Fully human post-translationally modified antibody therapeutics

Abstract

Methods and compositions for delivering fully human post-translationally modified therapeutic monoclonal antibodies and antigen-binding fragments thereof are provided. Fully human post-translationally modified therapeutic monoclonal antibodies may be preferably delivered to appropriate tissues by gene therapy, e.g., as recombinant adeno-associated virus (rAAV) vectors. Methods for producing AAV vectors, pharmaceutical compositions, and methods of treatment are also provided. Additionally, methods for generating "bio-better" therapeutic antibodies as fully human post-translationally modified therapeutic antibodies are provided. These fully human post-translationally modified therapeutic antibodies can be administered to subjects in need of treatment with the therapeutic antibody.

Description

[Technical field]

[0001] 0. Sequence List This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on April 24, 2020, is named 38013_0001P1_SL.txt and is 690,185 bytes in size.

[0002] 1. Introduction Compositions and methods are described for delivering a fully human post-translationally modified (HuPTM) therapeutic monoclonal antibody ("mAb"), or a HuPTM antigen-binding fragment of a therapeutic mAb (e.g., a fully human glycosylated (HuGly) Fab of a therapeutic mAb), to a human subject diagnosed with a disease or condition for which treatment with the therapeutic mAb is indicated. [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 agents are only effective for a short period of time, necessitating repeated injections over extended periods of time, which often results in a significant treatment burden for patients. Summary of the Invention

[0004] 3. Overview of the Invention Compositions and methods are described for delivering HuPTM mAbs or HuPTM antigen-binding fragments of therapeutic mAbs (e.g., fully human glycosylated Fab (HuGlyFab) of a therapeutic mAb) to patients (human subjects) diagnosed with a disease or condition for which treatment with a therapeutic mAb is indicated. Such antigen-binding fragments of a therapeutic mAb include Fab, F(ab') and / or other fragments of the therapeutic mAb. 2, or scFv (single chain variable fragment) (collectively referred to herein as "antigen binding fragment"). As used herein, "HuPTM Fab" may include other antigen binding fragments of mAbs. In alternative embodiments, full length mAbs may be used. Delivery may advantageously be achieved via gene therapy, e.g., by administering a viral vector or other DNA expression construct encoding a therapeutic mAb or an antigen binding fragment thereof (or a hyperglycosylated derivative of either) to a patient (human subject) diagnosed with a condition indicated for treatment with the therapeutic mAb, to create a permanent depot within the patient's tissues or organs that continually supplies the HuPTM mAb or an antigen binding fragment of the therapeutic mAb, e.g., a human glycosylated transgene product, to the target tissue where the mAb or its antigen binding fragment exerts its therapeutic effect.

[0005] The HuPTM mAb or HuPTM antigen-binding fragment encoded by the transgene can be Nervous system targets, e.g., amyloid beta (Aβ or Aβ) peptides derived from the amyloid precursor protein (APP), including but not limited to solanezumab, GSK933776, and lecanemab (see Figures 2A-2C), indicated for the treatment of Alzheimer's disease; sortilin, including but not limited to AL-001 (see Figure 3), for treating frontotemporal dementia (FTD); tauopathies, involved in tauopathies, including Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, chronic traumatic encephalopathy, Pick's complex, primary age-related tauopathy, including but not limited to ABBV-8E12, UCB-0107, and NI-105 (BIIB076) (see Figures 4A-4C), for treating tauopathies proteins; SEMA4D, including but not limited to VX15 / 2503 (see FIG. 5) for treating Huntington's disease and juvenile Huntington's disease; alpha-synuclein, including but not limited to prasinezumab, NI-202 (BIIB054) and MED-1341 (see FIG. 6A-C) for treating Parkinson's disease and synucleinopathies; superoxide dismutase-1 (SOD-1), including but not limited to NI-204 (see FIG. 7A and 7B) for treating ALS and Alzheimer's disease; and CGRP receptor, including but not limited to eptinezumab, fremanezumab and galcanezumab (see FIG. 8A-C) for treating migraine and cluster headaches; ocular antiangiogenic targets, including but not limited to VEGF (vascular endothelial growth factor), including but not limited to sevacizumab (see FIG. 9A) for treating retinal disorders including diabetic retinopathy (DR), myopic choroidal neovascularization (mCNV), age-related macular degeneration (AMD), and macular edema; erythropoietin receptor, including but not limited to LKA-651 (see FIGS. 9B and 9C), indicated for the treatment of retinal diseases such as retinal vein occlusion (RVO), wet AMD, and macular edema; amyloid beta (Aβ or Aβ) peptide, derived from the amyloid precursor protein (APP), including but not limited to solanezumab, GSK933776, or lecanemab (see FIGS. 2A-2C) for the treatment of dry AMD; asculinbacumab (see FIG. 10A) for the treatment of neovascular age-related macular degeneration; complement component 5 (C5), including but not limited to, tesidolumab and ravulizumab (see Figures 10B and 10D), indicated for the treatment of dry AMD and non-infectious uveitis; endoglin (END or CD105), including but not limited to, carotuximab (see Figure 10C), indicated for the treatment of wet AMD and other retinal disorders resulting from increased angiogenesis; complement component 1Q (C1Q), including but not limited to, ANX-007 (see Figure 11), indicated for the treatment of glaucoma; and plasma protein targets such as human complement proteins, including but not limited to, lanadelumab (see Figure 19), including but not limited to, plasma kallikrein (pKal), for the treatment of diabetic retinopathy and diabetic macular edema; Complement component 5, including but not limited to ravulizumab, which is indicated for the treatment of myasthenia gravis (see Figure 10D); TNF-α, including but not limited to adalimumab (HUMIRA®), infliximab (REMICADE®), and golimumab, indicated for the treatment of non-infectious uveitis (see Figures 12A-C); Repulsive guidance molecules-A, including but not limited to elezanumab (see FIG. 13) for treating multiple sclerosis; Transthyretin (TTR), including but not limited to NI-301 and PRX-004 (see Figures 14A and B), which are indicated for the treatment of amyloidosis; Connective tissue growth factor (CTGF), including but not limited to pamrevlumab (see FIG. 15), which is indicated for the treatment of fibrotic diseases (e.g., diabetic nephropathy, hepatic fibrosis, idiopathic pulmonary fibrosis); Neuromyelitis optica (NMO) / non-infectious uveitis targets, such as the TNF-α-targeting antibodies mentioned above, and interleukin 6 (IL6)- and interleukin 6 receptor (IL6R)-targeting antibodies, including but not limited to satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilimuzumab, and tocilizumab (see Figures 16A-H), indicated for the treatment of NMO, DR, DME, and non-infectious uveitis; and CD19, including but not limited to inebilizumab (see Figure 16I), indicated for the treatment of NMO; · immune response targets, e.g., interleukin 6 (IL6)- and interleukin 6 receptor (IL6R)-targeting antibodies, including but not limited to satralizumab, sarilumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilimuzumab, and tocilizumab (see Figures 16A-H), indicated for the treatment of adverse immune responses, such as those associated with bacterial or viral infections, such as cytokine release syndrome, and those administered in conjunction with immune agents such as CAR-T and other cell-based therapies, as well as immuno-oncology agents that counteract, reduce, or ameliorate adverse immune responses associated with such therapies; Integrin β7, including but not limited to etrolizumab (see FIG. 17), which is indicated for the treatment of ulcerative colitis and Crohn's disease; sclerostin, including but not limited to romosozumab (EVENITY®) (see FIG. 18), which is indicated for the treatment of osteoporosis and abnormal bone loss or weakness; Plasma protein targets, e.g., human complement proteins, including but not limited to, lanadelumab (see FIG. 19), including but not limited to plasma kallikrein, for treating hereditary angioedema and ocular indications, including diabetic retinopathy and diabetic macular edema; and Anti-IL and IL-receptor and other targets for autoimmune, respiratory and allergic diseases, such as thymic stromal lymphopoietin (TSLP), including but not limited to interleukin 5 (IL5), including but not limited to benralizumab (see FIG. 29A); interleukin 5 receptor (IL5R), including but not limited to reslizumab (see FIG. 29B); interleukin 13 (IL13), including but not limited to tralokinumab (see FIG. 29C); interleukin 31 receptor alpha (IL-31RA), including but not limited to nemolizumab (see FIG. 29D); immunoglobulin E (IgE), including but not limited to omalizumab (see FIG. 29E); and tezepelumab (see FIG. 29F). The therapeutic antibodies may include, but are not limited to, a full length therapeutic antibody or an antigen-binding fragment thereof that binds to

[0006] The recombinant vector used to deliver the transgene includes non-replicating recombinant adeno-associated virus vector ("rAAV"). However, other viral vectors can also be used, including but not limited to lentivirus vectors, vaccinia virus vectors, or non-viral expression vectors, referred to as "naked DNA" constructs. The expression of the transgene can be controlled by constitutive expression control elements or tissue-specific expression control elements.

[0007] The gene therapy construct is designed to express both heavy and light chains. The coding sequences for the heavy and light chains can be engineered in a single construct, separated by a cleavable linker or IRES, to express heavy chains with separate heavy chain polypeptides, and light chain polypeptides. In certain embodiments, the coding sequences are Fab or F(ab') 2 or scFv. In certain embodiments, the full-length heavy and full-length light chains of the antibody are expressed. In other embodiments, the construct expresses an scFv in which the heavy chain variable domain and the light chain variable domain are connected via a flexible, non-cleavable linker. In certain embodiments, the construct expresses an scFv in which the heavy chain variable domain and the light chain variable domain are connected via a flexible, non-cleavable linker from the N-terminus, 2 -V L -Linker-V H -COOH or NH 2 -V H -Linker-V L Expresses -COOH.

[0008] Therapeutic antibodies delivered by gene therapy have several advantages over injected or infused therapeutic antibodies, which dissipate over time resulting in peak and trough levels. In contrast to repeated injections of antibodies, sustained expression of the transgene product antibody allows more consistent levels of antibody to be present at the site of action, and fewer injections need to be administered, resulting in less risk and greater convenience for the patient. Furthermore, antibodies expressed from transgenes are post-translationally modified differently than directly injected antibodies due to the different microenvironments present during and after translation. Without being bound to any particular theory, this results in antibodies with different diffusion, bioactivity, distribution, affinity, pharmacokinetic, and immunogenicity characteristics, such that the antibodies delivered to the site of action are "bio-better" compared to directly injected antibodies.

[0009] In addition, in vivo, antibodies expressed from transgenes are less likely to contain degradation products associated with recombinantly produced antibodies, such as protein aggregation and protein oxidation. Aggregation is a problem associated with protein production and storage due to high protein concentration, surface interactions with manufacturing equipment and vessels, and purification with certain buffer systems. These conditions that promote aggregation are not present with transgene expression in gene therapy. Oxidation, such as oxidation of methionine, tryptophan, and histidine, is also associated with protein production and storage and is caused by stress conditions in cell culture, contact with metals and air, and impurities in buffers and excipients. In vivo, proteins expressed from transgenes may also oxidize under stress conditions. However, humans, and many other organisms, are equipped with antioxidant defense systems that not only reduce oxidative stress, but also repair and / or reverse oxidation in some cases. Thus, proteins produced in vivo are less likely to be in oxidized form. Both aggregation and oxidation can affect efficacy, pharmacokinetics (clearance), and immunogenicity.

[0010] Pharmaceutical compositions suitable for administration to human subjects include suspensions of the recombinant vector in a formulation buffer containing physiologically compatible aqueous buffers, surfactants, and optional excipients.

[0011] The present invention is based in part on the following principles: (i) Currently marketed mAb therapeutics are immunoglobulin G (IgG) isotypes, such as IgG1, IgG2, and IgG4, which generally have pharmacokinetic (PK) characteristics such as slow clearance, extended half-life, and limited tissue distribution. After intravenous administration, the serum PK profile of a typical mAb is biphasic with a rapid distribution phase and a slow elimination phase, so repeated dosing is required to maintain the dose required to treat chronic conditions. Furthermore, the distribution of mAbs is generally limited to the intravascular and interstitial spaces due to their large size and hydrophilicity. The extent of distribution of mAbs from the circulation to most tissues is generally in the range of about 5-15%, except for the brain, where it is very low (see, e.g., Kamath, 2016, Drug Discovery Today: Technologies 21-22:75-83, incorporated herein by reference in its entirety). Continuous production of HuPTM mAbs or HuPTM Fabs in situ avoids repeated administration and allows the use of Fabs with systemic half-lives that are too short to achieve efficacy otherwise; the described administration methods allow direct access to target tissues, such as the brain, where high dose delivery to such tissues can be achieved. (ii) The Fab regions of many therapeutic mAbs possess glycosylation sites. See, e.g., Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F, which identify and highlight in blue and green, respectively, consensus and non-consensus asparaginyl ("N") glycosylation sites, as well as glutamine ("Q") residues that are glycosylation sites, within the Fab regions of certain therapeutic mAbs (see, e.g., Valliere-Douglass et al., 2001, each of which is incorporated by reference in its entirety for identification of N-linked glycosylation sites within antibodies). (see, e.g., et al., 2009, J. Biol. Chem. 284:32493-32506; and Valliere-Douglass et al., 2010, J. Biol. Chem. 285:16012-16022). In addition, O-glycosylation involves the enzymatic addition of N-acetyl-galactosamine to serine or threonine residues. It has been demonstrated that amino acid residues present within the hinge region of antibodies can be O-glycosylated. Again, because E. coli does not naturally contain a machinery equivalent to that used in human O-glycosylation (instead, O-glycosylation in E. coli is documented only when the bacteria is modified to contain specific O-glycosylation machinery; see, e.g., Farid-Moayer et al., 2007, J. Bacteriol. 189:8088-8098), the possibility of O-glycosylation confers another advantage to the therapeutic antibodies presented herein, e.g., compared to antigen-binding fragments produced in E. coli.Additionally, the Fab amino acid sequence can be modified to engineer hyperglycosylated variants (e.g., see the amino acid substitutions that can be made to engineer hyperglycosylated Fab regions of therapeutic antibodies shown in Figures 20A and 20B; also see Courtois et al., 2016, mAbs 8:99-112, which is incorporated by reference in its entirety for its description of antibody derivatives that are hyperglycosylated on the Fab domain of a full-length antibody). (iii) In addition to glycosylation sites, the Fab region may contain tyrosine ("Y") sulfation sites within or near the CDRs. See Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F, which identify tyrosine-O-sulfation sites within the Fab region of certain therapeutic mAbs. (See, e.g., Yang et al., 2015, Molecules 20:2138-2164 (especially page 2154), which is incorporated by reference in its entirety, for an analysis of amino acids surrounding tyrosine residues that are tyrosine sulfated in proteins.) The "rules" can be summarized as follows: Y residue, with E or D at position +5 to -5 from Y, in which case the -1 position from Y is a neutral or acidic charged amino acid, not a basic amino acid, e.g., R, K, or H, which abolishes sulfation. (iv) Glycosylation of the Fab region by human cells (see FIG. 22 and Table 7), such as the glycosylations shown in FIGS. 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F, would result in the addition of glycans that may improve stability, half-life, and reduce unwanted aggregation and / or immunogenicity of the transgene product (see, e.g., Bovenkamp et al., 2016, J. Immunol. 196:1435-1441 for a review of the emerging importance of Fab glycosylation; and FIG. 22 (Bondt et al., 2016, J. Immunol. 196:1435-1441), which identifies glycans that can be conjugated to HuGlyFab. (see Bondt et al., 2014, Mol. & Cell. Proteomics 13.1:3029-3039, reprinted here). The Fab and Fc portions of antibodies have been shown to have significantly different glycosylation patterns, with the Fab glycans being highly galactosylated, sialylated, and branched (e.g., with bisecting GlcNAc) and the Fc glycans being less fucosylated (see, e.g., Bondt et al., 2014, Mol. & Cell. Proteomics 13.11:3029-3039, the disclosure of which is incorporated herein by reference in its entirety for its disclosure of Fab-associated N-glycans). (v) It is significant that the glycans added to the HuPTM mAbs and HuGlyFabs of the invention are highly processed complex-type N-glycans containing 2,6-sialic acid that are not present in (a) therapeutic mAbs produced in E. coli (which are completely unglycosylated); (b) therapeutic antibodies produced in CHO cells, which lack the 2,6-sialyltransferase required to add 2,6-sialic acid during glycosylation; or (c) therapeutic antibodies produced in CHO or mouse cell lines, which add N-glycosylneuraminic acid ("Neu5Gc" or "NeuGc"), which is not native to humans (and is potentially immunogenic), rather than the predominant human sialic acid, N-acetylneuraminic acid ("Neu5Ac"). See, e.g., Dumont et al., 2015, Crit. Rev. Biotechnol. 36(6):1110-1122; Huang et al., 2006, Anal. Biochem. 349:197-207 (NeuGc is the predominant sialic acid in murine cell lines such as SP2 / 0 and NS0); and Song et al., 2014, Anal. Chem. 86:5661-5666, each of which is incorporated herein by reference in its entirety. (vi) The human glycosylation pattern of the HuPTM mAbs and HuGlyFabs of the invention should reduce immunogenicity and improve efficacy of the transgene products. When the antigen-binding fragments used according to the methods described herein are expressed in human target cells, it is important that the need for in vitro production in prokaryotic host cells (e.g., E. coli) or in eukaryotic host cells (e.g., CHO cells or murine NS0 or SP2 / 0 cells) is avoided. Instead, as a result of the methods described herein (e.g., the use of human target cells to express antigen-binding fragments), N-glycosylation sites of full-length antibodies and antigen-binding fragments are advantageously decorated with glycans that are relevant and beneficial for human treatment. For example, (a) CHO cells lack the components required for the addition of certain glycans (e.g., 2,6 sialic acid and branched GlcNAc); (b) CHO cells and mouse cells (NS0 and SP2 / 0 cells) add the atypical human Neu5Gc sialic acid instead of Neu5Ac; (c) CHO cells react with anti-α-Gal antibodies present in most individuals and, at high concentrations, can induce anaphylaxis. Such advantages are not achieved when utilizing CHO cells, mouse cells, or E. coli in the production of antibodies / antigen-binding fragments because (a) E. coli also produces the α-Gal antigen, an immunogenic glycan that is involved in N-glycosylation (see, e.g., Bosques, 2010, Nat. Biotech. 28:1153-1156); and (d) E. coli does not naturally contain the components required for N-glycosylation. (vii) Tyrosine sulfation of the Fab region, such as that shown in Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F (a robust post-translational process in many human cells), should result in transgene products with increased avidity for their molecular targets. Indeed, tyrosine sulfation of antibody Fabs has been shown to dramatically increase avidity and activity for antigens (see, e.g., Loos et al., 2015, PNAS 112:12675-12680; and Choe et al., 2003, Cell 114:161-170). Such post-translational modifications are absent on therapeutic antibodies made in E. coli (a host lacking the enzymes required for tyrosine sulfation) and are, at best, underrepresented in therapeutic mAbs made in CHO cells, which are not secretory cells and have limited post-translational tyrosine sulfation capacity (see, e.g., Mikkelsen & Ezban, 1991, Biochemistry 30:1533-1537, especially the discussion at page 1537).

