically active molecules (e.g., gold particles), polymerized molecules (e.g., dendrimers) , naked DNA, plasmids, phages, transposons, cosmids, or epitopes In some embodiments, the vector comprises a targeting vector, e.g., Vectors targeted to retinal pigment epithelial cells, CNS cells, muscle cells, or liver cells is.

[0031] In some embodiments, the disclosure provides a HuPTM mAb or HuGlyFab, or These other antigen-binding fragments are encoded as transgenes as described herein. A nucleotide sequence that is targeted to express a transgene. A promoter selected for expression in the tissue, e.g., the CB7 / CAG promoter. (SEQ ID NO: 411, Figure 24A) and associated upstream regulatory sequences (see Figure 1), CMV promoter, Rous sarcoma virus (RSV) promoter -, GFAP promoter (glial fibrillary acidic protein), MBP promoter (myelination) phosphobasic protein), MMT promoter, EF-1α promoter (SEQ ID NO: 41 5), mU1a (SEQ ID NO: 414), UB6 promoter, chicken β-actin (CB A) promoter, RPE65 promoter, and opsin promoter, TBG ( amylolytic globulin (Ag-1) promoter (SEQ ID NO: 423), APOA2 promoter , SERPINA1 (hAAT) promoter, ApoE.hAAT (SEQ ID NO: 412) , or a liver-specific promoter such as the mIR122 promoter, or human desmin promoter, CK8 promoter (SEQ ID NO: 413), or Pitx3 promoter Muscle-specific promoters such as hypoxia-inducible promoters or rapamycin-induced promoters Inducible promoters, such as, but not limited to, inducible promoters The present invention provides a nucleic acid for use comprising a nucleotide sequence operably linked to

[0032] In some aspects herein, transgene expression is liver-specific or liver-specific. Both liver-specific and muscle-specific expression, or both liver-specific and bone-specific expression It contains regulatory elements arranged in tandem (two or three copies) that promote engineered vectors with two or more regulatory elements (promoters or enhancers), These regulatory elements include the liver-specific For the specific expression, LSPX1 (SEQ ID NO: 315), LSPX2 (SEQ ID NO: 316), L TP1 (SEQ ID NO: 317), LTP2 (SEQ ID NO: 318), or LTP3 (SEQ ID NO: 3 19), and for liver and muscle expression, LMTP6 (SEQ ID NO: 320), LMTP13 ( SEQ ID NO: 321), LMTP14 (SEQ ID NO: 322), LMTP15 (SEQ ID NO: 323) , LMTP18 (SEQ ID NO: 324), LMTP19 (SEQ ID NO: 325), or LMTP 20 (SEQ ID NO: 326), or for liver and bone expression, LBTP1 (SEQ ID NO: 32 7) or LBTP2 (SEQ ID NO: 328), the sequences of which are provided in Table 1.

[0033] In certain embodiments herein, one or more nucleic acids (e.g., polynucleotides) The nucleic acid may be DNA, RNA, or a combination of DNA and RNA. In certain embodiments, the DNA may comprise a promoter sequence , the sequence of the gene of interest (transgene, e.g., HuP™ mAb or HuGly Fab, or other antigen-binding fragment), non- It comprises one or more sequences selected from the group consisting of a translation region, a translational region, and a termination sequence. In certain embodiments, the viral vectors provided herein are designed to target a gene of interest. It contains an operably linked promoter.

[0034] In certain embodiments, the nucleic acids (e.g., polynucleotides) and The nucleic acid sequence may be codon optimized, for example, via any codon optimization method known to those of skill in the art. (e.g., Quax et al., 2015, Mol Cell 59:149 (See the review by J.-161.) In this specification, in Table 6, Nucleotide sequences for the heavy and light chains of β-lactamase inhibitors that are codon-optimized for expression in human cells are provided. is shown.

[0035] In specific embodiments, the constructs described herein comprise the following components: (1) an expression cassette; AAV2 ITR (inverted terminal repeat) (2) a) one or more regulatory elements, b) a chicken β-actin intron, and c) rabbit β-globin poly(A) signal; and (3) an equal amount of heavy chain polypeptide. Self-cleaving Furin (F) / F2, which ensures expression of heavy and light chain polypeptides containing A linker (SEQ ID NO: 231 or 429) separates the overlapping portions of the mAb or Fab. The constructs include nucleic acid sequences encoding the light and dark chains. An exemplary construct is shown in FIG.

[0036] In specific embodiments, the constructs described herein comprise the following components: (1) an expression cassette; AAV2 ITR (inverted terminal repeat) (2) a) one or more regulatory elements, b) a chicken β-actin intron, and c) rabbit β-globin poly(A) signal; and (3) F of the heavy chain including the hinge region sequence. ab portion plus sequences encoding heavy and light chain Fc polypeptides of the appropriate isotype The present invention relates to a nucleic acid sequence encoding a full-length antibody comprising heavy and light chain sequences, The nucleotide sequence is a self-cleaving furin (F) / (F / T)2A linker (SEQ ID NO: 23 1 or 429) to ensure expression of equal amounts of heavy and light chain polypeptides. An exemplary construct is shown in Figure 24A.

[0037] 5.1.1 mRNA vectors In certain embodiments, the vectors presented herein are used as an alternative to DNA vectors. The vector contains a gene of interest (e.g., a transgene, e.g., a HuP™ mAb or or HuGlyFab, or other antigen-binding fragments thereof) Modified and unmodified mRNA for transgene delivery to retinal pigment epithelial cells Synthesis of mRNA can be performed, for example, using methods such as those described in Ha, which is incorporated herein by reference in its entirety. nsson et al.,J.Biol.Chem.,2015,290(9):56 61-5672. In certain embodiments herein, HuPT M modified mRNA encoding mAb, HuPTM Fab, or HuPTM scFv A is presented.

[0038] 5.1.2 Viral vectors Viral vectors include adenoviruses, adeno-associated viruses (AAVs, e.g., AAV 8, AAV9, AAVrh10, AAV2.7m8), lentivirus, helper-dependent Adenovirus, herpes simplex virus, poxvirus, Japanese hemagglutinin virus HVJ, alphavirus, vaccinia virus, and retrovirus vectors Retroviral vectors include murine leukemia virus (MLV)-based vectors. and human immunodeficiency virus (HIV)-based vectors. Alphavirus vectors Examples include Semliki Forest virus (SFV) and Sindbis virus (SIN). In certain embodiments, the viral vectors provided herein are recombinant viral vectors. In certain embodiments, the viral vectors provided herein are In certain embodiments, the virus is modified to be replication-deficient in humans. Viral vectors include hybrid vectors, such as "helpless" adenoviral vectors. In certain embodiments herein, the first virus is an AAV vector introduced into the host. The viral capsid is derived from one virus and the viral envelope is derived from a second virus. In a specific embodiment, a viral vector is provided comprising a second viral protein. In a more specific embodiment, the virus is a vesicular stomatitis virus (VSV). The target protein is the VSV-G protein.

[0039] In certain embodiments, the viral vectors provided herein are HIV-based In certain embodiments, the HIV-based vectors presented herein are The vector contains at least two polynucleotides, in this case the gag gene. The pol and env genes are derived from the HIV genome, and the env gene is derived from another virus. do.

[0040] In certain embodiments, the viral vectors provided herein are directed against herpes simplex viruses. In certain embodiments, the vectors presented herein are virus-based viral vectors. Herpes simplex virus-based vectors are those that express one or more immediate early (I E) Gene-free and modified to be non-cytotoxic.

[0041] In certain embodiments, the viral vectors provided herein are MLV-based In certain embodiments, the MLV-based vectors presented herein are The vectors contain up to 8 kb of heterologous DNA in place of the viral genes.