[0012] For the foregoing reasons, the generation of a HuPTM mAb or HuPTM Fab should result in a "bio-better" molecule for the treatment of disease achieved via gene therapy, e.g., by administering a viral vector or other DNA expression construct encoding the full-length HuPTM mAb or HuPTM Fab of a therapeutic mAb to a patient (human subject) diagnosed with a disease for which the mAb is indicated, to create in the subject a permanent depot of a continuous supply of human glycosylated, sulfated transgene product produced by the subject's transduced cells. The cDNA construct for the HuPTM mAb or HuPTM Fab should contain a signal peptide that ensures proper co- and post-translational processing (glycosylation and protein sulfation) by the transduced human cells.

[0013] As an alternative or additional treatment to gene therapy, full-length HuTPM mAbs or HuPTM Fabs can be produced by recombinant DNA technology in human cell lines and the glycoproteins administered to patients.

[0014] The methods of the invention encompass combination therapy in which delivery of full-length HuPTM mAb or HuPTM Fab to a patient is accompanied by administration of other available treatments. The additional treatments may be administered prior to, concurrently with, or subsequent to the gene therapy treatment. Such additional treatments may include, but are not limited to, combination therapy with a therapeutic mAb.

[0015] Also provided is a method for producing a viral vector, particularly an AAV-based viral vector. In a specific embodiment, a method for producing a recombinant AAV is provided, comprising culturing a host cell containing an artificial genome comprising a transgene encoding a therapeutic antibody, the transgene comprising a cis expression cassette flanked by AAV ITRs, the cis expression cassette being operably linked to an expression control element that controls the expression of the transgene in human cells; a trans expression cassette lacking AAV ITRs, the trans expression cassette encoding AAV rep and capsid proteins driving the expression of AAV rep and capsid proteins in a host cell in culture, the trans expression cassette being operably linked to an expression control element that provides the rep and cap proteins in trans; and sufficient adenovirus helper functions to allow the AAV capsid proteins to replicate and package the artificial genome; and recovering the recombinant AAV encapsidating the artificial genome from the cell culture.

[0016] The inventors have also found that full-length antibodies can be expressed from AAV-based vectors (see Examples 36 and 37). The nucleotide sequences encoding the heavy and light chains of the full-length antibody can be codon optimized for expression in human cells and may have a reduced number of CpG dimers in the sequence. Thus, compositions are provided that include AAV vectors expressing transgenes encoding full-length heavy (including Fc domain) and light chains of therapeutic antibodies. Methods of administration and manufacture are also provided. 3.1 Exemplary Embodiments composition 1. A pharmaceutical composition for treating Alzheimer's disease (AD), frontotemporal dementia (FD), 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, synucleinopathy, ALS, migraine, or cluster headache in a human subject in need of such treatment, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), an AAVrh10 capsid (SEQ ID NO: 145), an AAVrh20 capsid, an AAVrh39 capsid, or an AAVcy5 capsid; and (b) an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITRs), the expression cassette comprising a transgene, the transgene encoding an anti-amyloid beta (anti-Aβ), anti-sortilin, anti-tau protein (anti-tau), anti-semaphorin 4D (anti-SEMA4D), anti-alpha-synuclein (anti-SNCA), anti-superoxide dismutase-1 (anti-SOD1) or anti-calcitonin gene-related peptide receptor (anti-CGRPR) monoclonal antibody (mAb), or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in a human CNS cell, a human hepatocyte, and / or a human muscle cell; The adeno-associated virus (AAV) vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for administration to the subject, and optionally, the administration is intrathecal, intravenous, subcutaneous, intranasal, or intramuscular. 2. The pharmaceutical composition according to item 1, wherein 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); the anti-SEMA4D mAb is VX15 / 2503; the anti-SNCA mAb is prasinezumab, NI-202 (BIIB054), or MED-1341; the anti-SOD1 mAb is NI-2041.10D12 or NI-204.12G7; and the anti-CGRPR mAb is eptinezumab, fremanezumab, or galcanezumab. 3. The antigen-binding fragment is Fab, F(ab') 2 3. The pharmaceutical composition according to item 1 or 2, wherein the antibody is a single chain variable domain (scFv). 4. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO:1, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:290, and a light chain having an amino acid sequence of SEQ ID NO:2; or a heavy chain having an amino acid sequence of SEQ ID NO:3, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:291, and a light chain having an amino acid sequence of SEQ ID NO:4; or a heavy chain having an amino acid sequence of SEQ ID NO:360, and optionally 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:361; or a heavy chain having an amino acid sequence of SEQ ID NO:5, and optionally an Fc polypeptide of an IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO:283), and a light chain having an amino acid sequence of SEQ ID NO:6; or a heavy chain having an amino acid sequence of SEQ ID NO:7, and optionally an Fc polypeptide of an IgG4 isotype (e.g., the amino acid sequence of SEQ ID NO:285), and a light chain having an amino acid sequence of SEQ ID NO:8; or an amino acid sequence of SEQ ID NO:9, and optionally an amino acid sequence of SEQ ID NO:292. or a heavy chain having an amino acid sequence of SEQ ID NO: 11, and optionally an Fc polypeptide of an IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283), and a light chain having the amino acid sequence of SEQ ID NO: 12; or a heavy chain having an amino acid sequence of SEQ ID NO: 13, and optionally an Fc polypeptide of an IgG4 isotype (e.g., the amino acid sequence of SEQ ID NO: 285), and a light chain having the amino acid sequence of SEQ ID NO: 14; or a heavy chain having an amino acid sequence of SEQ ID NO: 15, and optionally an Fc polypeptide of an amino acid sequence of SEQ ID NO: 293, and a light chain having the amino acid sequence of SEQ ID NO: 16; or a heavy chain having an amino acid sequence of SEQ ID NO: 17, and optionally an Fc polypeptide of an IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283), and a light chain having the amino acid sequence of SEQ ID NO: 18; or a heavy chain having an amino acid sequence of SEQ ID NO: 19, and optionally an Fc polypeptide of an amino acid sequence of SEQ ID NO: 294, and a light chain having the amino acid sequence of SEQ ID NO: 20;or a heavy chain having an amino acid sequence of SEQ ID NO: 21 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 295, and a light chain having an amino acid sequence of SEQ ID NO: 22; or a heavy chain having an amino acid sequence of SEQ ID NO: 23 and optionally an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283) and a light chain having an amino acid sequence of SEQ ID NO: 24; or a heavy chain having an amino acid sequence of SEQ ID NO: 25 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 296, and a light chain having an amino acid sequence of SEQ ID NO: 26; or a heavy chain having an amino acid sequence of SEQ ID NO: 27 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 297, and a light chain having an amino acid sequence of SEQ ID NO: 28; or a heavy chain having an amino acid sequence of SEQ ID NO: 29 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 298, and a light chain having an amino acid sequence of SEQ ID NO: 30. 5. The transgene comprises a nucleotide sequence of SEQ ID NO: 71 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 72 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 73 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 74 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 376 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 377 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 75 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 76 encoding a light chain; or a heavy chain having the nucleotide sequence of 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 light chain having the nucleotide sequence of SEQ ID NO: 80; or a heavy chain having the nucleotide sequence of SEQ ID NO: 81 and a light chain having the nucleotide sequence of SEQ ID NO: 82; or a heavy chain having the nucleotide sequence of SEQ ID NO: 83 and a nucleotide sequence of SEQ ID NO: 84. or a heavy chain having a nucleotide sequence of SEQ ID NO: 91 and a light chain having a nucleotide sequence of SEQ ID NO: 92; or a heavy chain having a nucleotide sequence of SEQ ID NO: 93 and a light chain having a nucleotide sequence of SEQ ID NO: 94; or a heavy chain having a nucleotide sequence of SEQ ID NO: 95 and a light chain having a nucleotide sequence of SEQ ID NO: 96; or a heavy chain having a nucleotide sequence of SEQ ID NO: 97 and a light chain having a nucleotide sequence of SEQ ID NO: 98; or a heavy chain having a nucleotide sequence of SEQ ID NO: 99 and a light chain having a nucleotide sequence of SEQ ID NO: 100. 6. The pharmaceutical composition according to any of items 1 to 4, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 7. The pharmaceutical composition according to any of items 1 to 6, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human CNS, muscle, or hepatic cells. 8. The pharmaceutical composition according to item 7, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (sequence number 146), or a signal sequence according to Table 2. 9. The pharmaceutical composition according to any of items 1 to 8, wherein the AAV capsid is AAV8 or AAV9. 10. In a human subject in need of treatment for a retinal disorder, including 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 following retinal vein occlusion (RVO) or diabetic macular edema (DME)), retinal vein occlusion, diabetic retinopathy (DR), non-infectious uveitis, or glaucoma, or abnormal vascularization of the retina. 1. A pharmaceutical composition for treating a retinal disorder, including 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 following retinal vein occlusion (RVO) or diabetic macular edema (DME)), retinal vein occlusion, diabetic retinopathy (DR), non-infectious uveitis, or glaucoma, or abnormal vascularization of the retina, comprising (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV2.7m8 capsid (SEQ ID NO: 142), an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144); or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding 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 anti-pKal mAb, or a substantially full-length or full-length mAb of an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in a human retinal cell; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for subretinal, intravitreal, intranasal, or suprachoroidal administration to the subject. 11. The pharmaceutical composition according to item 10, wherein the anti-VEGF mAb is sevacizumab; the anti-EPOR mAb is LKA-651 (NSV2) or LKA-651 (NSV3); the anti-Aβ mAb is solanezumab, lecanemab, or GSK933776; the anti-ALK1 mAb is asclinbacumab; 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. 12. The antigen-binding fragment is Fab, F(ab') 2 12. The pharmaceutical composition according to item 10 or 11, wherein the antibody is a Fv or scFv. 13. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO:1, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:290, and a light chain having an amino acid sequence of SEQ ID NO:2; or a heavy chain having an amino acid sequence of SEQ ID NO:360, and optionally 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:361; or a heavy chain having an amino acid sequence of SEQ ID NO:31, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:299, and a light chain having the amino acid sequence of SEQ ID NO:32; or a heavy chain having an amino acid sequence of SEQ ID NO:33, and optionally an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO:283), and a light chain having the amino acid sequence of SEQ ID NO:34; or a heavy chain having an amino acid sequence of SEQ ID NO:35, and optionally an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO:283), and a light chain having the amino acid sequence of SEQ ID NO:36; or an amino acid sequence of SEQ ID NO:3, and optionally an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO:283), and a light chain having the amino acid sequence of SEQ ID NO:36; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:291, and a light chain having the amino acid sequence of SEQ ID NO:4; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:37, and optionally the amino acid sequence of SEQ ID NO:300, and a light chain having the amino acid sequence of SEQ ID NO:38; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:39, and optionally the amino acid sequence of SEQ ID NO:301, and a light chain having the amino acid sequence of SEQ ID NO:40; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:362, and optionally the amino acid sequence of SEQ ID NO:393, and a light chain having the amino acid sequence of SEQ ID NO:363; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:41, and optionally the amino acid sequence of SEQ ID NO:302, and a light chain having the amino acid sequence of SEQ ID NO:42; or a heavy chain having an amino acid sequence of SEQ ID NO:43, and optionally an Fc polypeptide of the IgG1 isotype (e.g. the amino acid sequence of SEQ ID NO:283), and a light chain having the amino acid sequence of SEQ ID NO:44;or the pharmaceutical composition according to any of items 10 to 12, comprising a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 69, and optionally an amino acid sequence of SEQ ID NO: 314, and a light chain having the amino acid sequence of SEQ ID NO: 70; 14. The transgene comprises a nucleotide sequence of SEQ ID NO: 71 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 72 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 376 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 377 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 101 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 102 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 103 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 104 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 105 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 106 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 73 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 74 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 107 encoding a heavy chain. 14. The pharmaceutical composition according to item 13, comprising a nucleotide sequence of SEQ ID NO: 108 encoding a heavy chain, and a nucleotide sequence of SEQ ID NO: 109 encoding a heavy chain, and a nucleotide sequence of SEQ ID NO: 110 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 378 encoding a heavy chain, and a nucleotide sequence of SEQ ID NO: 379 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 111 encoding a heavy chain, and a nucleotide sequence of SEQ ID NO: 112 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 113 encoding a heavy chain, and a nucleotide sequence of SEQ ID NO: 114 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 139 encoding a heavy chain, and a nucleotide sequence of SEQ ID NO: 140 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 141, 286, 287, or 435 to 443. 15. The pharmaceutical composition according to any of items 10 to 13, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 16. The pharmaceutical composition according to any of items 10 to 15, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct secretion and post-translational modification in the human retinal cells. 17. The pharmaceutical composition according to item 16, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 2, Table 3 or Table 4. 18. The pharmaceutical composition according to any of items 10 to 17, wherein the AAV capsid is AAV8. 19. A pharmaceutical composition for treating non-infectious uveitis in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of 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); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-TNFα) mAb or antigen-binding fragment thereof, a substantially full-length or full-length anti-complement component 5 (C5) mAb or antigen-binding fragment thereof, a substantially full-length or full-length anti-interleukin-6 (IL-6) mAb or antigen-binding fragment thereof, or a substantially full-length or full-length anti-interleukin-6 receptor (IL-6R) mAb or antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in a human retinal cell; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for subretinal, intravitreal, intranasal, or suprachoroidal administration to the subject. 20. The pharmaceutical composition according to item 19, wherein the anti-TNFα mAb is adalimumab, infliximab or golimumab; the anti-C5 mAb is tesidolumab or ravulizumab; the anti-IL-6 mAb is siltuximab, clazakimuzumab, sirukumab, olokizumab or gerilizumab; or the anti-IL-6R mAb is satralizumab, sarilumab or tocilizumab. 21. The antigen-binding fragment is Fab, F(ab') 2 21. The pharmaceutical composition according to item 19 or 20, wherein the antibody is a Fv or an scFv. 22. The full-length mAb or antigen-binding fragment comprises a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 45, and optionally, the amino acid sequence of SEQ ID NO: 303, and a light chain having the amino acid sequence of SEQ ID NO: 46, or SEQ ID NO: 451, 452 or 453; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 47, and optionally, the amino acid sequence of SEQ ID NO: 304, and a light chain having the amino acid sequence of SEQ ID NO: 48; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 49, and optionally, the amino acid sequence of SEQ ID NO: 305, and a light chain having the amino acid sequence of SEQ ID NO: 50; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 39, and optionally, the amino acid sequence of SEQ ID NO: 301, and a light chain having the amino acid sequence of SEQ ID NO: 40; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 362, and optionally, the amino acid sequence of SEQ ID NO: 393, and a light chain having the amino acid sequence of SEQ ID NO: 363; an 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 having the amino acid sequence of SEQ ID NO:333 and, optionally, the amino acid sequence of SEQ ID NO:356 and, optionally, 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:335 and, optionally, the amino acid sequence of SEQ ID NO:357 and, optionally, the amino acid sequence of SEQ ID NO:336; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:337 and, optionally, the amino acid sequence of SEQ ID NO:358 and, optionally, the amino acid sequence of SEQ ID NO:338; a light chain having an amino acid sequence of SEQ ID NO:339 and, optionally, the amino acid sequence of SEQ ID NO:340; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:59 and, optionally, the amino acid sequence of SEQ ID NO:309 and, optionally, the amino acid sequence of SEQ ID NO:60; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:61 and, optionally, the amino acid sequence of SEQ ID NO:310 and, optionally, the amino acid sequence of SEQ ID NO:62;22. The pharmaceutical composition according to any of items 19 to 21, comprising a heavy chain having an Fc polypeptide having 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. 23. The transgene comprises a nucleotide sequence of SEQ ID NO: 115 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 116 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 117 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 118 encoding a light chain; a nucleotide sequence of SEQ ID NO: 119 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 120 encoding a light chain; a nucleotide sequence of SEQ ID NO: 109 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 110 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 378 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 379 encoding a light chain; a nucleotide sequence of SEQ ID NO: 343 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 344 encoding a light chain; a nucleotide sequence of SEQ ID NO: 345 encoding a heavy chain, and 23. The pharmaceutical composition according to item 22, comprising a nucleotide sequence of SEQ ID NO: 346 encoding the light chain; a nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 348 encoding the light chain; a nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 350 encoding the light chain; a nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 352 encoding the light chain; a nucleotide sequence of SEQ ID NO: 129 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 130 encoding the light chain; a nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 132 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 341 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 342 encoding the light chain. 24. The pharmaceutical composition according to any of items 19 to 22, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 25. The pharmaceutical composition according to any of items 19 to 24, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct secretion and post-translational modification in the human retinal cells. 26. The pharmaceutical composition according to item 25, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 2, Table 3 or Table 4. 27. The pharmaceutical composition according to any of items 19 to 26, wherein the AAV capsid is AAV8. 28. A pharmaceutical composition for treating multiple sclerosis in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), an AAVrh10 capsid (SEQ ID NO: 145), an AAVrh20 capsid, an AAVrh39 capsid, or an AAVcy5 capsid; and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-repulsive guidance molecule-A (anti-RGMa) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human CNS cells, human hepatocytes, and / or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for administration to the subject, and optionally, the administration is intrathecal, intravenous, subcutaneous, intranasal, or intramuscular. 29. The pharmaceutical composition of item 28, wherein the anti-RGMa mAb is elezanumab. 30. The antigen-binding fragment is Fab, F(ab') 2 30. The pharmaceutical composition according to item 28 or 29, wherein the antibody is a Fv or an scFv. 31. The pharmaceutical composition according to any of items 28 to 30, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 51, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 306, and a light chain having the amino acid sequence of SEQ ID NO: 52. 32. The pharmaceutical composition according to item 31, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 121 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 122 encoding the light chain. 33. The pharmaceutical composition according to any of items 28 to 31, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 34. The pharmaceutical composition according to any of items 28 to 33, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human CNS cells. 35. The pharmaceutical composition according to item 34, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 2, Table 3 or Table 4. 36. A pharmaceutical composition according to any of items 28 to 35, wherein the AAV capsid is AAV9. 37. A pharmaceutical composition for treating amyloidosis (ATTR), familial amyloid cardiomyopathy (FAC), or familial amyloid polyneuropathy (FAP) in a human subject in need of such treatment, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-transthyretin (anti-TTR) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The pharmaceutical composition, wherein the AAV vector is formulated for subcutaneous, intramuscular, or intravenous administration to a subject. 38. The pharmaceutical composition of item 37, wherein the anti-TTR mAb is NI-301 or PRX-004. 39. The antigen-binding fragment is Fab, F(ab') 2 39. The pharmaceutical composition according to item 37 or 38, wherein the antibody is a Fv or an scFv. 40. The pharmaceutical composition according to any of items 37 to 39, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having 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), and a light chain having the amino acid sequence of SEQ ID NO: 54; or a heavy 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, and a light chain having the amino acid sequence of SEQ ID NO: 56. 41. The pharmaceutical composition according to item 40, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 123 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 124 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 125 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 126 encoding a light chain. 42. The pharmaceutical composition according to any of items 37 to 41, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 43. The pharmaceutical composition according to any of items 37 to 42, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 44. The pharmaceutical composition according to item 43, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 3 or Table 4. 45. The pharmaceutical composition according to any of items 37 to 44, wherein the AAV capsid is AAV8. 46. ​​A pharmaceutical composition for treating fibrotic disorders, pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, ulcerative colitis, mediastinal fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and retroperitoneal fibrosis (RPF) in a human subject in need of such treatment, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-connective tissue growth factor (anti-CTGF) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for subcutaneous, intramuscular, or intravenous administration to a subject. 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 48. The pharmaceutical composition according to item 46 or 47, wherein the antibody is a Fv or an scFv. 49. The pharmaceutical composition according to any of items 46 to 48, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 57, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 308, and a light chain having the amino acid sequence of SEQ ID NO: 58. 50. The pharmaceutical composition according to item 49, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 127 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 128 encoding the light chain. 51. The pharmaceutical composition according to any of items 44 to 50, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 52. The pharmaceutical composition according to any of items 44 to 51, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 53. The pharmaceutical composition according to item 52, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 3 or Table 4. 54. The pharmaceutical composition according to any of items 44 to 53, wherein the AAV capsid is AAV8. 55. A pharmaceutical composition for treating non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR), or diabetic macular edema (DME) in a human subject in need of such treatment, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV2.7m8 capsid (SEQ ID NO: 142), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-interleukin-6 receptor (anti-IL6R), anti-interleukin-6 (IL6), or anti-cluster of differentiation 19 (anti-CD19) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in a human retinal cell; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for subretinal, intravitreal, intranasal, or suprachoroidal administration to the subject. 56. The pharmaceutical composition according to item 55, wherein the anti-IL6R mAb is satralizumab, sarilumab, or tocilizumab, or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, olokizumab, or gerilizumab, or the anti-CD19 mAb is inebilizumab. 57. The antigen-binding fragment is Fab, F(ab') 2 57. The pharmaceutical composition according to item 55 or 56, wherein the antibody is a Fc.sub.1 or a scFv. 58. The full length mAb or antigen-binding fragment comprises a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:59, and optionally, the amino acid sequence of SEQ ID NO:309, and a light chain having the amino acid sequence of SEQ ID NO:60; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:61, and optionally, the amino acid sequence of SEQ ID NO:310, and a light chain having the amino acid sequence of SEQ ID NO:62; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:331, and optionally, the amino acid sequence of SEQ ID NO:355, and a light chain having the amino acid sequence of SEQ ID NO:332; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:333, and optionally, the amino acid sequence of SEQ ID NO:356, and a light chain having the amino acid sequence of SEQ ID NO:334; or an Fc polypeptide having the amino acid sequence of SEQ ID NO:335, and optionally, the amino acid sequence of SEQ ID NO:357. 58. The pharmaceutical composition according to any of items 55 to 57, comprising a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 336; or a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 337 and optionally, the amino acid sequence of SEQ ID NO: 358, and a light chain having the amino acid sequence of SEQ ID NO: 338; or a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 339 and optionally, the amino acid sequence of SEQ ID NO: 283, and a light chain having the amino acid sequence of SEQ ID NO: 340; or a heavy chain having an Fc polypeptide having an 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; a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 63 and optionally, the amino acid sequence of SEQ ID NO: 311, and a light chain having the amino acid sequence of SEQ ID NO: 64. 59. The transgene comprises a nucleotide sequence of SEQ ID NO: 129 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 130 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 131 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 132 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 343 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 344 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 345 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 346 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 347 encoding a heavy chain, 59. The pharmaceutical composition according to item 58, comprising a nucleotide sequence of SEQ ID NO: 348 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 350 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 352 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 354 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 133 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 134 encoding the light chain. 60. The pharmaceutical composition according to any of items 55 to 59, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 61. The pharmaceutical composition according to any of items 55 to 60, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct secretion and post-translational modification in the human retinal cells. 62. The pharmaceutical composition according to item 61, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 2, Table 3 or Table 4. 63. The pharmaceutical composition according to any of items 55 to 62, wherein the AAV capsid is AAV8. 64. U.C.A pharmaceutical composition for treating inflammatory bowel disease (IBD), including UC and CD, in a human subject in need of such treatment, comprising: (a )A AV8 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 and (b) an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITGB7), the expression cassette comprising a substantially full-length or full-length anti-integrin β7 subunit (anti-ITGB7) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of a transgene in a human hepatocyte or a human muscle cell; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for subcutaneous, intramuscular, or intravenous administration to the subject. 65. The pharmaceutical composition according to item 64, wherein the anti-ITGB7 mAb is etrolizumab. 66. The antigen-binding fragment is Fab, F(ab') 2 66. The pharmaceutical composition according to item 64 or 65, wherein the antibody is a Fv or an scFv. 67. The pharmaceutical composition according to any of items 64 to 66, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 65, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 312, and a light chain having the amino acid sequence of SEQ ID NO: 66. 68. The pharmaceutical composition according to item 67, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 135 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 136 encoding a light chain. 69. The pharmaceutical composition according to any of items 64 to 68, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 70. The pharmaceutical composition according to any of items 64 to 69, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 71. The pharmaceutical composition according to item 70, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 3 or Table 4. 72. The pharmaceutical composition according to any of items 64 to 71, wherein the AAV capsid is AAV8. 73. A pharmaceutical composition for treating osteoporosis or abnormal bone loss or bone wasting (e.g., treating giant cell tumor of bone, treating treatment-induced bone loss, slowing bone loss (or increasing bone mass) in patients with breast and prostate cancer, preventing skeletal-related events due to bone metastases, or reducing bone resorption and bone turnover) in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143); an AAVrh10 capsid (SEQ ID NO: 145); or an AAV9 capsid (SEQ ID NO: 144); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-sclerostin (anti-SOST) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous, intramuscular, or subcutaneous administration to the subject. 74. The pharmaceutical composition of item 73, wherein the anti-SOST mAb is romosozumab. 75. The pharmaceutical composition according to item 73 or 74, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 76. The pharmaceutical composition according to any of items 73 to 75, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 67, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 313, and a light chain having the amino acid sequence of SEQ ID NO: 68. 77. The pharmaceutical composition according to item 76, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 137 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 138 encoding a light chain. 78. The pharmaceutical composition according to any of items 73 to 77, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 79. The pharmaceutical composition according to any of items 73 to 78, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 80. The pharmaceutical composition according to item 79, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (sequence number 146), or a signal sequence according to Table 3 or Table 4. 81. The pharmaceutical composition according to any of items 73 to 80, wherein the AAV capsid is AAV8. 82. A pharmaceutical composition for treating angioedema, including hereditary angioedema, in a human subject in need thereof, comprising: (a )A AV8 capsid (SEQ ID NO: 143); AAVrh10 capsid (SEQ ID NO: 145); or AAV9 capsid (SEQ ID NO: 144) A viral capsid that is at least 95% identical to the amino acid sequence of and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-kallikrein (anti-pKal) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous, intramuscular, or subcutaneous administration to the subject. 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 84. The pharmaceutical composition according to item 82 or 83, wherein the antibody is a Fv or an scFv. 85. The pharmaceutical composition according to any of items 82 to 84, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 69, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 314, and a light chain having the amino acid sequence of SEQ ID NO: 70. 86. The pharmaceutical composition according to item 85, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 139 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 140 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 141, 286, 287, or 435 to 443. 87. The pharmaceutical composition according to any of items 82 to 85, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 88. The pharmaceutical composition according to any of items 82 to 87, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment that direct secretion and post-translational modification in the human retinal cells. 89. The pharmaceutical composition according to item 88, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 3 or Table 4. 90. The pharmaceutical composition according to any of items 82 to 89, wherein the AAV capsid is AAV8. Treatment 91. A method for treating Alzheimer's disease (AD), frontotemporal dementia (FD), 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, synucleinopathy, ALS, migraine, or cluster headache in a human subject in need of such treatment, comprising: The method comprises delivering to the cerebrospinal fluid (CSF) of the human subject a therapeutically effective amount of an anti-amyloid beta (anti-Aβ), anti-sortilin, anti-tau protein (anti-tau), anti-semaphorin 4D (anti-SEMA4D), anti-alpha-synuclein (anti-SNCA), anti-superoxide dismutase-1 (anti-SOD1) or anti-calcitonin gene-related peptide receptor (anti-CGRPR) mAb, or an antigen-binding fragment thereof, expressed from a transgene and produced by human CNS cells. 92. A method for treating Alzheimer's disease, frontotemporal dementia (FD), 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, synucleinopathy, ALS, migraine, or cluster headache in a human subject in need of such treatment, comprising: The method comprises administering to the subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-amyloid beta (anti-Aβ), anti-sortilin, anti-tau protein (anti-tau), anti-semaphorin 4D (anti-SEMA4D), anti-alpha-synuclein (anti-SNCA), anti-superoxide dismutase-1 (anti-SOD1) or anti-calcitonin gene-related peptide receptor (anti-CGRPR) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences controlling expression of the transgene in human CNS cells such that depots are formed that release human post-translationally modified (HuPTM) forms of the mAb or antigen-binding fragment thereof. 93. The method of item 91 or 92, wherein 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); the anti-SEMA4D mAb is VX15 / 2503; the anti-SNCA mAb is prasinezumab, NI-202 (BIIB054), or MED-1341; the anti-SOD1 mAb is NI-2041.10D12 or NI-204.12G7; and the anti-CGRPR mAb is eptinezumab, fremanezumab, or galcanezumab. 94. The method of any of items 91 to 93, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 95. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO: 1, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 290, and a light chain having an amino acid sequence of SEQ ID NO: 2; or a heavy chain having an amino acid sequence of SEQ ID NO: 3, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 292, and a light chain having an amino acid sequence of SEQ ID NO: 4; or a heavy chain having an amino acid sequence of SEQ ID NO: 360, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 392, and a light chain having an amino acid sequence of SEQ ID NO: 361; or a heavy chain having an amino acid sequence of SEQ ID NO: 5, and optionally an Fc polypeptide of an IgG1 isotype (e.g., an amino acid sequence of SEQ ID NO: 283), and a light chain having an amino acid sequence of SEQ ID NO: 6; or a heavy chain having an amino acid sequence of SEQ ID NO: 7, and optionally an Fc polypeptide of an IgG4 isotype (e.g., an amino acid sequence of SEQ ID NO: 285), and a light chain having an amino acid sequence of SEQ ID NO: 8; or an amino acid sequence of SEQ ID NO: 9, and optionally an amino acid sequence of SEQ ID NO: 292. or a heavy chain having an amino acid sequence of SEQ ID NO: 11, and optionally an Fc polypeptide of an IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283), and a light chain having the amino acid sequence of SEQ ID NO: 12; or a heavy chain having an amino acid sequence of SEQ ID NO: 13, and optionally an Fc polypeptide of an IgG4 isotype (e.g., the amino acid sequence of SEQ ID NO: 285), and a light chain having the amino acid sequence of SEQ ID NO: 14; or a heavy chain having an amino acid sequence of SEQ ID NO: 15, and optionally an Fc polypeptide of an amino acid sequence of SEQ ID NO: 293, and a light chain having the amino acid sequence of SEQ ID NO: 16; or a heavy chain having an amino acid sequence of SEQ ID NO: 17, and optionally an Fc polypeptide of an IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283), and a light chain having the amino acid sequence of SEQ ID NO: 18; or a heavy chain having an amino acid sequence of SEQ ID NO: 19, and optionally an Fc polypeptide of an amino acid sequence of SEQ ID NO: 294, and a light chain having the amino acid sequence of SEQ ID NO: 20;or a heavy chain having an amino acid sequence of SEQ ID NO: 21 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 295, and a light chain having an amino acid sequence of SEQ ID NO: 22; or a heavy chain having an amino acid sequence of SEQ ID NO: 23 and optionally an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO: 283) and a light chain having an amino acid sequence of SEQ ID NO: 24; or a heavy chain having an amino acid sequence of SEQ ID NO: 25 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 296, and a light chain having an amino acid sequence of SEQ ID NO: 26; or a heavy chain having an amino acid sequence of SEQ ID NO: 27 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 297, and a light chain having an amino acid sequence of SEQ ID NO: 28; or a heavy chain having an amino acid sequence of SEQ ID NO: 29 and optionally an Fc polypeptide having an amino acid sequence of SEQ ID NO: 298, and a light chain having an amino acid sequence of SEQ ID NO: 30. 96. The transgene comprises a nucleotide sequence of SEQ ID NO: 71 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 72 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 73 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 74 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 376 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 377 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 75 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 76 encoding a light chain; or a heavy chain having the nucleotide sequence of 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 light chain having the nucleotide sequence of SEQ ID NO: 80; or a heavy chain having the nucleotide sequence of SEQ ID NO: 81 and a light chain having the nucleotide sequence of SEQ ID NO: 82; or a heavy chain having the nucleotide sequence of SEQ ID NO: 83 and a nucleotide sequence of SEQ ID NO: 84. or a heavy chain having a nucleotide sequence of SEQ ID NO: 91 and a light chain having a nucleotide sequence of SEQ ID NO: 92; or a heavy chain having a nucleotide sequence of SEQ ID NO: 93 and a light chain having a nucleotide sequence of SEQ ID NO: 94; or a heavy chain having a nucleotide sequence of SEQ ID NO: 95 and a light chain having a nucleotide sequence of SEQ ID NO: 96; or a heavy chain having a nucleotide sequence of SEQ ID NO: 97 and a light chain having a nucleotide sequence of SEQ ID NO: 98; or a heavy chain having a nucleotide sequence of SEQ ID NO: 99 and a light chain having a nucleotide sequence of SEQ ID NO: 100. 97. The method of any of items 91 to 95, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 98. The method of any of items 91 to 97, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 99. The method of any of items 91 to 98, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc and / or α-Gal. 100. The method of any of items 91 to 99, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 101. The method according to any of items 92 to 100, wherein the recombinant expression vector is AAV9. 102. The method of any of items 92 to 101, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. 103. A method for treating 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 following retinal vein occlusion (RVO) or diabetic macular edema (DME)), RVO, diabetic retinopathy (DR), non-infectious uveitis, glaucoma, or abnormal retinal vascularization in a human subject in need of treatment for 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 following retinal vein occlusion (RVO) or diabetic macular edema (DME)), RVO, diabetic retinopathy (DR), non-infectious uveitis, glaucoma, or abnormal retinal vascularization, The method comprises delivering to the retina of the human subject 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 anti-pKal mAb, or an antigen-binding fragment thereof, expressed from a transgene and produced by human retinal cells. 104. A method for treating 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 following retinal vein occlusion (RVO) or diabetic macular edema (DME)), RVO, diabetic retinopathy (DR), non-infectious uveitis, glaucoma, or abnormal retinal angiogenesis in a human subject in need of treatment, comprising administering to said subject a therapeutically effective amount of at least one of the following: The method comprises delivering to the retina of the human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length mAb 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 anti-pKal mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences controlling expression of the transgene in human retinal cells, such that a depot is formed that releases a HuPTM form of the mAb or antigen-binding fragment thereof. 105. The method according to item 103 or 104, wherein the anti-VEGF mAb is sevacizumab; the anti-EPOR mAb is LKA-651 (NSV2) or LKA-651 (NSV3); the anti-Aβ mAb is solanezumab, lecanemab, or GSK933776; the anti-ALK1 mAb is asclinbacumab; 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 method of any of items 103 to 105, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 107. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO: 1, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 290, and a light chain having an amino acid sequence of SEQ ID NO: 2; or a heavy chain having an amino acid sequence of SEQ ID NO: 360, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 392, and a light chain having an amino acid sequence of SEQ ID NO: 361; or a heavy chain having an amino acid sequence of SEQ ID NO: 31, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 299, and a light chain having an amino acid sequence of SEQ ID NO: 32; or a heavy chain having an amino acid sequence of SEQ ID NO: 33, and optionally an Fc polypeptide of an IgG1 isotype (e.g., an amino acid sequence of SEQ ID NO: 283), and a light chain having an amino acid sequence of SEQ ID NO: 34; or a heavy chain having an amino acid sequence of SEQ ID NO: 35, and optionally an Fc polypeptide of an IgG1 isotype (e.g., an amino acid sequence of SEQ ID NO: 283), and a light chain having an amino acid sequence of SEQ ID NO: 36; or an 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 a light chain having the amino acid sequence of SEQ ID NO:4; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:37, and optionally, the amino acid sequence of SEQ ID NO:300, and a light chain having the amino acid sequence of SEQ ID NO:38; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:39, and optionally, the amino acid sequence of SEQ ID NO:301, and a light chain having the amino acid sequence of SEQ ID NO:40; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:362, and optionally, the amino acid sequence of SEQ ID NO:393, and a light chain having the amino acid sequence of SEQ ID NO:363; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:41, and optionally, the amino acid sequence of SEQ ID NO:302, and a light chain having the amino acid sequence of SEQ ID NO:42; or a heavy chain having an amino acid sequence of SEQ ID NO:43, and optionally, an Fc polypeptide of the IgG1 isotype (e.g., the amino acid sequence of SEQ ID NO:283), and a light chain having the amino acid sequence of SEQ ID NO:44;or the method according to any of items 103 to 106, comprising a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO: 69, and optionally an amino acid sequence of SEQ ID NO: 314, and a light chain having the amino acid sequence of SEQ ID NO: 70. 108. The transgene is a nucleotide sequence of SEQ ID NO: 71 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 72 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 376 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 377 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 101 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 102 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 103 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 104 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 105 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 106 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 73 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 74 encoding a light chain. or a nucleotide sequence of SEQ ID NO: 107 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 108 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 109 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 110 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 378 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 379 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 111 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 112 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 113 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 114 encoding the light chain, or a nucleotide sequence of SEQ ID NO: 141, 286, 287, or 435 to 443. 109. The method according to any of items 103 to 105, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 110. The method of any of items 103 to 109, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 111. The method of any of items 103 to 110, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 112. The method of any of items 103 to 111, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 113. The method according to any of items 104 to 112, wherein the recombinant expression vector is AAV2.7m8, AAV8, or AAV9. 114. The method of any of items 104 to 113, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human retinal cells in culture and expressing the mAb or antigen-binding fragment thereof. 115. A method for treating non-infectious uveitis in a human subject in need thereof, comprising: A method comprising delivering to the retina of the human subject a therapeutically effective amount of a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-TNFα) mAb or an antigen-binding fragment thereof, expressed from a transgene and produced by human retinal cells. 116. A method for treating non-infectious uveitis in a human subject in need thereof, comprising: The method comprises administering to the retina of the human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-TNFα) mAb, or antigen-binding fragment thereof, a substantially full-length or full-length anti-complement component 5 (C5) mAb, or antigen-binding fragment thereof, a substantially full-length or full-length anti-interleukin-6 (IL-6) mAb, or antigen-binding fragment thereof, or a substantially full-length or full-length anti-interleukin-6 receptor (IL-6R) mAb, or antigen-binding fragment thereof, operably linked to one or more regulatory sequences controlling expression of the transgene in human retinal cells, such that depots are formed that release HuPTM forms of the mAbs or antigen-binding fragments. 117. The method according to item 115 or 116, wherein the anti-TNFα mAb is adalimumab, infliximab or golimumab, the anti-C5 mAb is tesidolumab or ravulizumab; the anti-IL-6 mAb is siltuximab, clazakimuzumab, sirukumab, olokizumab or gerilimuzumab; or the anti-IL-6R mAb is satralizumab, sarilumab or tocilizumab. 118. The method of any of items 115 to 117, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 119. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO: 45, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 303, and a light chain having an amino acid sequence of SEQ ID NO: 46; or a heavy chain having an amino acid sequence of SEQ ID NO: 47, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 304, and a light chain having an amino acid sequence of SEQ ID NO: 48; or an Fc polypeptide having an amino acid sequence of SEQ ID NO: 49, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 305; and a light chain having an amino acid sequence of SEQ ID NO: 50; a heavy chain having an Fc polypeptide having an 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 an amino acid sequence of SEQ ID NO: 40; a heavy chain having an Fc polypeptide having an amino acid sequence of SEQ ID NO: 362, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 393, and a light chain having an amino acid sequence of SEQ ID NO: 363; an Fc polypeptide having an amino acid sequence of SEQ ID NO: 331, and optionally an amino acid sequence of SEQ ID NO: 355. a heavy chain having an amino acid sequence of SEQ ID NO: 333 and, optionally, an Fc polypeptide having an amino acid sequence of SEQ ID NO: 356 and, optionally, a light chain having an amino acid sequence of SEQ ID NO: 334; a heavy chain having an amino acid sequence of SEQ ID NO: 335 and, optionally, an Fc polypeptide having an amino acid sequence of SEQ ID NO: 357 and, optionally, a light chain having an amino acid sequence of SEQ ID NO: 336; a heavy chain having an amino acid sequence of SEQ ID NO: 337 and, optionally, an Fc polypeptide having an amino acid sequence of SEQ ID NO: 358 and, optionally, a light chain having an amino acid sequence of SEQ ID NO: 338; a light chain having an amino acid sequence of SEQ ID NO: 339 and, optionally, an Fc polypeptide having an amino acid sequence of SEQ ID NO: 340; a heavy chain having an amino acid sequence of SEQ ID NO: 59 and, optionally, an Fc polypeptide having an amino acid sequence of SEQ ID NO: 309 and, optionally, a light chain having an amino acid sequence of SEQ ID NO: 60; a heavy chain having an amino acid sequence of SEQ ID NO: 61 and, optionally, an Fc polypeptide having an amino acid sequence of SEQ ID NO: 310 and, optionally, a light chain having an amino acid sequence of SEQ ID NO: 62;and a heavy chain with an Fc polypeptide having the amino acid sequence of SEQ ID NO: 341, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 359, and a light chain with the amino acid sequence of SEQ ID NO: 342. 120. The transgene comprises a nucleotide sequence of SEQ ID NO: 115 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 116 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 117 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 118 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 119 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 120 encoding a light chain; a nucleotide sequence of SEQ ID NO: 109 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 110 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 378 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 379 encoding a light chain; a nucleotide sequence of SEQ ID NO: 343 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 344 encoding a light chain; a nucleotide sequence of SEQ ID NO: 345 encoding a heavy chain. 119. The method of claim 118, comprising the steps of: a nucleotide sequence of SEQ ID NO: 341 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 346 encoding the light chain; a nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 348 encoding the light chain; a nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 350 encoding the light chain; a nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 352 encoding the light chain; a nucleotide sequence of SEQ ID NO: 129 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 130 encoding the light chain; a nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 132 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 341 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 342 encoding the light chain. 121. The method according to any of items 115 to 118, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 122. The method of any of items 115 to 121, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 123. The method of any of items 115 to 122, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 124. The method of any of items 115 to 123, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 125. The method according to any of items 116 to 124, wherein the recombinant expression vector is AAV2.7m8, AAV8, or AAV9. 126. The method of any of items 116 to 125, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human retinal cells in culture and expressing the mAb or antigen-binding fragment thereof. 127. A method for treating multiple sclerosis in a human subject in need thereof, comprising: The method comprises delivering a therapeutically effective amount of a substantially full-length or full-length anti-repulsive guidance molecule-A (anti-RGMa) mAb or an antigen-binding fragment thereof, expressed from a transgene and produced by human CNS cells, to the cerebrospinal fluid (CSF) of the human subject. 128. A method for treating multiple sclerosis in a human subject in need thereof, comprising: A method comprising administering to the CNS of a human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-repulsive guidance molecule-A (anti-RGMa) mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in human CNS cells, so as to form a depot that releases a HuPTM form of the mAb or antigen-binding fragment. 129. The method according to item 127 or 128, wherein the anti-RGMa mAb is elezanumab. 130. The method of any of items 127 to 129, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 131. The method of any of items 127 to 130, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 51, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 306, and a light chain having the amino acid sequence of SEQ ID NO: 52. 132. The method according to item 131, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 121 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 122 encoding the light chain. 133. The method according to any of items 127 to 131, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 134. The method of any of items 127 to 133, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 135. The method of any of items 127 to 134, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 136. The method of any of items 127 to 135, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 137. The method according to any of items 128 to 136, wherein the recombinant expression vector is AAV9. 138. The method of any of items 128 to 136, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. 139. A method for treating amyloidosis (ATTR), familial amyloid cardiomyopathy (FAC), or familial amyloid polyneuropathy (FAP) in a human subject in need of such treatment, comprising delivering to the circulation of the human subject a therapeutically effective amount of a substantially full-length or full-length anti-transthyretin (anti-TTR) mAb, or an antigen-binding fragment thereof, expressed from a transgene and produced by human hepatocytes or human muscle cells. 140. A method for treating asthma in a human subject in need thereof, comprising: The method comprises administering to liver cells or muscle cells of the human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-transthyretin (anti-TTR) mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 141. The method according to item 139 or 140, wherein the anti-TTR mAb is NI-301 or PRX-004. 142. The method according to any of items 139 to 141, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 143. The method of any of items 139 to 142, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having 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), and a light chain having the amino acid sequence of SEQ ID NO: 54; or a heavy 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, and a light chain having the amino acid sequence of SEQ ID NO: 56. 144. The method according to item 143, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 123 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 124 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 125 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 126 encoding a light chain. 145. The method according to any of items 139 to 143, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 146. The method according to any of items 139 to 145, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 147. The method of any of items 139 to 146, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 148. The method of any of items 139 to 147, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 149. The method according to any of items 140 to 148, wherein the recombinant expression vector is AAV8 or AAV9. 150. The method of any of items 140 to 149, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human hepatocytes or human muscle cells in culture and expressing the mAb or antigen-binding fragment thereof. 151. A method for treating a fibrotic disorder, including pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, mediastinal fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and retroperitoneal fibrosis (RPF), in a human subject in need of such treatment, comprising: A method comprising delivering to the circulation of the human subject a therapeutically effective amount of a substantially full-length or full-length anti-connective tissue growth factor (anti-CTGF) mAb, or an antigen-binding fragment thereof, expressed from a transgene and produced by human liver cells or human muscle cells. 