[0042] In certain embodiments, the viral vectors provided herein are lentiviruses. In certain embodiments, the recombinant human leukocyte-based viral vectors presented herein are In certain embodiments, the present invention provides a method for the production of human lentivirus vectors. The lentiviral vectors presented herein are derived from non-human lentiviruses. In certain embodiments, the lentiviral vectors provided herein are In certain embodiments, the lentiviruses provided herein are packaged in a pod. The viral vector contains the following elements: LTR (long terminal repeat eat), primer binding site, polypurine tract, att site, and encapsidation The nucleotide sequence comprises one or more of the following sites:

[0043] In certain embodiments, the viral vectors provided herein are alphavirus vectors. In certain embodiments, the antigen-based viral vectors presented herein are Lufa virus vectors are recombinant, replication-deficient alphaviruses. In one embodiment, the alphavirus replicas within the alphavirus vectors provided herein Consequences of this are the display of functional heterologous ligands on the surface of their virions, which allows specific The antibody is targeted to a target cell type.

[0044] In certain embodiments, the viral vectors provided herein are AAV-based In certain embodiments, the AAV-based viral vectors presented herein are The vector contains the AAV rep gene (required for replication) and / or the AAV cap gene (required for synthesis of capsid protein) (rep protein and ca p protein may be provided in trans by the packaging cell Multiple AAV serotypes have been identified. In certain embodiments, The AAV-based vectors presented are derived from one or more serotypes of AAV. In certain embodiments, the AAV-based vectors provided herein comprise AAV1 (SEQ ID NO: 274), AAV2 (SEQ ID NO: 275), AAV2.7m8 (SEQ ID NO: 276), Sequence number 142), AAV3 (sequence number 276), AAV4 (sequence number 277), AAV5 , AAV6 (SEQ ID NO: 279), AAV7 (SEQ ID NO: 280), AAV8 (SEQ ID NO: 14 3), AAV9 (SEQ ID NO: 144), AAV10, AAV11, or AAVrh10 ( The capsid components are derived from one or more of the following: In embodiments, the AAV-based vectors provided herein include AAV8, AAV9, Derived from one or more of the AAV10, AAV11, or AAVrh10 serotypes The capsid protein contains a mutant AAV8 capsid protein (SEQ ID NO: No. 143), AAV9 capsid protein (SEQ ID NO: 144), or AAVrh10 capsid protein The capsid protein (SEQ ID NO: 145) is, for example, a native capsid protein. AAV8 capsid protein (SEQ ID NO: 143), while retaining the biological function of the capsid. AAV9 capsid protein (SEQ ID NO: 144), or AAVrh10 capsid protein Identifies at least 95%, 96%, 97%, 98%, or 100% identical amino acid sequence to the amino acid sequence of protein (SEQ ID NO: 145) Viral vectors that are 99%, or 99.9% identical to the vectors described above are provided. In terms of morphology, the encoded AAV capsids are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, SEQ ID NO: 1 with 24, 25, 26, 27, 28, 29, or 30 amino acid substitutions 143, 144, or 145, and AAV8, AAV9, or AAVrh10 The biological function of the capsid is maintained. Figure 21 shows the results based on a comparison of the SUBS-labeled lines. Potential amino acids that can be substituted at a particular position in the aligned sequences Comparative alignment of the amino acid sequences of the capsid proteins of different AAV serotypes, including Thus, in a specific embodiment, the AAV vector comprises the SUBS line of FIG. , which are not present at this position in the native AAV capsid sequence, as identified in , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 8, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 AAV8, AAV9, or AAVrh10 capsid variants with amino acid substitutions at three sites The sequence for AAVrhlO, including variants, is presented in Figure 21.

[0045] In some embodiments, the AAV-based vector comprises one or more serotypes of AAV. In some embodiments, the AAV-based vectors provided herein comprise components from the The vectors are AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rhlO, AAVrh20, AAV .rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.A nc80, AAV.Anc80L65, AAV.7m8, AAVPHP.B, AAV.P HP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAVH SC1, AAVHSC2, AAVHSC3, AAV.HSC4, AAV.HSC5, AA V.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HS C10, AAVHSC11, AAV.HSC12, AAV.HSC13, AAV.HSC 14, AAV.HSC15, or AAV.HSC16, or one of the other rAAV particles or containing components from multiple serotypes, or a combination of two or more thereof. In embodiments, the AAV-based vectors provided herein include AAV1, AAV2 , AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV1 0, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AA V.rh8, AAV.rhlO, AAV.rh20, AAV.rh39, AAV.Rh7 4, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc8 0L65, AAV.7m8, AAVPHP.B, AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2 , AAVHSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV. HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAV.HSC ll, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC 15, or AAV.HSC16, or one or more components of other rAAV particles, or or a combination of two or more of these serotypes. , rAAV particles are AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, A AV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AA V14, AAV15, AAV16, AAV.rh8, AAV.rhlO, AAV.rh2 0, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, rAAV.Anc80L65, AAV.7m8, AAVPHP.B , AAV.PHP.eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK0 3, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AA V.HSC5, AAV.HSC6, AAV.HSC7, AAVHSC8, AAV.HSC 9, AAV.HSC10, AAV.HSCll, AAV.HSC12, AAV.HSC1 3, AAV.HSC14, AAV.HSC15, or AAV.HSC16, or AAV capsid serotypes selected from derivatives, modifications, or pseudotypes of the above, e.g., VP1, VP2 and / or VP3 sequences, e.g., at least 80% or more identical, e.g., 8 5%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 9 5%, 96%, 97%, 98%, 99%, 99.5%, etc., i.e., up to 100% It contains a capsid protein.

[0046] In certain embodiments, the AAV used in the compositions and methods described herein Zinn et al., 2015, C, which is incorporated by reference in its entirety. ellRep.12(6):1056-1068, or Anc80L65. In certain embodiments, in the methods described herein The recombinant AAVs used are those described in the art, each of which is incorporated herein by reference in its entirety. US9,193,956; US9,458,517; US9,587,28 2; US2016 / 0376323, and WO2018 / 075798 In certain embodiments, the vectors described herein are AAV.7m8 (including variants thereof). The AAV used in the described methods may be AAV-PHP.B, such as US 9,585 In certain embodiments, the AAV is any of the AAVs disclosed herein. The AAV used in the compositions and methods described in CharbelIssa et al., 2013, incorporated herein by reference , PLoSOne8(4):e60361, AAV8 capsid, and hybrid capsids derived from capsids of serotypes cy5, rh20, or rh39. AAV2 / Rec2 vector or AAV2 / Rec3 vector having a nucleotide sequence. In certain embodiments, the AAV used in the methods described herein is The following patents and patent applications are incorporated herein by reference in their entirety: Applications: US7,282,199; US7,906,111; US8,524,446; U S8,999,678;US8,628,966;US8,927,514;US8,7 34,809;US9,284,357;US9,409,953;US9,169,2 99; US9,193,956; US9,458,517; and US9,587,282 ;US2015 / 0374803;US2015 / 0126588;US2017 / 00 67908;US2013 / 0224836;US2016 / 0215024;US20 17 / 0051257; and PCT / US2015 / 034799; PCT / EP20 15 / 053335. In embodiments, the rAAV particles are those described herein in their entirety by reference to each other. The following patents and patent applications are incorporated herein: U.S. Patent No. 7,906,111; U.S. Patent No. 8, No. 524,446; No. 8,999,678; No. 8,628,966; No. 8,9 27,514; 8,734,809; 9,284,357; , No. 409,953; No. 9,169,299; No. 9,193,956; No. 9, 458,517; and 9,587,282; U.S. Patent Application Publication No. 2015 / 03 No. 74803; No. 2015 / 0126588; No. 2017 / 0067908; No. 2017 / 0067908; No. 2013 / 0224836; No. 2016 / 0215024; No. 2017 / 00 51257; and International Patent Application No. PCT / US2015 / 034799; The AAV capsules disclosed in any of the above publications are also included in the AAV capsules disclosed in the above publications. At least 80% or more identical to Sid, e.g., 85%, 85%, 87%, 88% %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 %, 99%, 99.5%, etc., i.e., up to 100% identical capsid proteins It has quality.

[0047] In some embodiments, the rAAV particles are each referred to in their entirety by reference. No. 9,840,719 and WO2015 / 014444, which are incorporated herein by reference. 3313, such as AAV.Rh74 and RHM4-1. In some embodiments, the rAAV particles comprise a V capsid. A, which is disclosed in WO2014 / 172669, the contents of which are incorporated herein by reference. In some embodiments, the rAA V particles are GeV particles, each of which is incorporated herein by reference in its entirety. orgiadis et al.,2016,Gene Therapy 23:857 -862 and Georgiadis et al., 2018, Gene Therap In some embodiments, the capsid comprises an AAV2 / 5 capsid, as described in U.S. Pat. No. 6,254,450. rAAV particles are disclosed in WO201 Any AAV capsid, such as AAV2tYF, disclosed in US Pat. No. 7 / 070491, In some embodiments, the rAAV particles include Puzzo et al.,2017,Sci.Transl.Med.29(9 ):418. In this embodiment, the rAAV particles are those described herein in their entirety by reference to each other. US Patent Nos. 8,628,966; US Patent No. 8,927,514; US Patent No. 9 HSC1, as disclosed in WO2016 / 049230, , HSC2, HSC3, HSC4, HSC5, HSC6, HSC7, HSC8, HSC9 , HSC10, HSC11, HSC12, HSC13, HSC14, HSC15, or Any AAV capsid, such as HSC16.

[0048] In some embodiments, the rAAV particles are such that the contents of each of them are incorporated herein by reference in their entirety. International Application Publication No. WO2003 / 052051 (e.g., See, for example, SEQ ID NO: 2 of the '051 publication), WO2005 / 033321 (e.g. See, for example, SEQ ID NOs: 123 and 88 in the '321 publication), WO 03 / 0423 97 (see, e.g., SEQ ID NOS: 2, 81, 85, and 97 of the '397 publication), WO2006 / 068888 (see, e.g., SEQ ID NOS: 1 and 3-6 of the '888 publication) WO2006 / 110689 (e.g., SEQ ID NOs: 5-38 of the '689 publication) See WO2009 / 104964 (e.g., SEQ ID NOs: 1 to 5 of the '964 publication) 5, 7, 9, 20, 22, 24 and 31), WO2010 / 127097 (See, e.g., SEQ ID NOS: 5-38 of the '097 publication), and WO2015 / 1 91508 (see, e.g., SEQ ID NOS: 80-294 of the '508 publication), and Publication No. 20150023924 (e.g., SEQ ID NOs: 1, 5-1 of the '924 publication) 0). In embodiments, the rAAV particles are prepared using the methods described in International Application Publication No. WO 2003 / 052051 (e.g., '051 publication), WO2005 / 033321 (e.g., See SEQ ID NOs: 123 and 88 of the '321 publication), WO03 / 042397 ( See, e.g., SEQ ID NOS: 2, 81, 85, and 97 of the '397 publication), WO2 006 / 068888 (see, e.g., SEQ ID NOS: 1 and 3-6 of the '888 publication) ), WO2006 / 110689 (see, e.g., SEQ ID NOS: 5-38 of the '689 publication). WO2009 / 104964 (for example, SEQ ID NOs: 1 to 5, 7, 9 of the 964 publication) , 20, 22, 24 and 31), WO2010 / 127097 (e.g., See SEQ ID NOS: 5-38 of the '097 publication), and WO2015 / 191508 (See, e.g., SEQ ID NOS: 80-294 of the '508 publication), and U.S. Patent Application Publication No. No. 20150023924 (see, e.g., SEQ ID NOS: 1, 5-10 of the '924 publication) VP1, VP2, and / or VP3 of the AAV capsid disclosed in sequence at least 80% or more identical, e.g., 85%, 85%, 87%, 88% or more identical to the sequence %, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 %, 99%, 99.5%, etc., i.e., up to 100% identical capsid proteins It has quality.

[0049] In further embodiments, the rAAV particles comprise pseudotyped AAV capsids. In embodiments, the pseudotyped AAV capsid is an rAAV2 / 8 or rAAV2 / 9 pseudotyped AAV capsid. V capsid. Methods for making and using pseudotyped rAAV particles are known in the art. (e.g., Duan et al., J. Virol., 75:7662-767 1(2001);Halbert et al., J. Virol.,74:1524- 1532(2000);Zolotukhin et al.,Methods 28: 158-167(2002); and Auricchio et al., Hum. Mol See ec. Genet. 10:3075-3081 (2001).

[0050] AAV8-based, AAV9-based, and AAVrh10-based viral vectors It is used in certain of the methods described herein. Nucleotide sequences of V-based viral vectors and recombinant AAV and AAV capsids Methods for making the bonds are described, for example, in the US Pat. No. 6,49 ... each of which is incorporated herein by reference in its entirety. Included in U.S. Patent No. 7,282,199 B2, U.S. Patent No. 7,790,449 B2 , U.S. Patent No. 8,318,480 B2, U.S. Patent No. 8,962,332 B2, and the This is taught in International Patent Application No. PCT / EP2014 / 076466. In one embodiment, an AAV (e.g., a Fab) encoding a transgene (e.g., a HuPTM Fab) is For example, AAV8, AAV9, or AAVrh10)-based viral vectors are presented. The amino acid sequences of AAV capsids, including AAV8, AAV9, and AAVrh10, are shown in Table 1. , presented in Figure 21.

[0051] In certain embodiments, the aforementioned single-stranded AAV (ssAAV) can be used. In certain embodiments, self-complementary vectors, e.g., scAAV, may be used. (e.g., see U.S. Pat. No. 6,499,399, each of which is incorporated herein by reference in its entirety. , Wu,2007,Human Gene Therapy,18(2):171-82 ,McCarty et al,2001,Gene Therapy,Vol8,Nu amber16, Pages 1248-1254; and U.S. Patent No. 6,596,535 7,125,717; and 7,456,683).

[0052] In certain embodiments, the viral vectors used in the methods described herein The vector is an adenovirus-based viral vector. The HuPTMmAb or HuGlyFab, or antigen-binding fragment, was cloned using The recombinant adenovirus can be used to introduce a transgene that encodes the E1 gene. The E3 was either deleted or not, and the expression cassette was inserted into either of the deleted regions. The recombinant adenovirus may be a first generation vector in which the E2 region and It may be a second generation vector containing a complete or partial deletion of the E4 region. Par-dependent adenoviruses are characterized by the adenoviral ITR (inverted termination repeat). al repeat) and packaging signal (phi). The gene contains an inclusion sequence that keeps the genome close to the wild-type size of approximately 36 kb. It is inserted between the packaging signal and the 3' ITR, with or without a An exemplary protocol for generating denoviral vectors is provided herein by reference in its entirety. Incorporated in Alba et al., 2005, “Gutless ade novirus:last generation adenovirus for g ene therapy,” Gene Therapy 12:S18-S27 can be found.

[0053] In certain embodiments, the viral vectors used in the methods described herein The vector is a lentivirus-based viral vector. The transgene encoding the antigen-binding fragment of the HuPTM mAb was introduced using Four plasmids can be used: a plasmid containing the Gag / pol sequence, Re Plasmids containing the v sequence, plasmids containing envelope proteins (i.e. , VSV-G), and packaging elements and anti-VEGF antigen-binding fragment genes. The accompanying cis plasmid is used to make the construct.