152. A method for treating a fibrotic disorder, including pulmonary fibrosis, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, atrial fibrosis, endomyocardial fibrosis, old myocardial infarction, arthrofibrosis, Crohn's disease, mediastinal fibrosis, myelofibrosis (MF), nephrogenic systemic fibrosis (NSF), progressive massive fibrosis (PMF), and retroperitoneal fibrosis (RPF), in a human subject in need of such treatment, comprising: in hepatocytes or muscle cells of said human subject, so as to form a depot that releases a HuPTM form of the mAb or antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of a transgene in the human hepatocytes or human muscle cells; The method comprises administering a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-connective tissue growth factor (anti-CTGF) mAb, or an antigen-binding fragment thereof. 153. The method according to item 151 or 152, wherein the anti-CTGF mAb is pamrevlumab. 154. The method according to any of items 151 to 153, wherein the antigen-binding fragment is a Fab, a F(ab')2, or a scFv. 155. The method of any of items 151 to 154, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 57, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 308, and a light chain having the amino acid sequence of SEQ ID NO: 58. 156. The method according to item 155, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 127 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 128 encoding the light chain. 157. The method according to any of items 151 to 155, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 158. The method of any of items 151 to 157, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 159. The method of any of items 151 to 158, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 160. The method of any of items 151 to 159, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 161. The method according to any of items 152 to 160, wherein the recombinant expression vector is AAV8 or AAV9. 162. The method of any of items 152 to 161, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human hepatocytes or human muscle cells in culture and expressing the mAb or antigen-binding fragment thereof. 163. A method for treating non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR) or diabetic macular edema (DME) in a human subject in need thereof, comprising: The method comprises delivering to the retina of the human subject a therapeutically effective amount of an anti-interleukin-6 receptor (anti-IL6R) mAb, an anti-interleukin-6 (IL6) mAb, or an anti-cluster of differentiation 19 (anti-CD19) mAb, or a substantially full-length or full-length mAb of an antigen-binding fragment thereof, expressed from a transgene and produced by human retinal cells. 164. A method for treating non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR) or diabetic macular edema (DME) in a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of 50 mg / kg / day of non-infectious uveitis, neuromyelitis optica (NMO), diabetic retinopathy (DR) or diabetic macular edema (DME) treatment ... The method comprises administering to the retina of the human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length mAb of an anti-interleukin-6 receptor (anti-IL6R) mAb, an anti-interleukin-6 (IL6) mAb, or an anti-cluster of differentiation 19 (anti-CD19) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human retinal cells, such that depots are formed that release a HuPTM form of the mAb or its antigen-binding fragment. 165. The method according to item 163 or 164, wherein the anti-IL6R is satralizumab, sarilumab, or tocilizumab, or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, olokizumab, or gerilizumab, or the anti-CD19 mAb is inebilizumab. 166. The method according to any of items 163 to 165, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 167. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO:59, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:309, and a light chain having an amino acid sequence of SEQ ID NO:60; or a heavy chain having an amino acid sequence of SEQ ID NO:61, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:310, and a light chain having an amino acid sequence of SEQ ID NO:62; or a heavy chain having an amino acid sequence of SEQ ID NO:341, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:359, and a light chain having an amino acid sequence of SEQ ID NO:342; or a heavy chain having an amino acid sequence of SEQ ID NO:331, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:355, and a light chain having an amino acid sequence of SEQ ID NO:332; or a heavy chain having an amino acid sequence of SEQ ID NO:333, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:356, and a light chain having an amino acid sequence of SEQ ID NO:334; or a heavy chain having an amino acid sequence of SEQ ID NO:335; 167. The method according to any of items 163 to 166, comprising a heavy chain having an amino acid sequence of SEQ ID NO: 335 and optionally 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: 336; or a heavy chain having an amino acid sequence of SEQ ID NO: 337 and optionally 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: 338; or a heavy chain having an amino acid sequence of SEQ ID NO: 339 and optionally 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 a heavy chain having an amino acid sequence of SEQ ID NO: 341 and optionally 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; a heavy chain having an amino acid sequence of SEQ ID NO: 63 and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 311, and a light chain having the amino acid sequence of SEQ ID NO: 64. 168. The transgene comprises a nucleotide sequence of SEQ ID NO: 129 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 130 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 131 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 132 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 343 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 344 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 345 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 346 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 347 encoding a heavy chain, or a nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 350 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 352 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 354 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 133 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 134 encoding the light chain. 169. The method according to any of items 163 to 167, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 170. The method of any of items 163 to 168, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 171. The method of any of items 163 to 169, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 172. The method of any of items 163 to 170, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 173. The method according to any of items 164 to 171, wherein the recombinant expression vector is AAV8, AAV2.7m8 or AAV9. 174. The method of any of items 164 to 172, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human retinal cells in culture and expressing the mAb or antigen-binding fragment thereof. 175. A method for treating inflammatory bowel disease (IBD), including UC and CD, in a human subject in need of such treatment, comprising delivering to the circulation of the human subject a therapeutically effective amount of a substantially full-length or full-length anti-integrin β7 subunit (anti-ITGB7) mAb, or an antigen-binding fragment thereof, expressed from a transgene and produced by human hepatocytes or human muscle cells. 176. A method for treating inflammatory bowel disease (IBD), including UC and CD, in a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of 5-aminobutyric acid (ABA) to said subject, The method comprises administering to liver cells or muscle cells of the human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-integrin β7 subunit (anti-ITGB7) mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells, such that depots are formed that release a HuPTM form of the mAb or its antigen-binding fragment. 177. The method according to item 175 or 176, wherein the anti-ITGB7 mAb is etrolizumab. 178. The method according to any of items 175 to 177, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 179. The method of any of items 175 to 178, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 65, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 312, and a light chain having the amino acid sequence of SEQ ID NO: 66. 180. The method according to item 179, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 135 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 136 encoding the light chain. 181. The method according to any of items 175 to 179, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 182. The method of any of items 175 to 181, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 183. The method of any of items 175 to 182, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 184. The method of any of items 175 to 183, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 185. The method according to any of items 176 to 184, wherein the recombinant expression vector is AAV8 or AAV9. 186. The method of any of items 176 to 185, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human hepatocytes or human muscle cells in culture and expressing the mAb or antigen-binding fragment thereof. 187. A method for treating systemic osteoporosis or abnormal bone loss or bone wasting (e.g., treating giant cell tumor of bone, treating treatment-induced bone loss, slowing bone loss (or increasing bone mass) in patients with breast and prostate cancer, preventing skeletal-related events due to bone metastases, or reducing bone resorption and bone turnover, in a human subject in need thereof, comprising administering to said subject a therapeutically effective amount of ... The method comprises delivering a therapeutically effective amount of a substantially full-length or full-length anti-sclerostin (anti-SOST) mAb or an antigen-binding fragment thereof expressed from a transgene and produced by human liver cells or human muscle cells into the circulation of the human subject. 188. A method for treating osteoporosis or abnormal bone loss or bone wasting (e.g., treating giant cell tumor of bone, treating treatment-induced bone loss, slowing bone loss (or increasing bone mass) in patients with breast and prostate cancer, preventing skeletal-related events due to bone metastases, or reducing bone resorption and bone turnover in a human subject in need thereof, comprising: The method comprises administering to the subject's liver cells or muscle cells a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-sclerostin (anti-SOST) mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 189. The method according to item 187 or 188, wherein the anti-SOST mAb is romosozumab. 190. The method according to any of items 187 to 189, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 191. The method of any of items 187 to 190, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 67, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 313, and a light chain having the amino acid sequence of SEQ ID NO: 68. 192. The method according to item 191, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 137 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 138 encoding the light chain. 193. The method according to any of items 187 to 191, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 194. The method of any of items 187 to 193, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 195. The method of any of items 187 to 194, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 196. The method of any of items 187 to 195, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 197. The method according to any of items 188 to 196, wherein the recombinant expression vector is AAV8 or AAV9. 198. The method of any of items 188 to 196, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human hepatocytes or human muscle cells in culture and expressing the mAb or antigen-binding fragment thereof. 199. A method for treating angioedema in a human subject in need thereof, comprising: The method comprises delivering a therapeutically effective amount of a substantially full-length or full-length anti-kallikrein (anti-pKal) mAb or an antigen-binding fragment thereof, expressed from a transgene and produced by human muscle cells or human hepatic cells, into the circulation of the human subject. 200. A method for treating angioedema in a human subject in need thereof, comprising: The method comprises administering to the subject's muscle cells or hepatocytes a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length anti-kallikrein (anti-pKal) mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in the human muscle cells or human hepatocytes, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 201. The method according to item 199 or 200, wherein the anti-pKal mAb is lanadelumab. 202. The method of any of items 199 to 201, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 203. The method of any of items 199 to 202, wherein the full length mAb or antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 69, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 314, and a light chain having the amino acid sequence of SEQ ID NO: 70. 204. The method according to item 203, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 139 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 140 encoding the light chain. 205. The method of any of items 199 to 203, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 206. The method of any of items 199 to 205, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 207. The method of any of items 199 to 206, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 208. The method of any of items 199 to 207, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 209. The method according to any of items 200 to 208, wherein the recombinant expression vector is AAV8 or AAV9. 210. The method of any of items 200 to 209, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human hepatocytes or human muscle cells in culture and expressing the mAb or antigen-binding fragment thereof. Manufacturing method 211. A method for producing a recombinant AAV comprising: (a)(i) an artificial genome comprising a therapeutic antibody-encoding transgene, the transgene comprising a cis expression cassette flanked by AAV ITRs, the cis expression cassette being operably linked to an expression control element that controls expression of the transgene in a human cell; (ii) a trans expression cassette lacking AAV ITRs, encoding AAV rep and capsid proteins operably linked to expression control elements that drive expression of the AAV rep and capsid proteins in a host cell in culture, the trans expression cassette supplying the rep and cap proteins in trans; (iii) adenovirus helper functions sufficient to allow replication and packaging of the artificial genome by AAV capsid proteins; Culturing a host cell containing the compound; and (b) recovering recombinant AAVs encapsidating the artificial genome from the cell culture; The method comprising: 212. The method of claim 211, wherein the transgene encodes a substantially full-length or full-length mAb or antigen-binding fragment comprising the heavy and light chain variable domains of solanezumab, lecanemab, GSK933776, AL-001, ABBV-8E12, UCB-0107, NI-105 (BIIB076), VX15 / 2503, prasinezumab, NI-202 (BIIB054), MED-1341, NI-2041.10D12, NI-204.12G7, eptinezumab, fremanezumab, galcanezumab, or elezanumab. 213. The method of claim 212, wherein the AAV capsid protein is an AAV9, AAVrh10, AAVrh20, AAVrh39, or AAVcy5 capsid protein. 214. The method of claim 211, wherein the transgene encodes a substantially full-length or full-length mAb or antigen-binding fragment comprising the heavy and light chain variable domains of sevacizumab, LKA-651(NSV2), LKA-651(NSV3), GSK933776, solanezumab, lecanemab, asclinbacumab, tesidolumab, ravulizumab, carotuximab, ANX-007, lanadelumab, adalimumab, infliximab, golimumab, satralizumab, sarilumab, tocilizumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, or inebilizumab. 215. The method of claim 214, wherein the AAV capsid protein is an AAV2.7m8, AAV8, or AAV9 capsid protein. 216. The method of claim 211, wherein the transgene encodes a substantially full-length or full-length mAb or an antigen-binding fragment comprising the heavy and light chain variable domains of NI-301, PRX-004, pamrevlumab, etrolizumab, romosozumab, or lanadelumab. 217. The method of claim 216, wherein the AAV capsid protein is an AAV8, AAV9, or AAVrh10 capsid protein. 218. The method of claim 211, wherein the transgene encodes a substantially full-length or full-length mAb. Autoimmune, Respiratory, and Allergic Diseases Material composition 219. A pharmaceutical composition for treating atopic dermatitis in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding an anti-IL13 mAb or anti-IL31RA, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. 220. The pharmaceutical composition according to item 219, wherein the anti-IL13 or IL31RA is tralokinumab or nemolizumab. 221. The antigen-binding fragment is Fab, F(ab') 2 221. The pharmaceutical composition according to item 219 or 220, wherein the antibody is a Fv or an scFv. 222. The pharmaceutical composition according to any of items 219 to 221, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 368 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 396, and a light chain having the amino acid sequence of SEQ ID NO: 369; or the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 370 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 397, and a light chain having the amino acid sequence of SEQ ID NO: 371. 223. The pharmaceutical composition according to item 222, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 384 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 385 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 386 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 387 encoding a light chain. 224. The pharmaceutical composition according to any of items 219 to 221, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant. 225. The pharmaceutical composition according to any of items 219 to 224, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 226. The pharmaceutical composition according to item 225, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 227. The pharmaceutical composition according to any of items 219 to 226, wherein the AAV capsid is AAV8. 228. A pharmaceutical composition for treating eosinophilic asthma in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding an anti-IL5R mAb or an anti-IgE mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. 229. The pharmaceutical composition according to item 228, wherein the anti-IL5R or anti-IgE mAb is reslizumab or omalizumab. 230. The antigen-binding fragment is Fab, F(ab') 2 229. The pharmaceutical composition according to item 228 or 229, wherein the antibody is a Fv or an scFv. 231. The pharmaceutical composition according to any of items 228 to 230, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 364 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 394, and a light chain having the amino acid sequence of SEQ ID NO: 365; or a heavy chain having the amino acid sequence of SEQ ID NO: 372 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and a light chain having the amino acid sequence of SEQ ID NO: 373. 232. The pharmaceutical composition according to item 231, wherein the transgene comprises a nucleotide sequence according to SEQ ID NO: 380 encoding a heavy chain and a nucleotide sequence according to SEQ ID NO: 381 encoding a light chain; or a nucleotide sequence according to SEQ ID NO: 388 encoding a heavy chain and a nucleotide sequence according to SEQ ID NO: 389 encoding a light chain. 233. The pharmaceutical composition according to any of items 228 to 231, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant. 234. The pharmaceutical composition according to any of items 228 to 233, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 235. The pharmaceutical composition according to item 234, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 236. The pharmaceutical composition according to any of items 228 to 235, wherein the AAV capsid is AAV8. 237. A pharmaceutical composition for treating asthma or chronic obstructive pulmonary disease (COPD) in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding an anti-IL5, anti-IL-5R, anti-IgE, or anti-TSLP mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. 238. The pharmaceutical composition according to item 237, wherein the anti-IL-5, anti-IL5R, anti-IgE, or anti-TSLP mAb is benralizumab, reslizumab, omalizumab, or tezepelumab. 239. The antigen-binding fragment is Fab, F(ab') 2 239. The pharmaceutical composition according to item 237 or 238, wherein the antibody is a Fv or an scFv. 240. The pharmaceutical composition according to any of items 237 to 239, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 364 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 394, and a light chain having the amino acid sequence of SEQ ID NO: 365; a heavy chain having the amino acid sequence of SEQ ID NO: 366 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 395, and a light chain having the amino acid sequence of SEQ ID NO: 367; a light chain having the amino acid sequence of SEQ ID NO: 372 and the amino acid sequence of SEQ ID NO: 373; or an IgG2 Fc polypeptide of the amino acid sequence of SEQ ID NO: 374 and, optionally, an IgG2 Fc polypeptide of the amino acid sequence of SEQ ID NO: 284, and a light chain having the amino acid sequence of SEQ ID NO: 375. 241. The pharmaceutical composition according to item 240, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 380 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 381 encoding a light chain; a nucleotide sequence of SEQ ID NO: 382 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 383 encoding a light chain; a nucleotide sequence of SEQ ID NO: 388 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 389 encoding a light chain; a nucleotide sequence of SEQ ID NO: 390 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 391 encoding a light chain. 242. The pharmaceutical composition according to any of items 237 to 240, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant. 243. The pharmaceutical composition according to any of items 237 to 242, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 244. The pharmaceutical composition according to item 243, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 245. The pharmaceutical composition according to any of items 237 to 244, wherein the AAV capsid is AAV8. 246. A pharmaceutical composition for treating chronic idiopathic urticaria in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding an anti-IgE mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. 247. The pharmaceutical composition according to item 246, wherein the anti-IgE mAb is omalizumab. 248. The pharmaceutical composition according to item 246 or 247, wherein the antigen-binding fragment is a Fab, F(ab')2, or scFv. 249. The pharmaceutical composition according to any of items 246 to 248, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 372 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and a light chain having the amino acid sequence of SEQ ID NO: 373. 250. The pharmaceutical composition according to item 249, wherein the transgene comprises 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. 251. The pharmaceutical composition according to any of items 246 to 249, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant. 252. The pharmaceutical composition according to any of items 246 to 251, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 253. The pharmaceutical composition according to item 252, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 254. The pharmaceutical composition according to any of items 246 to 253, wherein the AAV capsid is AAV8. Treatment 254. A method for treating atopic dermatitis in a human subject in need thereof, comprising: The method comprises delivering into the circulation of the human subject a therapeutically effective amount of an anti-IL13 or anti-IL31RA mAb, or an antigen-binding fragment thereof, produced by human liver cells or human muscle cells. 255. A method for treating atopic dermatitis in a human subject in need thereof, comprising: such that a depot is formed that releases the HuPTM form of the mAb or antigen-binding fragment thereof. The method comprises administering to the subject's liver cells or muscle cells a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding an anti-IL13 or anti-IL31RA mAb or an antigen-binding fragment thereof operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells. 256. The method according to item 254 or 255, wherein the anti-IL13 or anti-IL31RA mAb is tralokinumab or nemolizumab. 257. The antigen-binding fragment is Fab, F(ab') 2 257. The method of any of items 254 to 256, wherein the antibody is a Fv or scFv. 258. The method according to any of items 254 to 257, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 368 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 396, and a light chain having the amino acid sequence of SEQ ID NO: 369; or a heavy chain having the amino acid sequence of SEQ ID NO: 370 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 397, and a light chain having the amino acid sequence of SEQ ID NO: 371. 259. The method according to item 258, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 384 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 385 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 386 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 387 encoding a light chain. 260. The method of any of items 254 to 258, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 261. The method according to any of items 254 to 260, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 262. The method of any of items 254 to 261, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 263. The method of any of items 254 to 262, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 264. The method according to any of items 254 to 263, wherein the recombinant expression vector is AAV8 or AAV9. 265. The method of any of items 254 to 264, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. 266. A method for treating eosinophilic asthma in a human subject in need thereof, comprising: The method comprises delivering a therapeutically effective amount of an anti-IL5R or anti-IgE mAb, or an antigen-binding fragment thereof, produced by human hepatocytes or human muscle cells into the circulation of the human subject. 267. A method for treating eosinophilic asthma in a human subject in need thereof, comprising: A method comprising administering to liver cells or muscle cells of the subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding an anti-IL5R or anti-IgE mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells, such that depots are formed that release a HuPTM form of the mAb or its antigen-binding fragment. 268. The method according to item 266 or 267, wherein the anti-IL5R or anti-IgE mAb is reslizumab or omalizumab. 269. The antigen-binding fragment is Fab, F(ab') 2 269. The method according to any of items 266 to 268, wherein the antibody is a Fv or scFv. 270. The method according to any of items 266 to 269, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 366 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 395, and a light chain having the amino acid sequence of SEQ ID NO: 367; or a heavy chain having the amino acid sequence of SEQ ID NO: 372 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and a light chain having the amino acid sequence of SEQ ID NO: 373. 271. The method according to item 270, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 382 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 383 encoding a light chain; or a nucleotide sequence of SEQ ID NO: 388 encoding a heavy chain and a nucleotide sequence of SEQ ID NO: 389 encoding a light chain. 272. The method according to any of items 266 to 270, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 273. The method of any of items 266 to 272, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 274. The method of any of items 266 to 273, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 275. The method of any of items 266 to 274, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 276. The method according to any of items 266 to 275, wherein the recombinant expression vector is AAV8 or AAV9. 277. The method of any of items 266 to 276, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. 278. A method for treating asthma or COPD in a human subject in need thereof, comprising: The method comprises delivering a therapeutically effective amount of an anti-IL5, anti-IL5R, anti-IgE, or anti-TSLP mAb, or an antigen-binding fragment thereof, produced by human hepatocytes or human muscle cells into the circulation of the human subject. 279. A method for treating eosinophilic asthma in a human subject in need thereof, comprising: The method comprises administering to the subject's liver cells or muscle cells a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding an anti-IL5R, anti-IL5, anti-IgE, or anti-TSLP mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 280. The method according to item 278 or 279, wherein the anti-IL5R, anti-IL5, anti-IgE, or anti-TSLP mAb is benralizumab, reslizumab, omalizumab, or tezepelumab. 281. The antigen-binding fragment is Fab, F(ab') 2 281. The method according to any of items 278 to 280, wherein the antibody is a Fv or scFv. 282. The method according to any of items 278 to 281, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 364, and optionally an Fc polypeptide of the amino acid sequence of SEQ ID NO: 394, and a light chain having the amino acid sequence of SEQ ID NO: 365; or a heavy chain having the amino acid sequence of SEQ ID NO: 366, and optionally an Fc polypeptide of the amino acid sequence of SEQ ID NO: 395, and a light chain having the amino acid sequence of SEQ ID NO: 367; or a heavy chain having the amino acid sequence of SEQ ID NO: 372, and optionally an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and a light chain having the amino acid sequence of SEQ ID NO: 373; or an IgG2 Fc polypeptide of the amino acid sequence of SEQ ID NO: 284, and a light chain having the amino acid sequence of SEQ ID NO: 375. 283. The method according to item 282, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 380 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 381 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 383 encoding the heavy chain and 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 nucleotide sequence of SEQ ID NO: 389 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 390 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 391 encoding the light chain. 284. The method of any of items 278 to 283, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 285. The method of any of items 278 to 284, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 286. The method of any of items 278 to 285, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 287. The method of any of items 278 to 286, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 288. The method according to any of items 278 to 287, wherein the recombinant expression vector is AAV8 or AAV9. 289. The method of any of items 278 to 288, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. 290. A method for treating chronic idiopathic urticaria in a human subject in need thereof, comprising: The method comprises delivering to the circulation of the human subject a therapeutically effective amount of an anti-IgE mAb, or an antigen-binding fragment thereof, produced by human liver cells or human muscle cells. 291. A method for treating eosinophilic asthma in a human subject in need thereof, comprising: The method comprises administering to the subject's liver cells or muscle cells a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding an anti-IgE mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in the human liver cells or human muscle cells, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 292. The method according to item 290 or 291, wherein the anti-IgE mAb is omalizumab. 293. The antigen-binding fragment is Fab, F(ab') 2 293. The method of any of items 290 to 292, wherein the antibody is a Fv or scFv. 294. The method according to any of items 290 to 293, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 372 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 398, and a light chain having the amino acid sequence of SEQ ID NO: 373. 295. The method according to item 294, wherein the transgene comprises 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. 296. The method according to any of items 290 to 295, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 297. The method of any of items 290 to 296, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 298. The method of any of items 290 to 297, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 299. The method of any of items 290 to 298, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 300. The method according to any of items 290 to 299, wherein the recombinant expression vector is AAV8 or AAV9. 301. The method of any of items 290 to 300, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into human CNS cells in culture and expressing the mAb or antigen-binding fragment thereof. Manufacturing method 302. The method of claim 211, wherein the transgene encodes a substantially full-length or full-length mAb or an antigen-binding fragment comprising the heavy and light chain variable domains of benralizumab, reslizumab, tralokinumab, nemolizumab, omalizumab, or tezepelumab. 303. The method of claim 302, wherein the AAV capsid protein is an AAV8, AAV9, or AAVrh10 capsid protein. myasthenia gravis Material composition 304. A pharmaceutical composition for treating myasthenia gravis in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), or an AAVrh10 capsid (SEQ ID NO: 145); and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding an anti-C5 mAb or an antigen-binding fragment thereof operably linked to one or more regulatory sequences that control expression of the transgene in human hepatocytes or human muscle cells; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intravenous administration to liver cells or muscle cells of the subject. 305. The pharmaceutical composition according to item 304, wherein the anti-C5 is ravulizumab. 306. The antigen-binding fragment is Fab, F(ab') 2 306. The pharmaceutical composition according to item 304 or 305, wherein the antibody is a Fv or a scFv. 307. The pharmaceutical composition according to any of items 304 to 306, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 362 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 393, and a light chain having the amino acid sequence of SEQ ID NO: 363. 308. The pharmaceutical composition according to item 307, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 378 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 379 encoding the light chain. 309. The pharmaceutical composition according to any of items 304 to 308, wherein the antibody or antigen-binding fragment thereof is a hyperglycosylated mutant. 310. The pharmaceutical composition according to any of items 304 to 310, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 311. The pharmaceutical composition according to item 310, wherein the signal sequence is selected from the signal sequences of Table 2 or 3. 312. The pharmaceutical composition according to any of items 304 to 311, wherein the AAV capsid is AAV8. Treatment 313. A method for treating myasthenia gravis in a human subject in need thereof, comprising: The method comprises delivering to the circulation of the human subject a therapeutically effective amount of an anti-C5 mAb, or an antigen-binding fragment thereof, produced by human liver cells or human muscle cells. 314. A method for treating myasthenia gravis in a human subject in need thereof, comprising: The method comprises administering to the subject's liver cells or muscle cells a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding an anti-C5 mAb or its antigen-binding fragment, operably linked to one or more regulatory sequences that control expression of the transgene in human liver cells or human muscle cells, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 315. The method according to item 313 or 314, wherein the anti-C5 is ravulizumab. 316. The antigen-binding fragment is Fab, F(ab') 2 316. The method of any of items 313 to 315, wherein the antibody is a Fv or scFv. 317. The method according to any of items 313 to 316, wherein the antigen-binding fragment comprises a heavy chain having the amino acid sequence of SEQ ID NO: 362 and, optionally, an Fc polypeptide of the amino acid sequence of SEQ ID NO: 393, and a light chain having the amino acid sequence of SEQ ID NO: 363. 318. The method according to item 260, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 378 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 379 encoding the light chain. 319. The method according to any of items 313 to 318, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant. 320. The method of any of items 313 to 319, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 321. The method of any of items 313 to 320, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 322. The method of any of items 313 to 321, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 323. The method according to any of items 313 to 322, wherein the recombinant expression vector is AAV8 or AAV9. 324. The method of any of items 313 to 323, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. Manufacturing method 325. The method of item 211, wherein the transgene encodes a substantially full-length or full-length mAb or an antigen-binding fragment comprising the heavy and light chain variable domains of ravulizumab. 326. The method of claim 304, wherein the AAV capsid protein is an AAV8, AAV9, or AAVrh10 capsid protein. Compositions and methods for inhibiting an immune response 327. A pharmaceutical composition for reducing, inhibiting, or ameliorating a harmful immune response in a human subject in need thereof, comprising: (a )A AV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrh10 capsid (SEQ ID NO: 145) A viral capsid that is at least 95% identical to the amino acid sequence of and (b) a human liver or muscle cell, comprising an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length mAb of anti-interleukin-6 receptor (anti-IL6R) or anti-interleukin-6 (IL6), or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences controlling expression of the transgene within the artificial genome; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for subcutaneous, intramuscular, intravenous or pulmonary administration to a subject. 328. The pharmaceutical composition according to item 327, wherein the anti-IL6R mAb is satralizumab, sarilumab, or tocilizumab, or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, olokizumab, or gerilimuzumab. 329. The antigen-binding fragment is Fab, F(ab') 2 329. The pharmaceutical composition according to item 327 or 328, which is a Fv or scFv. 330. The full length mAb or antigen-binding fragment comprises a heavy chain having an amino acid sequence of SEQ ID NO:59, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:309, and a light chain having an amino acid sequence of SEQ ID NO:60; or a heavy chain having an amino acid sequence of SEQ ID NO:61, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:310, and a light chain having an amino acid sequence of SEQ ID NO:62; or a heavy chain having an amino acid sequence of SEQ ID NO:331, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:355, and a light chain having an amino acid sequence of SEQ ID NO:332; or a heavy chain having an amino acid sequence of SEQ ID NO:333, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:356, and a light chain having an amino acid sequence of SEQ ID NO:334; or a heavy chain having an amino acid sequence of SEQ ID NO:335, and a light chain having an amino acid sequence of SEQ ID NO:336; 329. The pharmaceutical composition according to any of items 327 to 329, comprising a heavy chain having an amino acid sequence of SEQ ID NO: 335 and optionally 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: 336; or a heavy chain having an amino acid sequence of SEQ ID NO: 337 and optionally 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: 338; or a heavy chain having an amino acid sequence of SEQ ID NO: 339 and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO: 283, and a light chain having the amino acid sequence of SEQ ID NO: 340; or a heavy chain having an amino acid sequence of SEQ ID NO: 341 and optionally 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. 331. The pharmaceutical composition according to item 330, wherein the transgene comprises a nucleotide sequence of SEQ ID NO: 129 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 130 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 132 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 343 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 344 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 345 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 346 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 348 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 350 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 352 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 354 encoding the light chain. 332. The pharmaceutical composition according to any of items 327 to 331, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 333. The pharmaceutical composition according to any of items 327 to 331, wherein the transgene encodes signal sequences at the N-terminus of the heavy and light chains of the antigen-binding fragment directing secretion and post-translational modification in the human liver cells or human muscle cells. 334. The pharmaceutical composition according to item 333, wherein the signal sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), or a signal sequence according to Table 3 or Table 4. 335. The pharmaceutical composition according to any of items 327 to 334, wherein the AAV capsid is AAV8. 336. A pharmaceutical composition for reducing, inhibiting, or ameliorating a harmful immune response in a human subject in need thereof, comprising: The method comprises delivering to the circulation or tissue that is a target of the immune response of the human subject a therapeutically effective amount of a substantially full-length or full-length anti-interleukin-6 receptor (anti-IL6R) mAb, an anti-interleukin-6 (IL6) mAb, or an antigen-binding fragment thereof, expressed from a transgene and produced by human muscle cells or liver cells. 337. A pharmaceutical composition for reducing, inhibiting, or ameliorating a harmful immune response in a human subject in need thereof, comprising: The method comprises administering to muscle or hepatic cells of the human subject a therapeutically effective amount of a recombinant nucleotide expression vector comprising a transgene encoding a substantially full-length or full-length mAb of an anti-interleukin-6 receptor (anti-IL6R) mAb, an anti-interleukin-6 (IL6) mAb, or an antigen-binding fragment thereof, operably linked to one or more regulatory sequences that control expression of the transgene in the human muscle or hepatic cells, so as to form depots that release a HuPTM form of the mAb or its antigen-binding fragment. 338. The method according to item 336 or 337, wherein the anti-IL6R is satralizumab, sarilumab, or tocilizumab, or the anti-IL6 mAb is siltuximab, clazakizumab, sirukumab, olokizumab, or gerilimuzumab. 339. The antigen-binding fragment is Fab, F(ab') 2 339. The method of any of items 336 to 338, wherein the antibody is a Fv or scFv. 340. The mAb or antigen-binding fragment comprises a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:59, and optionally the amino acid sequence of SEQ ID NO:309, and a light chain having the amino acid sequence of SEQ ID NO:60; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:61, and optionally the amino acid sequence of SEQ ID NO:310, and a light chain having the amino acid sequence of SEQ ID NO:62; or a heavy chain having an Fc polypeptide having 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; or a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:331, and optionally the amino acid sequence of SEQ ID NO:355, and a light chain having the amino acid sequence of SEQ ID NO:332; or an Fc polypeptide having the amino acid sequence of SEQ ID NO:333, and optionally the amino acid sequence of SEQ ID NO:356. or a heavy chain having an amino acid sequence of SEQ ID NO: 335 and optionally 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: 336; or a heavy chain having an amino acid sequence of SEQ ID NO: 337 and optionally 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: 338; or a heavy chain having an amino acid sequence of SEQ ID NO: 339 and optionally 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 a heavy chain having an amino acid sequence of SEQ ID NO: 341 and optionally 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. 341. The method according to item 340, wherein the transgene comprises 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; or the nucleotide sequence of SEQ ID NO: 131 encoding the heavy 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 nucleotide sequence of SEQ ID NO: 344 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 345 encoding the heavy chain 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; or the nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 350 encoding the light chain; or the nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and the nucleotide sequence of SEQ ID NO: 352 encoding the light chain; 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. 342. The method according to any of items 336 to 339, wherein the mAb or antigen-binding fragment thereof is a hyperglycosylated mutant or the Fc polypeptide of the mAb is glycosylated or non-glycosylated. 343. The method of any of items 336 to 342, wherein the mAb or antigen-binding fragment thereof contains α 2,6-sialylated glycans. 344. The method of any of items 336 to 343, wherein the mAb or antigen-binding fragment thereof is glycosylated but does not contain detectable NeuGc or α-Gal. 345. The method of any of items 336 to 344, wherein the mAb or antigen-binding fragment thereof contains tyrosine sulfation. 346. The method according to any of items 336 to 345, wherein the recombinant expression vector is AAV8 or AAV9. 347. The method of any of items 336 to 346, wherein production of the HuPTM form of the mAb or antigen-binding fragment thereof is confirmed by transducing the recombinant nucleotide expression vector into cultured human CNS cells and expressing the mAb or antigen-binding fragment thereof. AAV embodiments encoding full-length mAb compositions 348. A composition comprising an adeno-associated virus (AAV) vector, Adeno-associated virus (AAV) vectors a. a viral AAV capsid that is optionally at least 95% identical to the amino acid sequence of an AAV8 capsid (SEQ ID NO: 143), an AAV9 capsid (SEQ ID NO: 144), an AAVrh10 capsid (SEQ ID NO: 145), an AAVrh20 capsid, an AAVrh39 capsid, or an AAVcy5 capsid; and b. An artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length mAb operably linked to one or more regulatory sequences that control expression of the transgene in a human cell. having c. The composition, wherein a transgene encodes signal sequences at the N-terminus of the heavy and light chains of the mAb that direct secretion and post-translational modification of the mAb. 349. The composition of item 348, wherein the mAb comprises a heavy chain having an Fc polypeptide and a light chain having any one of the sequence combinations specified in items 4, 13, 22, 31, 40, 49, 58, 67, 76, 85, 95, 107, 119, 131, 143, 155, 167, 179, 191, 203, 222, 231, 240, 249, 258, 270, 282, 294, 307, and 317. 350. The composition according to items 348 to 349, wherein the mAb is full-length lanadelumab. 351. The composition according to item 350, wherein the transgene comprises a Furin / T2A linker between the nucleotide sequences encoding the heavy and light chains of the mAb. 352. The composition according to items 350 to 351, wherein the regulatory sequence comprises a regulatory sequence from Table 1. 353. The composition according to item 352, wherein the regulatory sequence is a LMTP6 promoter, an ApoE.hAAT regulatory sequence, a CAG promoter, a CK8 regulatory sequence, or a TBG promoter. 354. The composition according to items 350 to 353, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 141, 286, 287, or 435 to 444. 355. The composition according to items 350 to 354, wherein the viral capsid is an AAV8 viral capsid. 356. A pharmaceutical composition for delivering lanadelumab to the bloodstream to treat hereditary angioedema in a human subject in need thereof, comprising: the composition comprises a recombinant AAV comprising a transgene encoding lanadelumab operably linked to one or more regulatory sequences controlling expression of the transgene in muscle cells and / or liver cells; The pharmaceutical composition, wherein the recombinant AAV is administered to the bloodstream of a human subject in a dose sufficient to effect expression from the transgene and secretion of lanadelumab to produce a lanadelumab plasma level in the subject of at least 5 μg / ml to at least 35 μg / ml of lanadelumab. 357. A method for treating hereditary angioedema in a human subject in need thereof, comprising: The method comprises administering to a subject a dose of a composition comprising a recombinant AAV comprising a transgene encoding lanadelumab operably linked to one or more regulatory sequences that control expression of the transgene in muscle cells and / or liver cells, in an amount sufficient to effect expression from the transgene and secretion of lanadelumab to produce a lanadelumab plasma level in the subject of at least 5 μg / ml to at least 35 μg / ml of lanadelumab. 358. The method or composition according to item 356 or 357, wherein the transgene comprises the nucleotide sequence of SEQ ID NO: 141, 286, 287, or 435 to 444. 359. The method or composition according to items 356 to 358, wherein the lanadelumab plasma level is between 20 μg / ml and 35 μg / ml. 360. The method or composition according to items 356 to 359, wherein the lanadelumab plasma levels are maintained for at least 3 months. 361. The method or composition according to items 356 to 360, wherein the lanadelumab antibody secreted into plasma exhibits at least a 40%, 45%, 50%, 55%, 60%, 65% or greater than 70% reduction in pKal activity as measured by a kinetic enzyme function assay. 362. The method or composition according to item 361, wherein the activity of the lanadelumab antibody is measured at 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks after administration. 363. A method for determining human anti-pKal antibody activity in a sample, comprising: a. incubating the sample with activated human pKal; b. subsequently incubating the sample incubated with activated human pKal with the synthetic substrate Pro-Phe-Arg-AMC; c. Measuring the release of AMC over a 3 hour period compared to a control sample The method comprising: Further embodiments 364. A pharmaceutical composition for delivering an antibody or antigen-binding fragment thereof to the bloodstream of a human subject in need thereof, comprising: (a) an AAV viral capsid that infects hepatocytes and / or muscle cells; and (b) an artificial genome comprising an expression cassette flanked by AAV ITRs (inverted terminal repeats), the expression cassette comprising a transgene, the transgene encoding a full-length antibody or antigen-binding fragment thereof operably linked to a chimeric promoter directing expression in muscle cells and hepatocytes; The AAV vector comprises The pharmaceutical composition, wherein the AAV vector is formulated for intramuscular administration. 365. The pharmaceutical composition according to item 364, wherein the chimeric promoter is 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 LMTP20 (SEQ ID NO: 326). 366. The pharmaceutical composition according to item 365, wherein the chimeric promoter is LMPT6 (sequence number 320). 367. The pharmaceutical composition according to any one of items 364 to 366, wherein the AAV viral capsid is at least 95% identical to the amino acid sequence of the AAV8 capsid (SEQ ID NO: 143), the AAV9 capsid (SEQ ID NO: 144), the AAVrh10 capsid (SEQ ID NO: 145). 368. The pharmaceutical composition according to any of items 364 to 3673, wherein the antibody is sevacizumab, LKA-651, ravulizumab, adalimumab, infliximab, golimumab, elezanumab, NI-301, PRX-004, pamrevlumab, siltuximab, clazakizumab, sirukumab, olokizumab, gerilizumab, satralizumab, sarilumab, tocilizumab, inebilizumab, etrolizumab, romosozumab, lanadelumab, benralizumab, reslizumab, tralokinumab, nemolizumab, omalizumab, or tezepelumab. 369. The pharmaceutical composition according to any of items 364 to 366, wherein the transgene comprises the nucleotide sequence SEQ ID NO: 443. [Brief description 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 (FIG. 2A), GSK933776 (FIG. 2B), and lecanemab (FIG. 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 grey. [Figure 2B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against amyloid β peptide: solanezumab Fab (FIG. 2A), GSK933776 (FIG. 2B), and lecanemab (FIG. 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 grey. [Figure 2C] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies against amyloid β peptide: solanezumab Fab (FIG. 2A), GSK933776 (FIG. 2B), and lecanemab (FIG. 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 grey. [Diagram 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 grey. [Figure 4A] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies against tau: ABBV-8E12 (FIG. 4A), UCB-0107 (FIG. 4B), and NI-105 (FIG. 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 grey. [Figure 4B] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies against tau: ABBV-8E12 (FIG. 4A), UCB-0107 (FIG. 4B), and NI-105 (FIG. 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 grey. [Figure 4C] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies against tau: ABBV-8E12 (FIG. 4A), UCB-0107 (FIG. 4B), and NI-105 (FIG. 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 grey. [Diagram 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 grey. [Figure 6A] Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 6B] Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 6C] Amino acid sequences of transgene constructs for the Fab region 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 grey. [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 grey. [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 grey. [Figure 8A] Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 8B] Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 8C] Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 9A] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-VEGF, sevacizumab (FIG. 9A); anti-EpoR, LKA-651.NVS2 (FIG. 9B), and LKA-651.NVS3 (FIG. 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 grey. [Figure 9B] Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-VEGF, sevacizumab (FIG. 9A); anti-EpoR, LKA-651.NVS2 (FIG. 9B), and LKA-651.NVS3 (FIG. 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 grey. [Figure 9C]Amino acid sequences of transgene constructs for the Fab regions of therapeutic antibodies directed against biological factors: anti-VEGF, sevacizumab (FIG. 9A); anti-EpoR, LKA-651.NVS2 (FIG. 9B), and LKA-651.NVS3 (FIG. 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 grey. [Figure 10A] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-ALK1, asclin-bacumab (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 grey. [Figure 10B] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-ALK1, asclin-bacumab (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 grey. [Figure 10C]Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-ALK1, asclin-bacumab (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 grey. [Figure 10D] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-ALK1, asclin-bacumab (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 grey. [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. Glutamine glycosylation sites; asparagine (N) glycosylation sites; non-consensus asparagine (N) glycosylation sites; and tyrosine-O-sulfation sites (in italics) are indicated in the legend. The hinge region is highlighted in grey. [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 grey. [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 grey. [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 grey. [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 grey. [Figure 14A]Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 14B] Amino acid sequences of transgene constructs for the Fab region 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 grey. [Figure 15] Amino acid sequence of the transgene construct for the Fab region of pamrevlumab, a therapeutic antibody against CTGF. 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 grey. [Figure 16A]Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16B] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16C]Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16D] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16E]Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16F] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16G]Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16H] Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 16I]Amino acid sequences of transgene constructs for the Fab region of therapeutic antibodies directed against biological agents: anti-IL6R, satralizumab (Figure 16A), sarilumab (Figure 16B), tocilizumab (Figure 16H); anti-IL6, siltuximab (Figure 16C), clazakizumab (Figure 16D), sirukumab (Figure 16E), olokizumab (Figure 16F), gerilimuzumab (Figure 16G), and anti-CD19, inebilizumab (Figure 16I). 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 grey. [Figure 17] 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 grey. [Figure 18] 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 grey. [Figure 19] 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 grey. [Figure 20A]