[0054] To generate lentiviral vectors, cells (i.e., HEK293-based cells) were cultured. The four plasmids are co-transfected into cells (cells) in the presence of polyethyleneimine or or calcium phosphate, among others, can be used as transfection agents. The lentivirus is then collected in the supernatant (although the lentivirus is active). , because the cells need to bud off, there is no need / should not be harvested) The supernatant was filtered (0.45 μm), and then magnesium chloride and benzonase were added. Further downstream steps can vary widely but include TFF and column chromatography. The process using column chromatography is the most GMP-compliant process. Ultracentrifugation with or without filtration is used to generate lentiviral vectors. , all of which are incorporated herein by reference in their entireties. Incorporated herein, Lesch et al., 2011, “Production and purification of lentiviral vector g generated in 293T suspension cells with b aculoviral vectors,”Gene Therapy 18:531- 538; and Ausubel et al., 2012, “Production of CGMP-Grade Lentiviral Vectors,”Bioproce ss Int.10(2):32-43.

[0055] In a specific embodiment, the vectors for use in the methods described herein comprise: Once the vector is introduced into the participating cells, the antigen-binding fragment of the HuP™ mAb or Glycosylation and / or tyrosine sulfation variants of HuGlyFab are expressed in cells. The antigen-binding fragment of the HuP™ mAb, such as HuGlyFab, can be expressed more efficiently. It is a vector encoding the fragment.

[0056] 5.1.3 Promoters and Modifiers of Gene Expression In certain embodiments, the vectors provided herein are useful for gene delivery or inheritance. It contains components that modulate the expression of genes (e.g., "expression control elements"). In some embodiments, the vectors provided herein contain components that modulate the expression of genes. In certain embodiments, the vectors provided herein can bind to or bind to cells. In certain embodiments, the compounds provided herein include a component that affects targeting or targeting. The vectors shown are vectors that, after incorporation, In certain embodiments, the present invention provides a method for the preparation of a medicament for the treatment of a medicament comprising administering to a subject a medicament for the treatment of ... The vectors shown can be used, for example, to detect or select cells that have taken up the polynucleotide. In addition, the gene contains a component that can be used as a detectable or selectable marker.

[0057] In certain embodiments, the viral vectors provided herein contain a transgene. In certain embodiments, the promoter comprises one or more promoters that control the expression of the promoter. In certain embodiments, the promoter is a constitutive promoter. The CB7 promoter (also called the CAG promoter) is Dinculescu et al., 2005, Hu (See, e.g., J. Med. Gene Ther. 16:649-663). Some embodiments In this example, the CAG or CB7 promoter (SEQ ID NO: 411) is driven by the vector. The vector may contain other expression control elements that enhance expression of the transgene. In some embodiments, other expression control elements include a chicken β-actin intron and / or a rabbit β-actin intron. In certain embodiments, the promoter comprises a TA β-globin poly(A) signal. In certain embodiments, the promoter comprises one or more nucleotides. In certain embodiments, one or more promoter elements include: They can also be inverted and displaced relative to each other. , the promoter elements are positioned to function cooperatively. In this example, the promoter elements are arranged to function independently. In one embodiment, the viral vectors presented herein contain a human CMV immediate early gene promoter. SV40 early promoter, Rous sarcoma virus (RS) LTR (long term primal repeat), and rat insulin promoter In certain embodiments, the promoter comprises one or more of the promoters provided herein. The vectors shown are AAV, MLV, MMTV, SV40, RSV, HIV-1, and one or more long terminal repeats (LTRs) selected from the group consisting of the LTRs of HIV-2; In certain embodiments, the promoters described herein include The vectors presented herein may be used in combination with one or more tissue-specific promoters (e.g., retinal pigment epithelial cells). epithelial cell-specific promoters, CNS-specific promoters, liver-specific promoters, In certain embodiments, the promoters provided herein include a promoter specific for the gene encoding the gene for the target gene. The viral vectors used are those driven by the RPE65 promoter or the opsin promoter (retinocyte In certain embodiments, the present invention comprises a CNS-specific promoter (e.g., a CNS-specific promoter / CNS-specific promoter). The viral vectors presented herein contain TBG (thyroxine-binding globulin) promoter. motor, APOA2 promoter, SERPINA1 (hAAT) promoter, if In certain embodiments, promoters include hepatocyte-specific promoters, such as the MIR122 promoter. In some embodiments, the viral vectors provided herein may be derived from a promoter such as the human desmin promoter. Muscle-specific promoters (Jonuschies et al., 2014, Curr. Gene Ther. 14:276-288), CK8 promoter (SEQ ID NO: 413; H imeda et al., 2011 Muscle Gene Therapy:Me thods and protocols, Methods in Molecule r Biology, Dongsheng Duan (ed.), 709:3-19; column number 413), or the Pitx3 promoter (Coulon et al., 200 7, JBC 282:33192). In other embodiments, the viral vector comprises V In certain embodiments, the viral vectors herein comprise an MD2 promoter. Synthetic and tandem promoters include, for example, the promoters listed in Table 1 below.

[0058] In certain embodiments, the promoter is an inducible promoter. In embodiments, the promoter is a hypoxia-inducible promoter. In certain embodiments, the promoter contains a hypoxia-inducible factor (HIF) binding site. In certain embodiments, the promoter comprises a HIF-1α binding site. In certain embodiments, the promoter comprises a HIF-2α binding site. The HIF binding site contains an RCGTG motif. For more details, see, for example, Sch. odel, et al.,Blood,2011,117(23):e207-e217 In certain embodiments, the promoter is a low-oxygenase promoter other than a HIF transcription factor. In certain embodiments, the present invention provides a method for the production of a transcription factor comprising the steps of: The viral vectors shown express one or more genes that are preferentially translated under hypoxic conditions. Contains multiple IRES sites. Hypoxia-inducible gene expression and factors involved in this For teachings on this subject, see, for example, K. enneth and Rocha,Biochem J.,2008,414:19- 29. In a specific embodiment, the hypoxia-inducible promoter is a human N -WASP promoter (e.g., see reference for teachings of the N-WASP promoter) Incorporated into Salvi, 2017, Biochemistry and Bioph Biochemical Reports 9:13-21) or human E Hypoxia-inducible promoter of Epo (disclosure of hypoxia-inducible promoter of Epo) Tsuchiya et al., 1993, J. Biology, which is incorporated by reference. 113:395-400). In another embodiment, The motor is a drug-inducible promoter, e.g., induced by administration of rapamycin or its analogs. For example, for disclosure of drug-inducible promoters, PCT Publication No. WO94 / 18, which is incorporated herein by reference in its entirety. 317, WO96 / 20951, WO96 / 41865, WO99 / 10508, WO99 / 10510, WO99 / 36553, and W 099 / 41258, and US 7,067,526, See the disclosure regarding the motor.

[0059] Constructs containing certain ubiquitous and tissue-specific promoters are provided herein. Such promoters include synthetic and tandem promoters. Examples of motors and their nucleotide sequences are provided in Table 1 below. Table 1. Promoter and other regulatory element sequences JPEG2025121920000002.jpg219170JPEG2025121920000003.jpg245170JPEG2025121920000004.jpg139170JPEG202 5121920000005.jpg161170JPEG2025121920000006.jpg181170JPEG2025121920000007.jpg216170JPEG2025121920 000008.jpg126170JPEG2025121920000009.jpg235170JPEG2025121920000010.jpg206170JPEG2025121920000011. jpg206170JPEG2025121920000012.jpg234170JPEG2025121920000013.jpg238170JPEG2025121920000014.jpg81170

[0060] In certain embodiments, the viral vectors provided herein contain more than a promoter. In certain embodiments, the present invention includes one or more regulatory elements other than the above. The provided viral vectors comprise an enhancer. The viral vectors provided herein comprise a repressor. The viral vectors provided herein may contain an intron (e.g., a VH4 intron (sequence SEQ ID NO: 417) or a chimeric intron (SEQ ID NO: 416). The viral vectors presented herein contain polyadenylation sequences.