[0046] Figure 20A shows heavy chain Fab portions (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 1-228 of SEQ ID NO:28, residues 1-228 of SEQ ID NO:30, residues 1-228 of SEQ ID NO:31, residues 1-228 of SEQ ID NO:32, residues 1-228 of SEQ ID NO:33, residues 1-228 of SEQ ID NO:34, residues 1-230 of SEQ ID NO:40, residues 1-234 of SEQ ID NO:41, residues 1-231 of SEQ ID NO:42, residues 1-219 of SEQ ID NO:43, residues 1-227 of SEQ ID NO:44, residues 1-227 of SEQ ID NO:45, residues 1-227 of SEQ ID NO:46, residues 1-227 of SEQ ID NO:47, residues 1-227 of SEQ ID 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:370 373, 374, and 375, respectively).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 that are hyperglycosylated on the Fab domain of the full-length antibody). [Figure 20B]

[0046] Figure 20A shows heavy chain Fab portions (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 1-228 of SEQ ID NO:28, residues 1-228 of SEQ ID NO:30, residues 1-228 of SEQ ID NO:31, residues 1-228 of SEQ ID NO:32, residues 1-228 of SEQ ID NO:33, residues 1-228 of SEQ ID NO:34, residues 1-230 of SEQ ID NO:40, residues 1-234 of SEQ ID NO:41, residues 1-231 of SEQ ID NO:42, residues 1-219 of SEQ ID NO:43, residues 1-227 of SEQ ID NO:44, residues 1-227 of SEQ ID NO:45, residues 1-227 of SEQ ID NO:46, residues 1-227 of SEQ ID NO:47, residues 1-227 of SEQ ID 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:370 373, 374, and 375, respectively).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 that are hyperglycosylated on the Fab domain of the full-length antibody). [Figure 21] Multiple sequence alignment by Clustal for AAV capsids 1-9. Amino acid substitutions (shown in bold on the lower line) can be made to AAV9 and AAV8 capsids by "recruiting" amino acid residues from the corresponding positions of other aligned AAV capsids. Sequences shown in grey = hypervariable regions. Amino acid sequences of AAV capsids are assigned SEQ ID NO: 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 2 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 from residue 219 to residue 230 of the heavy chain 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 following transfection of different plasmid amounts (4 μg to non-transfected). The bottom left panel shows lanadelumab expression in cell lysates, while the bottom right panel detects plasmid that expressed lanadelumab secreted into the cell supernatant. [Figure 24C] Transfection titration comparing CAG.L02 and CAG.L03 proviral plasmid constructs. Panels show different exposure lengths (30 or 60 seconds) of expressed lanadelumab from CAG.L02 or CAG.L03 constructs secreted into cell supernatants. [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). [Diagram 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] Shown is the time course of antibody expression (lanadelumab serum levels) in NSG mice (n=5 / group) following 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 monoclonal antibody lanadelumab (Mab1) in C2C12 muscle cells upon transduction of 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]Serum expression levels of lanadelumab (μg / ml) upon intravenous injection of 2.5×1012 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). CAG (SEQ ID NO: 411) and TBG (SEQ ID NO: 423) promoters were used as controls. Data from blood draws 1, 3, 5 and 7 weeks after injection are shown. 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 liver. C57Bl / 6 mice were intravenously administered AAV8 vectors driven by different liver-specific promoters at equivalent doses (2.5x1012vg / kg). N=5 mice / group. Vector DNA was analyzed by ddPCR in mouse liver samples collected 49 days after vector administration. Data represent mean + SEM. [Figure 28B]Serum expression levels of lanadelumab (μg / ml) upon intravenous injection of 2.5×1012 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). CAG (SEQ ID NO: 411) and TBG (SEQ ID NO: 423) promoters were used as controls. Data from blood draws 1, 3, 5 and 7 weeks after injection are shown. 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 liver. C57Bl / 6 mice were intravenously administered AAV8 vectors driven by different liver-specific promoters at equivalent doses (2.5x1012vg / kg). N=5 mice / group. Vector DNA was analyzed by ddPCR in mouse liver samples collected 49 days after vector administration. Data represent mean + SEM. [Figure 29A] Amino acid sequences of transgene constructs for the Fab region 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. 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 grey. [Figure 29B]Amino acid sequences of transgene constructs for the Fab region 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. 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 grey. [Figure 29C] Amino acid sequences of transgene constructs for the Fab region 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. 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 grey. [Figure 29D] Amino acid sequences of transgene constructs for the Fab region 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. 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 grey. [Figure 29E]Amino acid sequences of transgene constructs for the Fab region 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. 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 grey. [Figure 29F] Amino acid sequences of transgene constructs for the Fab region 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. 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 grey. [Figure 30A] Route of administration and dose selection in Wistar rats. AAV8 vectors encoding vectorized lanadelumab driven by the CAG promoter were injected intramuscularly at 1x1013vg / kg body weight or intravenously at 1x1013vg / kg and 1x1014vg / kg into SD rats. Protein expression was quantified by ELISA from serum collected every 3-7 days. N=3 rats / vector. Data represent mean+SEM. * indicates p<0.05 by Welch's t-test, ** indicates p<0.01 by Welch's t-test. [Figure 30B]AAV8 vectors encoding vectorized lanadelumab driven by the CAG (SEQ ID NO: 411) or ApoE.hAAT (SEQ ID NO: 412) promoter were injected intravenously at 5x1013vg / 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 following AAV8 delivery. Animals received bilateral injections of 5x1010vg / 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 after Tukey's HSD post-hoc test. *P<0.05, **P<0.01. [Diagram 32] Antibody concentrations in 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 vectors at a dose of 2.5x1012vg / kg. [Figure 33A] The pKal titration curve and the signal to noise ratio for the indicated pKal concentrations are shown. [Figure 33B] The pKal titration curve and the 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 inhibition of lanadelumab (compared to a non-specific human IgG control antibody) in the antibody-dose response. C57BL / 6 mice (n=5) were administered 5x1010 vector genomes (vg) (2.5x1012 vg / kg) of ApoE.hAAT.L02.AAV8 intravenously 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, with significantly lower activity 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, with significantly lower activity 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 compilations of 2-5 mice / group. Student's t-test was used to determine significant differences (paired, two-tailed). Here, *p<0.05, **p<0.01, ***p<0.001. [Figure 34A] Quantification of mouse paw volume and paw swelling in carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. 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 carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. 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 carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Fig. 34D] Quantification of mouse paw volume and paw swelling in carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. 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 carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Fig. 34F] Quantification of mouse paw volume and paw swelling in carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. 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 carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Fig. 34H] Quantification of mouse paw volume and paw swelling in carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Fig. 34I] Quantification of mouse paw volume and paw swelling in carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Fig. 34J] Quantification of mouse paw volume and paw swelling in carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. 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 carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. 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 carrageenan-induced paw edema mice treated with test articles. 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 in paw volumes measured at each time point and at baseline. N=10 mice / group. Data analysis was performed by one-way ANOVA with Dunnett's post-hoc test for multiple comparisons. Data represent the mean + S.DEM. P values: *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001. [Diagram 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. [Diagram 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 the respective cis-plasmid. (B) Human TNFα binding ELISA from cells transfected with the cis-plasmid. pAAV.CAG.lanadelumab.IgG was used as a non-specific 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) following 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 supernatants from non-transfected cells. Vectored lanadelumab (pAAV.CAG.lanadelumab.IgG) served as a non-specific antibody control. Data are presented as mean ± SEM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] 5. Detailed Description of the Invention Compositions and methods are described for the delivery of a fully human post-translationally modified (HuPTM) therapeutic monoclonal antibody (mAb), or a HuPTM antigen-binding fragment of a therapeutic mAb (e.g., a fully human glycosylated Fab (HuGlyFab) of a therapeutic mAb), to a patient (human subject) diagnosed with a disease or condition for which treatment with the therapeutic mAb is indicated. Delivery may be advantageously achieved via gene therapy, e.g., by administering a viral vector or other DNA expression construct encoding the therapeutic mAb or its antigen-binding fragment (or any hyperglycosylated derivative) to a patient (human subject) diagnosed with a condition for which treatment with the therapeutic mAb is indicated, to create a permanent depot within the patient's tissue or organ that continuously supplies the HuPTM mAb or antigen-binding fragment of the therapeutic mAb, e.g., a human glycosylated transgene product, to the target tissue where the mAb or its antigen-binding fragment exerts its therapeutic effect.