[0061] A gene expression cassette and a rAAV containing the gene expression cassette, expression of the gene is liver-specific, or both liver-specific and muscle-specific, or Tandem (two or three codons) that promote both liver-specific and bone-specific expression two or more regulatory elements (promoter) controlled by an engineered nucleic acid regulatory element having a transcription factor (e.g., a transcription factor or enhancer), Gene expression cassettes and rAAVs containing the gene expression cassettes are provided. Nodal elements include LSPX1 (SEQ ID NO: 315) for liver-specific expression, LS PX2 (SEQ ID NO: 316), LTP1 (SEQ ID NO: 317), LTP2 (SEQ ID NO: 318) or LTP3 (SEQ ID NO: 319), for liver and muscle expression, LMTP6 (SEQ ID NO: SEQ ID NO: 320), LMTP13 (SEQ ID NO: 321), LMTP14 (SEQ ID NO: 322), L MTP15 (SEQ ID NO: 323), LMTP18 (SEQ ID NO: 324), LMTP19 (SEQ ID NO: SEQ ID NO: 325), or LMTP20 (SEQ ID NO: 326), or for liver and bone expression LBTP1 (SEQ ID NO: 327) or LBTP2 (SEQ ID NO: 328), These sequences are presented in Table 1, supra.

[0062] 5.1.4 Signal peptide In certain embodiments, the vectors provided herein modulate the delivery of proteins. In certain embodiments, the viral vectors presented herein include components that stimulate the The target contains one or more signal peptides. As used herein, a signal peptide is It may also be referred to as a "leader sequence" or "leader peptide." The signal peptide ensures that the transgene product is properly packaged (e.g., packaged) within the cell. In certain embodiments, the signal The peptide allows the transgene product to achieve proper localization within the cell. In certain embodiments, the signal peptide is used to ensure that the transgene product is expressed from the cell. This allows secretion to be achieved.

[0063] In the context of gene therapy or in cell culture, signal sequences for the production of proteins There are two general approaches to selecting a sequence. One is to select the protein to be expressed and Use a signal peptide from a homologous protein, e.g., a human antibody. The signal peptide of the IgG is used to express the IgG in CHO cells or other cells. Another approach is to use a recombinant vector optimized for the particular host cell used for expression. The goal is to identify the signal peptides that are involved in the transcription of different proteins. They can be exchanged between proteins, or between proteins from different organisms. However, the signal sequences of the most abundant secreted proteins in this cell type typically regulate protein expression. For example, the most abundant protein in plasma, human albumin, The signal peptide substantially increases the production yield of the protein in CHO cells. However, certain signal peptides were found to be involved in the expression of proteins. After being cleaved from the targeting site, the targeting site retains its function as a "post-targeting function" and exerts its activity. Thus, in a specific embodiment, a signal peptide is used for expression. Among the most abundant proteins secreted by cells that evade function after targeting In certain embodiments, the signal sequence is selected from the heavy chain and An exemplary sequence is the nucleotide sequence of SEQ ID NO: 422. MYRMQLLLLIALSLALVTNS (SEQ ID NO: 16) which can be coded as 1) (see Table 2, Figures 2-19 and Figures 29A-29F). Alternatively, HuPTM mAb or HuPTM F in the nucleus (including the CNS), muscle, or liver Suitable signal sequences for expression of ab or scFv are listed below in Tables 2, 3 and 4, respectively. Present. JPEG2025121920000015.jpg127170JPEG2025121920000016.jpg116170JPEG2025121920000017.jpg174170

[0064] 5.1.5 Polycistronic messages: IRES and F2A linker and sc Fv constructs Internal ribosome entry site: A single construct can be inserted into individual heavy chain polypeptides by transduced cells. cleavable linkers or cleavable linkers to express heavy and light chain polypeptides having the same polypeptide. or can be engineered to encode both heavy and light chains, separated by an IRES. In certain embodiments, the viral vectors provided herein are polycistronic. delivers a cyclic (e.g., bicistronic) message. For example, viral assembly The product comprises heavy and light chains separated by an internal ribosome entry site (IRES) element. (To create a bicistronic vector, an IRES element may be used.) For examples of the use of, see, e.g., Gurtu et al.,1996,Biochem.Biophys.Res.Co mm.229(1):295-8). IRES elements are proteins that bind to the ribosome. Bypassing the scanning model and initiating translation at an internal site. See, for example, Furlin, which is incorporated herein by reference in its entirety. g et al., 2001, Gene Ther 8(11):854-73 In certain embodiments, the bicistronic message includes The polynucleotide is contained within a viral vector that is constrained in size. In certain embodiments, the bicistronic message is delivered via an AAV viral-based vector. vector (e.g., AAV8-based vector, AAV9-based vector, or AAVr h10-based vector).

[0065] Furin-2A linker. In another embodiment, the viral vectors provided herein is an upstream furin cleavage site, e.g., furin / F2A (F / F2A) or furin / Self-cleavage with or without a Furin / 2A linker, such as a T2A (F / T2A) linker Encoding heavy and light chains separated by a cleavable linker such as type 2A and 2A-like peptides. (Fang et al., each of which is incorporated herein by reference in its entirety). al.,2005,Nature Biotechnology 23:584-59 0, Fang, 2007, Mol Ther 15:1153-9, and Chang, J .et al,MAbs 2015,7(2):403-412). For example, Fuling / A 2A linker is incorporated into the expression cassette to separate the heavy chain coding sequence from the light chain coding sequence. The resulting structure: A construct with leader-heavy chain-furin site-2A site-leader-light chain-polyA was also It can be done. Amino acid sequence RKRR(GSG)APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO: 231) containing the F2A site or the amino acid sequence RKRR(GSG)EGRGS a 2A site such as an F2A site containing LLTCGDVEENPGP (SEQ ID NO: 429); or The 2A-like site is self-processing, resulting in the final G amino acid residue and the P amino acid residue. The upstream flexible Gly-Ser-Gly (GSG) phosphorylation leads to "cleavage" with the hydroxyl group. Some linkers that can be used, with or without the car sequence (SEQ ID NO: 427), are: T2A: (GSG)EGRGSLLTCGDVEENPGP (SEQ ID NO: 227); P2A: (GSG)ATNFSLLKQAGDVEENPGP (SEQ ID NO: 228); E2A: (GSG)QCTNYALLKLAGDVESNPGP (SEQ ID NO: 229); F2A: (GSG) APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO: 2 30) These include, but are not limited to, (each of which is incorporated herein by reference in its entirety) For example, Szymczak, et al., 2004, Nature Biot echnol 22(5):589-594, and Donnelly, et al.,2 001, J Gen Virol, 82:1013-1025). Exemplary nucleotide sequences encoding different portions of the linker are listed in Table 1-1. JPEG2025121920000018.jpg55170