[0019] The HuPTM mAb or HuPTM antigen-binding fragment encoded by the transgene can be Nervous system targets, including amyloid beta (Aβ or Abeta) peptide, sortilin, tau protein, SEMA4D, α-synuclein, and CGRP receptors; Ocular targets, including VEGF, EpoR, ALK1, endoglin, complement component 5, and complement component 1Q Repulsive Guidance Molecule-A Transthyretin Connective tissue growth factor Neuromyelitis Optica (NMO) / Non-infectious Uveitis targets and immune response targets, including Interleukin 6 Receptor, Interleukin 6, and CD19 Integrin β7 Sclerostin TNF-α, and Plasma protein targets such as human complement proteins, including plasma kallikrein; Autoimmune, respiratory, and allergic disease targets such as interleukins and interleukin receptors, including IL5, IL5R, IL13, and IL31RA, immunoglobulin E, and thymic stromal lymphopoietin The antigen-binding fragments may include, but are not limited to, full length therapeutic antibodies or antigen-binding fragments thereof that bind to, or such mAbs or antigen-binding fragments that have been engineered to contain additional glycosylation sites on the Fab domain (see, e.g., Courtois et al., 2016, mAb8:99-112, which is incorporated by reference in its entirety for its description of antibody derivatives that are hyperglycosylated on the Fab domain of the full length antibody). The amino acid sequences of the heavy and light chains of the antigen-binding fragments described above are provided in Table 5 below, and the nucleotide sequences, including codon-optimized versions, encoding the heavy and light chains of the antigen-binding fragments are provided in Table 6.

[0020] Recombinant vectors used to deliver transgenes include non-replicating recombinant adeno-associated virus vectors ("rAAV"). rAAV is a particularly attractive vector for many reasons: rAAV can transduce non-replicating cells and therefore can be used to deliver transgenes to tissues where cell division occurs at low levels, such as the CNS; rAAV can be modified to preferentially target selected specific organs; and there are hundreds of capsid serotypes to choose from to obtain desired tissue specificity and / or to avoid neutralization by pre-existing patient antibodies against some AAVs. Such rAAVs include, but are not limited to, AAV-based vectors that include capsid components from one or more of AAV1, AAV2, AAV2.m78, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAVrhlO, or AAVrhl20. In certain embodiments, the AAV-based vectors presented herein comprise capsids derived from one or more of the following serotypes: AAV8, AAV9, AAV10, AAV11, AAVrhlO, or AAVrh20.

[0021] However, other viral vectors can also be used, including, but not limited to, lentiviral vectors, vaccinia viral vectors, or non-viral expression vectors referred to as "naked DNA" constructs. Expression of the transgene can be controlled by constitutive or tissue-specific expression control elements.

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

[0023] In certain embodiments, the nucleic acids (e.g., polynucleotides) and nucleic acid sequences disclosed herein can be codon-optimized, e.g., via any codon optimization method known to those of skill in the art (see, e.g., review by Quax et al., 2015, Mol Cell 59:149-161), and can also be optimized to reduce CpG dimers. Codon-optimized nucleotide sequences of therapeutic antibody heavy and light chain variable domains are disclosed in Table 6. Each heavy and light chain requires a leader to ensure proper post-translational processing and secretion (unless expressed as an scFv, in which only the N-terminal chain requires a leader sequence). Disclosed herein are leader sequences useful for expressing therapeutic antibody heavy and light chains in human cells. Exemplary recombinant expression constructs are shown in Figure 1 and Figure 24A.

[0024] The generation of HuPTM mAbs or HuPTM Fabs (including HuPTM scFvs) should result in a "bio-better" molecule for the treatment of disease achieved via gene therapy, for example, by administering a viral vector or other DNA expression construct encoding a full-length HuPTM mAb or HuPTM Fab or other antigen-binding fragment, such as full-length or HuPTM Fab, or scFv, of a therapeutic mAb to a patient (human subject) diagnosed with a disease for which the mAb is indicated, to create in the subject a permanent depot of a continuous supply of human glycosylated, sulfated transgene product produced by the subject's transduced cells. The cDNA construct for the HuPTM mAb or HuPTM Fab or HuPTM scFv should include a signal peptide that ensures proper co- and post-translational processing (glycosylation and protein sulfation) by the transduced human cells.

[0025] Pharmaceutical compositions suitable for administration to human subjects include suspensions of the recombinant vector in a formulation buffer comprising a physiologically compatible aqueous buffer, a surfactant, and optional excipients, such as a polysaccharide, a surfactant, a polymer, or an oil.

[0026] As an alternative or additional treatment to gene therapy, full-length HuPTM mAbs or HuPTM Fabs or other antigen-binding fragments thereof may be produced by recombinant DNA technology in human cell lines and the glycoproteins administered to patients. Human cell lines that may be used for such recombinant glycoprotein production include, but are not limited to, human embryonic kidney 293 cells (HEK293), fibrosarcoma HT-1080, HKB-11, CAP, HuH-7, and retinal cell lines PER.C6 or RPE, to name a few (see, e.g., Dumont et al., 2015, Crit. Rev. Biotechnol. 36(6):1110-1122, incorporated by reference in its entirety, for a review of human cell lines that may be used to recombinantly produce HuPTM Fab or HuPTM scFv products, e.g., HuPTM Fab glycoproteins). To ensure complete glycosylation, particularly sialylation, and tyrosine sulfation, cell lines used for production can be enhanced by engineering the host cells to co-express α-2,6-sialyltransferase (or both α-2,3-sialyltransferase and α-2,6-sialyltransferase), and / or the TPST-1 and TPST-2 enzymes, which are responsible for tyrosine-O-sulfation in human cells.

[0027] It is not essential that every molecule produced in a gene or protein therapy approach be fully glycosylated and sulfated. Instead, the population of glycoproteins produced should have sufficient glycosylation (including 2,6-sialylation) and sulfation to support efficacy. The goal of gene therapy treatment of the present invention is to slow or halt disease progression.

[0028] The methods of the invention encompass combination therapy involving delivery of full-length HuPTM mAb or HuPTM Fab, or antigen-binding fragments thereof, along with delivery of other available treatments to the patient. The additional treatments may be administered prior to, concurrently with, or subsequent to the gene therapy treatment. Such additional treatments may include, but are not limited to, conjoint therapy with a therapeutic mAb.

[0029] Also provided is a method for producing a viral vector, particularly an AAV-based viral vector. In a specific embodiment, a method for producing a recombinant AAV is provided, comprising culturing a host cell containing an artificial genome comprising a transgene encoding a therapeutic antibody, the transgene comprising a cis expression cassette flanked by AAV ITRs, the cis expression cassette being operably linked to an expression control element that controls the expression of the transgene in human cells; a trans expression cassette lacking AAV ITRs, the trans expression cassette encoding AAV rep and capsid proteins being operably linked to an expression control element that drives the expression of AAV rep and capsid proteins in a host cell in culture, the rep and cap proteins being provided in trans; and sufficient adenovirus helper functions to allow the AAV capsid proteins to replicate and package the artificial genome; and recovering the recombinant AAV encapsidating the artificial genome from the cell culture.

[0030] 5.1 Constructs Provided herein are viral vectors or other DNA expression constructs that encode HuPTMmAbs or antigen-binding fragments thereof, particularly hyperglycosylated derivatives of HuGlyFab or antigen-binding fragments of HuPTMmAbs. The viral vectors and other DNA expression constructs provided herein include any method suitable for delivering a transgene to a target cell. Means for delivering a 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 episomes. In some embodiments, the vector is a targeting vector, e.g., a vector targeted to retinal pigment epithelial cells, CNS cells, muscle cells, or liver cells.

[0031] In some aspects, the disclosure provides a nucleotide sequence encoding a HuPTM mAb or HuGlyFab, or other antigen-binding fragment thereof, as a transgene as described herein, where the promoter selected for expression in the tissue targeted for expression of the transgene is, for example, the CB7 / CAG promoter (SEQ ID NO: 411, FIG. 24A) and associated upstream regulatory sequences (see FIG. 1), the cytomegalovirus (CMV) promoter, the Rous sarcoma virus (RSV) promoter, the GFAP promoter (glial fibrillary acidic protein), the MBP promoter (myelin basic protein), the MMT promoter, the EF-1α promoter (SEQ ID NO: 415), mU1a (SEQ ID NO: 414), the UB6 promoter, the chicken Nucleic acids for use are provided that include a nucleotide sequence operably linked to a promoter, such as, but not limited to, an chicken beta-actin (CBA) promoter, an RPE65 promoter, and a liver-specific promoter, such as an opsin promoter, a TBG (thyroxine-binding globulin) promoter (SEQ ID NO: 423), an APOA2 promoter, a SERPINA1 (hAAT) promoter, an ApoE.hAAT (SEQ ID NO: 412), or an mIR122 promoter, or a muscle-specific promoter, such as a human desmin promoter, a CK8 promoter (SEQ ID NO: 413), or a Pitx3 promoter, an inducible promoter, such as a hypoxia-inducible promoter or a rapamycin-inducible promoter.

[0032] In some aspects herein, transgene expression is controlled by an engineered nucleic acid regulatory element having two or more regulatory elements (promoters or enhancers), including regulatory elements arranged in tandem (two or three copies) that promote liver-specific expression, or both liver-specific and muscle-specific expression, or both liver-specific and bone-specific expression. These regulatory elements include LSPX1 (SEQ ID NO: 315), LSPX2 (SEQ ID NO: 316), LTP1 (SEQ ID NO: 317), LTP2 (SEQ ID NO: 318), or LTP3 (SEQ ID NO: 319) for liver-specific 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 LMTP20 (SEQ ID NO: 326) for liver and muscle expression, or LBTP1 (SEQ ID NO: 327) or LBTP2 (SEQ ID NO: 328) for liver and bone expression, the sequences of which are presented in Table 1.

[0033] In certain embodiments, a recombinant vector is provided herein that includes one or more nucleic acids (e.g., polynucleotides). The nucleic acid may include DNA, RNA, or a combination of DNA and RNA. In certain embodiments, the DNA includes one or more sequences selected from the group consisting of a promoter sequence, a sequence of a gene of interest (a nucleotide sequence encoding the heavy and light chains of a transgene, e.g., HuPTM mAb or HuGlyFab, or other antigen-binding fragment), an untranslated region, and a termination sequence. In certain embodiments, the viral vector provided herein includes a promoter operably linked to a gene of interest.

[0034] In certain embodiments, the nucleic acids (e.g., polynucleotides) and nucleic acid sequences disclosed herein can be codon-optimized, for example, via any codon optimization method known to those of skill in the art (see, for example, the review by Quax et al., 2015, Mol Cell 59:149-161). Presented herein in Table 6 are nucleotide sequences for the heavy and light chains of HuGlyFab that are codon-optimized for expression in human cells.

[0035] In a specific embodiment, the constructs described herein contain the following components: (1) AAV2 ITRs (inverted terminal repeats) flanking the expression cassette; (2) a) one or more control elements, b) a chicken β-actin intron, and c) a rabbit β-globin polyA signal; and (3) nucleic acid sequences encoding the heavy and light chains of a mAb or Fab separated by a self-cleaving Furin (F) / F2A linker (SEQ ID NO: 231 or 429) that ensures expression of equal amounts of heavy chain with heavy chain polypeptides, and light chain polypeptides. Exemplary constructs are shown in FIG. 1.

[0036] In a specific embodiment, the constructs described herein comprise the following components: (1) AAV2 ITRs (inverted terminal repeats) flanking the expression cassette; (2) a) one or more control elements, b) a chicken β-actin intron, and c) a rabbit β-globin polyA signal; and (3) a nucleic acid sequence encoding a full-length antibody comprising heavy and light chain sequences, with sequences encoding the Fab portion of the heavy chain including a hinge region sequence plus heavy and light chain Fc polypeptides of the appropriate isotype, the heavy and light chain nucleotide sequences being separated by a self-cleaving Furin(F) / (F / T)2A linker (SEQ ID NO: 231 or 429) to ensure expression of equal amounts of heavy and light chain polypeptides. An exemplary construct is shown in FIG. 24A.

[0037] 5.1.1 mRNA vectors In certain embodiments, as an alternative to DNA vectors, vectors provided herein are modified mRNAs that encode a gene of interest (e.g., a transgene, such as a HuPTM mAb or HuGlyFab, or other antigen-binding fragment thereof). Synthesis of modified and unmodified mRNAs for delivery of transgenes to retinal pigment epithelial cells is taught, for example, in Hansson et al., J. Biol. Chem., 2015, 290(9):5661-5672, which is incorporated herein by reference in its entirety. Provided herein in certain embodiments are modified mRNAs that encode a HuPTM mAb, HuPTM Fab, or HuPTM scFv.

[0038] 5.1.2 Viral vectors Viral vectors include adenovirus, adeno-associated virus (AAV, e.g., AAV8, AAV9, AAVrhlO, 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 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 modified so that they are replication-deficient in humans. In certain embodiments, the viral vectors are hybrid vectors, e.g., AAV vectors introduced into a "helpless" adenovirus vector. In a specific embodiment of the present specification, a viral vector is provided, which comprises a viral capsid derived from a first virus and a viral envelope protein derived from a second virus.In a specific embodiment, the second virus is vesicular stomatitis virus (VSV).In a more specific embodiment, the envelope protein is VSV-G protein.

[0039] In certain embodiments, the viral vectors provided herein are HIV-based viral vectors. In certain embodiments, the HIV-based vectors provided herein comprise at least two polynucleotides, where the gag and pol genes are derived from the HIV genome and the env gene is derived from another virus.

[0040] In certain embodiments, the viral vector provided herein is a herpes simplex virus-based viral vector.In certain embodiments, the herpes simplex virus-based vector provided herein is modified so that they do not contain one or more immediate early (IE) genes and are non-cytotoxic.

[0041] In certain embodiments, the viral vector provided herein is an MLV-based viral vector.In certain embodiments, the MLV-based vector provided herein comprises up to 8 kb of heterologous DNA instead of viral genes.

[0042] In certain embodiments, the viral vector provided herein is a lentivirus-based viral vector. In certain embodiments, the lentivirus vector provided herein is derived from a human lentivirus. In certain embodiments, the lentivirus vector provided herein is derived from a non-human lentivirus. In certain embodiments, the lentivirus vector provided herein is packaged into a lentivirus capsid. In certain embodiments, the lentivirus vector provided herein comprises one or more of the following elements: long terminal repeat (LTR), primer binding site, polypurine tract, att site, and encapsidation site.

[0043] In certain embodiments, the viral vectors provided herein are alphavirus-based viral vectors. In certain embodiments, the alphavirus vectors provided herein are recombinant, replication-defective alphaviruses. In certain embodiments, the alphavirus replicons within the alphavirus vectors provided herein are targeted to specific cell types by displaying functional heterologous ligands on their virion surface.

[0044] In certain embodiments, the viral vectors provided herein are AAV-based viral vectors. In certain embodiments, the AAV-based vectors provided herein do not encode the AAV rep gene (required for replication) and / or the AAV cap gene (required for the synthesis of capsid protein) (rep and cap proteins can be provided in trans by packaging cells). Multiple AAV serotypes have been identified. In certain embodiments, the AAV-based vectors provided herein comprise components derived from one or more serotypes of AAV. In certain embodiments, the AAV-based vectors provided herein comprise capsid components derived from one or more of AAV1 (SEQ ID NO:274), AAV2 (SEQ ID NO:275), AAV2.7m8 (SEQ ID NO:142), AAV3 (SEQ ID NO:276), AAV4 (SEQ ID NO:277), AAV5, AAV6 (SEQ ID NO:279), AAV7 (SEQ ID NO:280), AAV8 (SEQ ID NO:143), AAV9 (SEQ ID NO:144), AAV10, AAV11, or AAVrhlO (SEQ ID NO:145). In certain embodiments, the AAV-based vectors provided herein comprise components derived from one or more of the AAV8, AAV9, AAV10, AAV11, or AAVrhlO serotypes. Viral vectors are provided in which the capsid protein is a mutant AAV8 capsid protein (SEQ ID NO: 143), AAV9 capsid protein (SEQ ID NO: 144), or AAVrh10 capsid protein (SEQ ID NO: 145), wherein the capsid protein is at least 95%, 96%, 97%, 98%, 99%, or 99.9% identical to the amino acid sequence of the AAV8 capsid protein (SEQ ID NO: 143), AAV9 capsid protein (SEQ ID NO: 144), or AAVrh10 capsid protein (SEQ ID NO: 145), e.g., while retaining the biological function of the native capsid.In certain embodiments, the encoded AAV capsid has a sequence of SEQ ID NO: 143, 144, or 145 with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acid substitutions and retains the biological function of an AAV8, AAV9, or AAVrhlO capsid. Figure 21 provides a comparative alignment of the amino acid sequences of capsid proteins of different AAV serotypes with potential amino acids that may be substituted at certain positions within the aligned sequences based on comparisons in the SUBS denoted rows. Thus, in a specific embodiment, the AAV vector comprises a capsid mutant of AAV8, AAV9, or AAVrhlO having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acid substitutions not present at this position in the native AAV capsid sequence identified in the SUBS line of Figure 21. The sequence for AAVrhlO is presented in Figure 21.