[0066] In certain embodiments, additional proteolytic cleavage sites, such as furin cleavage sites, are also included. The position is flanked by self-processing cleavage sites (e.g., 2A or 2A-like sequences) in the expression construct. By incorporating it into a product, the additional fragments remaining after cleavage by the self-processing cleavage sequence can be Without being bound by any one theory, a means for removing amino acids is provided. However, when the ribosome encounters the F2A sequence in an open reading frame, The peptide bond is omitted, resulting in the termination of translation or the continuation of translation of the downstream sequence (light chain). This self-processing sequence results in the addition of an additional amino acid sequence at the C-terminus of the heavy chain. However, this results in a chain of amino acids. The 2A site is located immediately before the 2A site and after the heavy chain sequence by the host cell's furin. It is cleaved at the furin site and further cleaved by carboxypeptidase. The resulting heavy chain may contain one, two, three, or The sequence of the Furin linker used may contain additional amino acids beyond this. and the linker, depending on the carboxypeptidase that cleaves it in vivo. In some cases, the nucleotide sequence does not contain additional amino acids (e.g., Fang et al., 17 April 2005,Nature Biotechnol.Advance Onl. ine Publication;Fang et al.,2007,Molecul ar Therapy 15(6):1153-1159;Luke,2012,Inn See Opportunities in Biotechnology, Ch.8, 161-186. A Furin linker that can be used is a chain of four basic amino acids, e.g. , RKRR (SEQ ID NO: 222), RRRR (SEQ ID NO: 223), RRKR (SEQ ID NO: 22 4), or RKKR (SEQ ID NO: 225). When cleaved by an enzyme, 0, 1, 2, 3, or 4 additional amino acids, e.g. For example, R, RR, RK, RKR, RRR, RRK, RKK, RKRR (SEQ ID NO: 222), RRRR (SEQ ID NO: 223), RRKR (SEQ ID NO: 224), or RKKR (SEQ ID NO: 225) can still remain on the C-terminus of the heavy chain, additional amino acids can still In certain embodiments, one linker can be cleaved by carboxypeptidase. In certain embodiments, the amino acid sequence described herein is truncated to a sequence that does not contain any additional amino acids. and antibodies, e.g., antigen-binding fragments, produced by the constructs for use in the methods described herein. 0.5%-1%, 1%-2%, 5%, 10%, 15%, or 20% of the population The cleavage product is a cleavage product of one, two, three, or four amino acids remaining on the C-terminus of the heavy chain. In certain embodiments, the Furin linker comprises an additional amino acid on the C-terminus of the heavy chain. The amino acid is R, RX, RXK, RXR, RXKR, or RXRR, where X is any the sequence RXK / RR is In certain embodiments, the additional amino acids may not remain on the C-terminus of the heavy chain. There is a match.

[0067] Flexible peptide linkers: In some embodiments, a single construct may comprise a heavy and light chains (preferably α- and β-glucan chains) separated by a flexible peptide linker, such as can be engineered to encode both heavy and light chain variable domains. The peptide linker allows adjacent heavy and light chain domains to bind independently to each other. It can be composed of flexible residues such as glycine and serine so that it can move freely. The construct comprises a heavy chain variable domain at the N-terminus of the scFv, followed by a linker, The light chain variable domain can then be arranged as follows. Alternatively, the construct can be The chain variable domains are at the N-terminus of the scFv, followed by a linker, then a heavy chain. The chain variable domains can be arranged such that the components are NH2-V L - Linker-V H -COOH or NH2-V H -Linker-V L Arranged as -COOH It is possible.

[0068] In certain embodiments, the expression cassettes descr...

Claims

1. Hereditary angioedema in a human subject in need of treatment for angioedema, including hereditary angioedema 1. A pharmaceutical composition for treating angioedema, including edema, comprising: (a) AAV8 capsid (SEQ ID NO: 143); AAVrhlO capsid (SEQ ID NO: 14 5); or a sequence at least 95% identical to the amino acid sequence of the AAV9 capsid (SEQ ID NO: 144). a viral capsid that is one of the (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. a full-length or substantially full-length antibody operably linked to one or more regulatory sequences that The artificial genome encoding a ribozyme (anti-pKal) mAb or an antigen-binding fragment thereof. Mm; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is intravenous. The pharmaceutical composition is administered intravenously, subcutaneously, intranasally, or intramuscularly.

2. The pharmaceutical composition of claim 2, wherein the anti-pKal mAb is lanadelumab.

3. For treating hereditary angioedema in a human subject in need thereof 1. A pharmaceutical composition for delivering lanadelumab to the bloodstream for the treatment of muscle cells, the composition comprising: and / or one or more regulatory sequences that control expression of the transgene in hepatocytes. A recombinant AAV containing an operably linked transgene encoding lanadelumab. wherein the recombinant AAV is administered to the subject at a concentration of at least 5 μg / ml to at least 35 μg / ml. The human subject is administered a transgene to produce a lanadelumab plasma level of 100 μg / ml. and administering the compound to the human subject at a dose sufficient to result in expression and secretion of lanadelumab from the human subject's bloodstream. The pharmaceutical composition is administered to

4. the lanadelumab plasma level is between 20 μg / ml and 35 μg / ml, 4. The method of claim 3, wherein lumab plasma levels are maintained for at least 3 months.

5. The lanadelumab antibody secreted into the plasma is detected by a kinetic enzyme function assay. At least 40%, 45%, 50%, 55%, 60% of pKal activity as measured , 65% or more than 70% reduction in the activity of the lanadelumab antibody 2 days after the administration. Week 1, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11 The method according to claim 3 or 4, wherein the measurement is performed at week 12 or 13.

6. The antibody or antigen-binding fragment thereof is delivered to the bloodstream of a human subject in need thereof. A pharmaceutical composition for delivering an antigen-binding fragment, comprising: (a) an AAV viral capsid that infects hepatocytes and / or muscle cells; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; The transgene is expressed by a chimeric promoter that directs expression in muscle cells and liver cells. the artificial genome encoding a full-length antibody or an antigen-binding fragment thereof, operably linked to the M and an AAV vector comprising: The pharmaceutical composition, wherein the AAV vector is formulated for intramuscular administration.

7. The chimeric promoter is selected from the group consisting of LMTP6 (SEQ ID NO: 320), LMTP13 (SEQ ID NO: 321), and LMTP4 (SEQ ID NO: 322). 321), LMTP14 (SEQ ID NO: 322), LMTP15 (SEQ ID NO: 323), LMT P18 (SEQ ID NO: 324), LMTP19 (SEQ ID NO: 325), or LMTP20 (SEQ ID NO: 326). The pharmaceutical composition according to claim 6, wherein the compound is selected from the group consisting of phenylalanine, ...

8. A method for treating non-infectious uveitis in a human subject in need thereof. A pharmaceutical composition for administering the drug to a patient, comprising: (a) AAV2.7m8 (SEQ ID NO: 142), AAV8 capsid (SEQ ID NO: 143); or at least 95% identical to the amino acid sequence of the AAV9 capsid (SEQ ID NO: 144). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human retinal cells. a substantially full-length or full-length anti-tumor necrosis factor alpha ( anti-TNFα) mAb or antigen-binding fragment thereof, substantially full-length or full-length anti-complement component 5 (C5) mAb or antigen-binding fragment thereof, substantially full-length or full-length anti-interleukin and / or a substantially full-length or full-length interleukin-6 (IL-6) mAb or antigen-binding fragment thereof. Encoding an anti-interleukin-6 receptor (IL-6R) mAb or an antigen-binding fragment thereof the artificial genome; and an AAV vector comprising: the AAV vector is administered subretinal, intravitreal, intranasal, or suprachoroidally to the subject The pharmaceutical composition is formulated for the following purpose:

9. the anti-TNFα mAb is adalimumab, infliximab, or golimumab; the anti-C5 mAb is tesidolumab or ravulizumab; the anti-IL-6 mAb is Ab is siltuximab, clazakimuzumab, sirukumab, olokizumab or geririm or the anti-IL-6R mAb is satralizumab, sarilumab or The pharmaceutical composition of claim 8, which is tocilizumab.

10. Alzheimer's disease, frontotemporal dementia (FD), tauopathy, progressive supranuclear palsy, chronic Traumatic encephalopathy, Pick's complex, and primary age-related tauopathies, Huntington's disease, early-onset Huntington's disease, Parkinson's disease, synucleinopathy, ALS, migraine, or cluster headache Alzheimer's disease, frontotemporal dementia (FD) in human subjects in need of pain treatment , tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, Pick's complex, and primary age-related Tauopathy, Huntington's disease, juvenile Huntington's disease, Parkinson's disease, synucleinopathies 1. A pharmaceutical composition for treating rheumatoid arthritis, ALS, migraine, or cluster headache, comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrhlO capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid or a virus that is at least 95% identical to the amino acid sequence of the AAVcy5 capsid Ruscapsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene is expressed in human CNS cells, muscle cells, or liver cells. full-length or substantially full-length polypeptides operably linked to one or more regulatory sequences that control expression Full-length anti-amyloid beta (anti-Aβ), anti-sortilin, anti-tau protein (anti-tau), anti-sema Folin 4D (anti-SEMA4D), anti-α-synuclein (anti-SNCA), anti-Superox Sidodismutase-1 (anti-SOD1) or anti-calcitonin gene-related peptide receptor the artificial genome encoding an (anti-CGRPR) mAb, or an antigen-binding fragment thereof; an adeno-associated virus (AAV) vector having The AAV vector is formulated for administration to the subject, and optionally, administration is intrathecal. The pharmaceutical composition is administered intravenously, intravenously, subcutaneously, intranasally, or intramuscularly.

11. the anti-Aβ mAb is solanezumab, lecanemab, or GSK933776; the anti-sortilin mAb is AL-001; and the anti-tau mAb is ABBV-8 E12, UCB-0107, or NI-105 (BIIB076); The MA4D mAb is VX15 / 2503; and the anti-SNCA mAb is Plascin izumab, NI-202 (BIIB054), or MED-1341; D1 mAb is NI-2041.10D12 or NI-204.12G7; and The anti-CGRPR mAb is eptinezumab, fremanezumab, or galcanezumab. The pharmaceutical composition according to claim 10.

12. Diabetic retinopathy, myopic choroidal neovascularization (mCNV), macular degeneration (e.g., neovascularization (wet) or dry age-related macular degeneration (nAMD)), macular edema (e.g., retinal stasis) macular edema after retinal vein occlusion (RVO) or diabetic macular edema (DME), retinal vein occlusion , diabetic retinopathy (DR), non-infectious uveitis, or glaucoma, or abnormal blood flow to the retina In a human subject in need of treatment for a retinal disorder, including neovascularization, diabetic retinopathy, myopia Choroidal neovascularization (mCNV), macular degeneration (e.g., neovascular (wet) or dry) age-related macular degeneration (nAMD), macular edema (e.g., retinal vein occlusion (RVO) or Macular edema after diabetic macular edema (DME), retinal vein occlusion, diabetic retinopathy (DR) retinal disorders, including non-infectious uveitis, or glaucoma, or abnormal vascularization of the retina A pharmaceutical composition for treating (a) AAV2.7m8 capsid (142), AAV8 capsid (SEQ ID NO: 143); or at least 95% identical to the amino acid sequence of the AAV9 capsid (SEQ ID NO: 144). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human retinal cells. Full-length or substantially full-length anti-vascular endothelial growth factors operably linked to multiple regulatory sequences - Patent Application 20070122997 (anti-VEGF), anti-erythropoietin receptor (anti-EPOR), anti-Aβ, anti-activin receptor Anti-alkenyl kinase 1 (anti-ALK1), anti-complement component 5 (anti-C5), anti-endoglin (anti-ENG) , anti-complement component 1Q (anti-CC1Q), anti-tumor necrosis factor alpha (anti-TNFα), or anti-pKal the artificial genome encoding a mAb or an antigen-binding fragment thereof; and an AAV vector comprising: The AAV vector is administered subretinal, intravitreal, suprachoroidally, or intranasally to the subject. The pharmaceutical composition is formulated for the following purpose:

13. The anti-VEGF mAb is sevacizumab; and the anti-EPOR mAb is LKA. -651 (NSV2) or LKA-651 (NSV3); , solanezumab, lecanemab, or GSK933776; b is asclinbacumab; and the anti-C5 mAb is tesidolumab or ravliz the anti-ENG mAb is carotuximab; the anti-CC1Q mAb is ANX-007; the anti-TNFα mAb is adalimumab, infliximab or is golimumab; and the anti-pKal mAb is lanadelumab. The pharmaceutical composition described in

14. Medicaments for treating multiple sclerosis in a human subject in need thereof 1. A composition comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrhlO capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid or a virus that is at least 95% identical to the amino acid sequence of the AAVcy5 capsid Ruscapsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene is expressed in human CNS cells, liver cells, or muscle cells. full-length or substantially full-length polypeptides operably linked to one or more regulatory sequences that control expression The full-length anti-repulsive guidance molecule-A (anti-RGMa) mAb or its antigen-binding fragment is the artificial genome; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is intrathecal. The pharmaceutical composition is administered intravenously, intravenously, subcutaneously, intranasally, or intramuscularly.

15. The pharmaceutical composition of claim 14, wherein the anti-RGM a mAb is elezanumab.

16. amyloidosis (ATTR), familial amyloid cardiomyopathy (FAC), or familial amyloidosis Amyloidosis in a human subject in need of treatment for amyloid polyneuropathy (FAP) tetanyloidosis (ATTR), familial amyloidosis cardiomyopathy (FAC), or familial amyloidosis A pharmaceutical composition for treating fast acting neuropathy (FAP), comprising: (c) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrhlO capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid, or a capsid that is at least 95% identical to the amino acid sequence of the AAVcy5 capsid. Irucapsid; and (a) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. a full-length or substantially full-length anti-T nucleotide sequence operably linked to one or more regulatory sequences that the artificial genome encoding a TR mAb or an antigen-binding fragment thereof; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is intravenous. The pharmaceutical composition is administered intravenously, subcutaneously, intranasally, or intramuscularly.

17. The method according to claim 16, wherein the anti-FTR mAb is NI-301 or PRX-004. The pharmaceutical composition described above.

18. Fibrotic disorders, pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, Atrial fibrosis, endomyocardial fibrosis, previous myocardial infarction, arthrofibrosis, Crohn's disease, ulcerative colitis inflammation, mediastinal fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis fibrotic fibrosis (PMF) and retroperitoneal fibrosis (RPF) in human subjects in need of treatment. Disorders, pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrial fibrosis disease, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, ulcerative colitis, mediastinal Fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF) ), and a pharmaceutical composition for treating retroperitoneal fibrosis (RPF), comprising: (c) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), or at least 95% identical to the amino acid sequence of AAVrhlO (SEQ ID NO: 145). a viral capsid; and (d) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. a full-length or substantially full-length anti-binding protein operably linked to one or more regulatory sequences that The artificial antibody encoding a synthetic tissue growth factor (anti-CTGF) mAb or an antigen-binding fragment thereof. genome; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is intravenous. The pharmaceutical composition is administered intravenously, subcutaneously, intranasally, or intramuscularly.

19. 19. The pharmaceutical composition of claim 18, wherein the anti-CTGF mAb is pamrevlumab.

20. Non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR), or diabetes Non-infectious uveitis, ophthalmopathy in human subjects in need of treatment for pathological macular edema (DME) Neuromyelitis (NMO), diabetic retinopathy (DR), or diabetic macular edema (DME) A pharmaceutical composition for treating (a) AAV8 capsid (SEQ ID NO: 143), AAV2.7m8 capsid (SEQ ID NO: 1 42) or a sequence at least 95% identical to the amino acid sequence of the AAV9 capsid (SEQ ID NO: 144). a viral capsid that is one of the (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human retinal cells. A full-length or substantially full-length anti-interleukin-11 antibody operably linked to multiple regulatory sequences. -6 receptor (anti-IL6R), anti-interleukin 6 (IL6), or anti-cluster of differentiation 19 (anti-CD19) mAb, or an antigen-binding fragment thereof; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is by intranasal administration. The pharmaceutical composition is intraretinal, subretinal, intravitreal, or suprachoroidal.

21. the anti-IL6R mAb is satralizumab, sarilumab, or tocilizumab; or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, oro or the anti-CD19 mAb is erythromycin, erythromycin, or erythromycin.

21. The pharmaceutical composition of claim 20, which is a mab.

22. Decreased, inhibited, or ameliorated adverse immune responses in a human subject in need thereof. A pharmaceutical composition for reducing, inhibiting, or ameliorating the response of a patient to steroids, comprising: (a) AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), At least 95% identical to the amino acid sequence of the AAVrhlO capsid (SEQ ID NO: 145). a viral capsid; and (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver or muscle cells. an anti-interleukin-6 receptor (anti-IL-6 receptor) operably linked to one or more regulatory sequences; IL6R) or anti-interleukin-6 (IL6), or an antigen-binding fragment thereof the artificial genome encoding a full-length or full-length mAb; and an AAV vector comprising: The AAV vector is formulated for subcutaneous, intramuscular, intravenous, or pulmonary administration to a subject. The pharmaceutical composition.

23. the anti-IL6R mAb is satralizumab, sarilumab, or tocilizumab; or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, oro 23. The pharmaceutical composition of claim 22, which is kizumab or gerilimuzumab.

24. In a human subject in need of treatment for inflammatory bowel disease (IBD), including UC and CD, A pharmaceutical composition for treating inflammatory bowel disease (IBD), comprising C and CD, (a) AAV8 capsid (SEQ ID NO: 143); AAV9 capsid (SEQ ID NO: 144); or a sequence at least 95% identical to the amino acid sequence of the AAVrhlO capsid (SEQ ID NO: 145). a viral capsid that is one of the (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. a full-length or substantially full-length antibody operably linked to one or more regulatory sequences that Integrin β7 subunit (anti-ITGB7) mAb, or an antigen-binding fragment thereof, the artificial genome; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is intravenous. The pharmaceutical composition is administered intravenously, subcutaneously, intranasally, or intramuscularly.

25. 25. The pharmaceutical composition of claim 24, wherein the anti-ITGB7 mAb is etrolizumab. 。

26. Treating osteoporosis or abnormal bone loss or weakness (e.g., giant cell tumor of bone) Treating treatment-induced bone loss; Bone loss in breast cancer and prostate cancer patients slowing (or increasing bone mass) the progression of bone metastases and preventing skeletal events due to bone metastases or osteoporosis or abnormal bone resorption and bone turnover in a human subject in need of attenuation. Treating bone loss or bone weakness (e.g., treating giant cell tumor of bone, treatment-induced Treating bone loss, slowing bone loss in breast and prostate cancer patients (or increase bone mass), prevent skeletal events caused by bone metastasis, or inhibit bone resorption and bone resorption A pharmaceutical composition for reducing translocation, comprising: (a) AAV8 capsid (SEQ ID NO: 143); AAVrhlO capsid (SEQ ID NO: 14 5); or a sequence at least 95% identical to the amino acid sequence of the AAV9 capsid (SEQ ID NO: 144). a viral capsid; (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. a full-length or substantially full-length anti-serotype polypeptide operably linked to one or more regulatory sequences that The artificial antibody encoding a clerostin (anti-SOST) mAb, or an antigen-binding fragment thereof. genome; and an AAV vector comprising: The AAV vector is formulated for administration to the subject, and optionally, administration is intravenous. The pharmaceutical composition is administered intravenously, subcutaneously, intranasally, or intramuscularly.

27. 27. The pharmaceutical composition of claim 26, wherein the anti-SOST mAb is romosozumab.

28. For treating atopic dermatitis in a human subject in need thereof A pharmaceutical composition for (a) AAV8 capsid (SEQ ID NO: 143) or AAV9 capsid (SEQ ID NO: 144) a viral capsid that is at least 95% identical to the amino acid sequence of (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. an anti-IL13 mAb or an anti-IL13 mAb operably linked to one or more regulatory sequences that the artificial genome encoding L31RA or an antigen-binding fragment thereof; and an AAV vector comprising: The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition.

29. The anti-IL13 or the anti-IL31RA is tralokinumab or nemolizumab.

29. The pharmaceutical composition of claim 28.

30. Pharmaceutical compositions for treating eosinophilic asthma in a human subject in need thereof A composition comprising: (a) AAV8 capsid (SEQ ID NO: 143) or AAV9 capsid (SEQ ID NO: 144) a viral capsid that is at least 95% identical to the amino acid sequence of (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. an anti-IL5R mAb or anti-IL5R mAb operably linked to one or more regulatory sequences that the artificial genome encoding a gE mAb or an antigen-binding fragment thereof; and an AAV vector comprising: The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition.

31. The anti-IL5R or anti-IgE mAb is reslizumab or omalizumab. The pharmaceutical composition of claim 30.

32. A method for treating asthma or chronic obstructive pulmonary disease (COPD) in a human subject in need of treatment for asthma or chronic obstructive pulmonary disease (COPD) or chronic obstructive pulmonary disease (COPD), comprising: (a) AAV8 capsid (SEQ ID NO: 143) or AAV9 capsid (SEQ ID NO: 144) a viral capsid that is at least 95% identical to the amino acid sequence of (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. anti-IL5, anti-IL-5R, anti-IL-1, operably linked to one or more regulatory sequences The artificial gE encoding the anti-TSLP mAb, or an antigen-binding fragment thereof. Nom; and an AAV vector comprising: The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition.

33. the anti-IL-5, the anti-IL5R, the anti-IgE, or the anti-TSLP mAb 32. Benralizumab, reslizumab, omalizumab, or tezepelumab. The pharmaceutical composition described in

34. For treating chronic idiopathic urticaria in a human subject in need thereof A pharmaceutical composition for (a) AAV8 capsid (SEQ ID NO: 143) or AAV9 capsid (SEQ ID NO: 144) a viral capsid that is at least 95% identical to the amino acid sequence of (b) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. an anti-IgE mAb or its anti-IgE mAb operably linked to one or more regulatory sequences that the artificial genome encoding a nucleotide-binding fragment; and an AAV vector comprising: The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition.

35. 35. The pharmaceutical composition of claim 34, wherein the anti-IgE mAb is omalizumab.

36. Medicaments for treating myasthenia gravis in a human subject in need thereof 1. A composition comprising: (c) AAV8 capsid (SEQ ID NO: 143) or AAV9 capsid (SEQ ID NO: 144) a viral capsid that is at least 95% identical to the amino acid sequence of (d) AAV ITR (inverted terminal repeat) an artificial genome comprising an expression cassette containing a transgene; wherein the transgene controls expression of the transgene in human liver cells or human muscle cells. an anti-C5 mAb or its antigen, operably linked to one or more regulatory sequences that the artificial genome encoding a binding fragment; and an AAV vector comprising: The AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. The pharmaceutical composition.

37. 37. The pharmaceutical composition of claim 36, wherein the anti-C5 is ravulizumab.

38. 1. A method for determining human anti-pKal antibody activity in a sample, comprising: a. incubating the sample with activated human pKal; b. The sample incubated with activated human pKal was then lysed with the synthetic substrate Pro -incubating with Phe-Arg-AMC; c. Measuring the release of AMC over a 3 hour period compared to a control sample The method comprising:

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