[0045] In some embodiments, the AAV-based vector comprises components from one or more serotypes of AAV. In some embodiments, the AAV-based vectors provided herein are selected from the group consisting of 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.Anc80, AAV.Anc80L65, AAV.7m8, AAVPHP.B, AAV.PHP. eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAVHSC1, AAVHSC2, AAVHSC3, AAV.HSC4, AAV.HSC5, AAV.HSC6, AAV.HSC7, AAV.HSC8, AAV.HSC9, AAV.HSC10, AAVHSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, or AAV.HSC16, or other rAAV particles, or a combination of two or more thereof. In some embodiments, the AAV-based vectors provided herein are selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rhlO, AAV.rh20, AAV.rh39, AAV.Rh74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, AAV.Anc80L65, 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.HSCll, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, or AAV.HSC16, or other rAAV particles, or components from a combination of two or more of these serotypes.In some embodiments, the rAAV particles are AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AA V11, AAV12, AAV13, AAV14, AAV15, AAV16, AAV.rh8, AAV.rhlO, AAV.rh20, AAV.rh39, AAV.R h74, AAV.RHM4-1, AAV.hu37, AAV.Anc80, rAAV.Anc80L65, AAV.7m8, AAVPHP.B, AAV.PHP. eB, AAV2.5, AAV2tYF, AAV3B, AAV.LK03, AAV.HSC1, AAV.HSC2, AAV.HSC3, AAV.HSC4, AAV.H AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, or AAV.HSC16, or a derivative, modification, or pseudotype thereof, or a capsid protein that is at least 80% or more identical, 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, to, for example, the VP1, VP2, and / or VP3 sequences of an AAV capsid serotype selected from AAV.HSC10, AAV.HSC11, AAV.HSC12, AAV.HSC13, AAV.HSC14, AAV.HSC15, or AAV.HSC16, or a derivative, modification, or pseudotype thereof.

[0046] In certain embodiments, the AAV used in the compositions and methods described herein is Anc80 or Anc80L65, as described in Zinn et al., 2015, Cell Rep. 12(6):1056-1068, which are incorporated by reference in their entireties. In certain embodiments, the recombinant AAV used in the methods described herein is AAV.7m8 (including variants thereof), as described in US9,193,956; US9,458,517; US9,587,282; US2016 / 0376323, and WO2018 / 075798, each of which is incorporated by reference in its entirety. In certain embodiments, the AAV used in the methods described herein is any AAV disclosed in US9,585,971, such as AAV-PHP.B. In certain embodiments, the AAV used in the compositions and methods described herein is an AAV2 / Rec2 vector or an AAV2 / Rec3 vector, which has a hybrid capsid sequence derived from the AAV8 capsid and the capsid of serotypes cy5, rh20, or rh39, as described in CharbelIssa et al., 2013, PLoSOne 8(4):e60361, which are incorporated herein by reference for these vectors. In certain embodiments, the AAV used in the methods described herein is described in any of the following patents and patent applications, each of which is incorporated herein by reference in its entirety: US 7,282,199; US 7,906,111; US ​​8,524,446; US 8,999,678; US 8,628,966; US 8,927,514; US 8,734,809; US 9,284,357; US 9,409,953; US 9,169 ,299; US9,193,956; US9,458,517; and US9,587,282; US2015 / 0374803; US2015 / 0126588; US2017 / 0067908; US2013 / 0224836; US2016 / 0215024; US2017 / 0051257; and PCT / US2015 / 034799; PCT / EP2015 / 053335.In some embodiments, the rAAV particles are disclosed in any of the following patents and patent applications, each of which is incorporated by reference in its entirety herein: U.S. Patent Nos. 7,906,111; 8,524,446; 8,999,678; 8,628,966; 8,927,514; 8,734,809; U.S. Patent Nos. 9,284,357; 9,409,953; 9,169,299; 9,193,956; 9,458,517; and 9,587,282; U.S. Patent Application Publication Nos. 2015 / 0374803; 2015 / 012658; No. 8, No. 2017 / 0067908, No. 2013 / 0224836, No. 2016 / 0215024, No. 2017 / 0051257, and International Patent Application Nos. PCT / US2015 / 034799 and PCT / EP2015 / 053335, and have a capsid protein that is at least 80% or more identical, 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, to the AAV capsid disclosed in any of the AAV capsids disclosed in PCT International Patent Application Nos. PCT / US2015 / 034799 and PCT / EP2015 / 053335.

[0047] In some embodiments, the rAAV particles comprise any AAV capsid, such as AAV.Rh74 and RHM4-1, disclosed in U.S. Pat. No. 9,840,719 and WO 2015 / 013313, each of which is incorporated herein by reference in its entirety. In some embodiments, the rAAV particles comprise any AAV capsid, such as AAV rh.74, disclosed in WO 2014 / 172669, each of which is incorporated herein by reference in its entirety. In some embodiments, the rAAV particles comprise an AAV2 / 5 capsid, described in Georgiadis et al., 2016, Gene Therapy 23:857-862 and Georgiadis et al., 2018, Gene Therapy 25:450, each of which is incorporated herein by reference in its entirety. In some embodiments, the rAAV particles comprise any AAV capsid, such as AAV2tYF, disclosed in WO2017 / 070491, which is incorporated by reference in its entirety. In some embodiments, the rAAV particles comprise the capsid of AAVLK03 or AAV3B, as described in Puzzo et al., 2017, Sci. Transl. Med. 29(9):418, which is incorporated by reference in its entirety. In some embodiments, the rAAV particles comprise any AAV capsid, such as HSC1, HSC2, HSC3, HSC4, HSC5, HSC6, HSC7, HSC8, HSC9, HSC10, HSC11, HSC12, HSC13, HSC14, HSC15, or HSC16, disclosed in U.S. Pat. Nos. 8,628,966; 8,927,514; 9,923,120, and WO2016 / 049230, each of which is incorporated by reference in its entirety herein.

[0048] In some embodiments, the rAAV particles are prepared using methods described in International Application Publication Nos. WO2003 / 052051 (see, e.g., SEQ ID NO: 2 of the '051 publication), WO2005 / 033321 (see, e.g., 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), WO2006 / 068888 (see, e.g., SEQ ID NOs: 1 and 3-6 of the '888 publication), WO2006 / 11068, the contents of each of which are incorporated herein by reference in their entireties. No. 9, (see, e.g., SEQ ID NOS: 5-38 of the '689 publication), WO 2009 / 104964 (see, e.g., SEQ ID NOS: 1-5, 7, 9, 20, 22, 24, and 31 of the '964 publication), WO 2010 / 127097 (see, e.g., SEQ ID NOS: 5-38 of the '097 publication), and WO 2015 / 191508 (see, e.g., SEQ ID NOS: 80-294 of the '508 publication), and U.S. Application Publication No. 20150023924 (see, e.g., SEQ ID NOS: 1, 5-10 of the '924 publication).In some embodiments, the rAAV particles are synthesized using methods described in International Application Publication Nos. WO 2003 / 052051 (see, e.g., SEQ ID NO: 2 of the '051 publication), WO 2005 / 033321 (see, e.g., SEQ ID NOs: 123 and 88 of the '321 publication), WO 03 / 042397 (see, e.g., SEQ ID NOs: 2, 81, 85, and 97 of the '397 publication), WO 2006 / 068888 (see, e.g., SEQ ID NOs: 1 and 3-6 of the '888 publication), WO 2006 / 110689 (see, e.g., SEQ ID NOs: 5-38 of the '689 publication), and WO 2009 / 104964 (see, e.g., SEQ ID NOs: 1-5, 7, 9, 20, 22, 24, and 31 of the '964 publication). ), WO2010 / 127097 (see, e.g., 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. Application Publication No. 20150023924 (see, e.g., SEQ ID NOS:1, 5-10 of the '924 publication), and have capsid proteins that are at least 80% or more identical, 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, to the VP1, VP2, and / or VP3 sequences of the AAV capsids disclosed in

[0049] In further embodiments, the rAAV particles comprise a pseudotyped AAV capsid. In some embodiments, the pseudotyped AAV capsid is a rAAV2 / 8 or rAAV2 / 9 pseudotyped AAV capsid. Methods for making and using pseudotyped rAAV particles are known in the art (see, e.g., Duan et al., J. Virol., 75:7662-7671 (2001); Halbert et al., J. Virol., 74:1524-1532 (2000); Zolotukhin et al., Methods 28:158-167 (2002); and Auricchio et al., Hum. Molec. Genet. 10:3075-3081 (2001)).

[0050] AAV8-based, AAV9-based, and AAVrhlO-based viral vectors are used in certain of the methods described herein. The nucleotide sequences of AAV-based viral vectors and the methods of making recombinant AAV and AAV capsids are taught, for example, 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 International Patent Application No. PCT / EP2014 / 076466, each of which is incorporated herein by reference in its entirety. In one aspect of the present specification, an AAV (e.g., AAV8, AAV9, or AAVrhlO)-based viral vector is provided that encodes a transgene (e.g., HuPTM Fab). The amino acid sequences of AAV capsids, including AAV8, AAV9, and AAVrhlO, are provided in FIG. 21.

[0051] In certain embodiments, the above-mentioned single-stranded AAV (ssAAV) can be used. In certain embodiments, self-complementary vectors, such as scAAV, can be used (see, for example, Wu, 2007, Human Gene Therapy, 18(2): 171-82; McCarty et al, 2001, Gene Therapy, Vol 8, Number 16, Pages 1248-1254; and U.S. Patent Nos. 6,596,535; 7,125,717; and 7,456,683, each of which is incorporated herein by reference in its entirety).

[0052] In certain embodiments, the viral vector used in the methods described herein is an adenovirus-based viral vector. Recombinant adenovirus vectors can be used to introduce transgenes encoding HuPTMmAb or HuGlyFab or antigen-binding fragments. The recombinant adenovirus can be a first generation vector with E1 deleted, E3 deleted or not deleted, and an expression cassette inserted into either deleted region. The recombinant adenovirus can be a second generation vector containing complete or partial deletion of E2 and E4 regions. Helper-dependent adenoviruses retain only the adenovirus ITR (inverted terminal repeat) and packaging signal (phi). The transgene is inserted between the packaging signal and the 3'ITR, with or without an encapsulation sequence, which keeps the genome close to the wild-type size of about 36 kb. Exemplary protocols for producing adenoviral vectors can be found in Alba et al., 2005, "Gutless adenovirus: last generation adenovirus for gene therapy," Gene Therapy 12:S18-S27, which is incorporated by reference in its entirety.

[0053] In certain embodiments, the viral vector used in the methods described herein is a lentivirus-based viral vector. The recombinant lentivirus vector can be used to introduce a transgene encoding an antigen-binding fragment of the HuPTM mAb. The construct is made using four plasmids: a plasmid containing the Gag / pol sequence, a plasmid containing the Rev sequence, a plasmid containing the envelope protein (i.e., VSV-G), and a cis plasmid with packaging elements and the anti-VEGF antigen-binding fragment gene.

[0054] To generate lentiviral vectors, cells (i.e., HEK293-based cells) are co-transfected with the four plasmids, where polyethyleneimine or calcium phosphate, among others, can be used as transfection agents. The lentivirus is then harvested in the supernatant (cells do not need / should not be harvested, since lentivirus needs to bud from cells to be active). The supernatant is filtered (0.45 μm), and then magnesium chloride and benzonase are added. Further downstream steps can vary widely, but the most GMP-compatible steps are those using TFF and column chromatography. Other steps use ultracentrifugation with / without column chromatography. Exemplary protocols for producing lentiviral vectors can be found in Lesch et al., 2011, "Production and purification of lentiviral vector generated in 293T suspension cells with baculoviral vectors," Gene Therapy 18:531-538; and Ausubel et al., 2012, "Production of CGMP-Grade Lentiviral Vectors," Bioprocess Int. 10(2):32-43, both of which are incorporated by reference in their entireties.

[0055] In a specific embodiment, a vector for use in the methods described herein is a vector that encodes an antigen-binding fragment of a HuPTM mAb, such as a HuGlyFab, such that, upon introduction of the vector into a participating cell, the antigen-binding fragment of the HuPTM mAb or a glycosylation variant and / or a tyrosine sulfate variant of the HuGlyFab is expressed by the cell.

[0056] 5.1.3 Promoters and Modifiers of Gene Expression In certain embodiments, the vectors provided herein include components that modulate gene delivery or gene expression (e.g., "expression control elements"). In certain embodiments, the vectors provided herein include components that modulate gene expression. In certain embodiments, the vectors provided herein include components that affect cell binding or targeting. In certain embodiments, the vectors provided herein include components that affect intracellular localization of a polynucleotide (e.g., a transgene) after uptake. In certain embodiments, the vectors provided herein include components that can be used as detection or selection markers, for example, to detect or select cells that have taken up a polynucleotide.

[0057] In certain embodiments, the viral vectors provided herein comprise one or more promoters that control expression of a transgene. In certain embodiments, the promoter is a constitutive promoter. In certain embodiments, the promoter is a CB7 promoter (also referred to as a CAG promoter) (see Dinculescu et al., 2005, Hum Gene Ther 16:649-663, incorporated herein by reference in its entirety). In some embodiments, the CAG or CB7 promoter (SEQ ID NO: 411) comprises other expression control elements that enhance expression of the vector-driven transgene. In certain embodiments, the other expression control elements comprise a chicken β-actin intron and / or a rabbit β-globin polyA signal. In certain embodiments, the promoter comprises a TATA box. In certain embodiments, the promoter comprises one or more elements. In certain embodiments, one or more promoter elements can be inverted or moved relative to each other. In certain embodiments, the elements of the promoter are arranged to function coordinately. In certain embodiments, the elements of the promoter are arranged to function independently. In certain embodiments, the viral vectors provided herein comprise one or more promoters selected from the group consisting of human CMV immediate early gene promoter, SV40 early promoter, Rous sarcoma virus (RS) LTR (long terminal repeat), and rat insulin promoter. In certain embodiments, the vectors provided herein comprise one or more LTR (long terminal repeat) promoters selected from the group consisting of AAV, MLV, MMTV, SV40, RSV, HIV-1, and HIV-2 LTR. In certain embodiments, the vectors provided herein comprise one or more tissue-specific promoters (e.g., retinal pigment epithelial cell-specific promoter, CNS-specific promoter, liver-specific promoter, or muscle-specific promoter).In certain embodiments, the viral vectors provided herein comprise RPE65 promoter or opsin promoter (retinal cell-specific promoter / CNS-specific promoter).In certain embodiments, the viral vectors provided herein comprise hepatocyte-specific promoters, such as TBG (thyroxine-binding globulin) promoter, APOA2 promoter, SERPINA1 (hAAT) promoter, or MIR122 promoter. In certain embodiments, the viral vectors provided herein comprise a muscle-specific promoter, such as the human desmin promoter (Jonuschies et al., 2014, Curr. Gene Ther. 14:276-288), the CK8 promoter (SEQ ID NO: 413; Himeda et al., 2011 Muscle Gene Therapy: Methods and Protocols, Methods in Molecular Biology, Dongsheng Duan (ed.), 709:3-19; SEQ ID NO: 413), or the Pitx3 promoter (Coulon et al., 2007, JBC 282:33192). In other embodiments, the viral vector comprises a VMD2 promoter. In certain embodiments, the viral vectors provided herein comprise synthetic and tandem promoters, such as those listed in Table 1 below.

[0058] In certain embodiments, the promoter is an inducible promoter. In certain embodiments, the promoter is a hypoxia-inducible promoter. In certain embodiments, the promoter comprises 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. In certain embodiments, the HIF binding site comprises an RCGTG motif. For details regarding the location and sequence of HIF binding sites, see, for example, Schodel, et al., Blood, 2011, 117(23):e207-e217, which is incorporated herein by reference in its entirety. In certain embodiments, the promoter comprises a binding site for a hypoxia-inducible transcription factor other than the HIF transcription factor. In certain embodiments, the viral vectors presented herein comprise one or more IRES sites that are preferentially translated in hypoxic conditions. For teachings regarding hypoxia-inducible gene expression and factors involved therein, see, e.g., Kenneth and Rocha, Biochem J., 2008, 414:19-29, which is incorporated by reference in its entirety. In specific embodiments, the hypoxia-inducible promoter is the human N-WASP promoter (see, e.g., Salvi, 2017, Biochemistry and Biophysics Reports 9:13-21, which is incorporated by reference for teachings of the N-WASP promoter), or the hypoxia-inducible promoter of human Epo (see Tsuchiya et al., 1993, J. Biochem. 113:395-400, which is incorporated by reference for disclosure of the Epo hypoxia-inducible promoter). In other embodiments, the promoter is a drug-inducible promoter, e.g., a promoter induced by administration of rapamycin or an analog thereof.For disclosure of drug-inducible promoters, see, e.g., PCT Publication Nos. WO94 / 18317, WO96 / 20951, WO96 / 41865, WO99 / 10508, WO99 / 10510, WO99 / 36553, and WO99 / 41258, which are incorporated by reference in their entireties herein, and the disclosure of rapamycin-inducible promoters in US 7,067,526.

[0059] Constructs containing certain ubiquitous and tissue-specific promoters are provided herein. Such promoters include synthetic and tandem promoters. Examples of promoters and their nucleotide sequences are provided in Table 1 below. Table 1. Promoter and other regulatory element sequences JPEG0007672344000001.jpg219170JPEG0007672344000002.jpg245170JPEG0007672344000003.jpg139170JPEG000 7672344000004.jpg161170JPEG0007672344000005.jpg181170JPEG0007672344000006.jpg216170JPEG0007672344 000007.jpg126170JPEG0007672344000008.jpg235170JPEG0007672344000009.jpg206170JPEG0007672344000010. jpg206170JPEG0007672344000011.jpg234170JPEG0007672344000012.jpg238170JPEG0007672344000013.jpg81170

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

[0061] Provided are gene expression cassettes, and rAAVs comprising the gene expression cassettes, where expression of a transgene is controlled by an engineered nucleic acid regulatory element having two or more regulatory elements (promoters or enhancers), including regulatory elements arranged in tandem (two or three copies) that promote liver-specific expression, or both liver-specific and muscle-specific expression, or both liver-specific and bone-specific expression. These regulatory elements include LSPX1 (SEQ ID NO: 315), LSPX2 (SEQ ID NO: 316), LTP1 (SEQ ID NO: 317), LTP2 (SEQ ID NO: 318), or LTP3 (SEQ ID NO: 319) for liver-specific 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 LMTP20 (SEQ ID NO: 326) for liver and muscle expression, or LBTP1 (SEQ ID NO: 327) or LBTP2 (SEQ ID NO: 328) for liver and bone expression, the sequences of which are provided in Table 1 supra.

[0062] 5.1.4 Signal peptides In certain embodiments, the vectors provided herein include components that modulate the delivery of proteins. In certain embodiments, the viral vectors provided herein include one or more signal peptides. Signal peptides are also referred to herein as "leader sequences" or "leader peptides." In certain embodiments, the signal peptides allow the transgene product to achieve proper packaging (e.g., glycosylation) within the cell. In certain embodiments, the signal peptides allow the transgene product to achieve proper localization within the cell. In certain embodiments, the signal peptides allow the transgene product to achieve secretion from the cell.

[0063] There are two general approaches to select a signal sequence for producing a protein in the context of gene therapy or in cell culture. One approach is to use a signal peptide from a protein of the same species as the protein to be expressed. For example, a signal peptide from a human antibody can be used to express IgG in CHO cells or other cells. Another approach is to identify a signal peptide optimized for the particular host cell used for expression. Signal peptides can be exchanged between different proteins or between proteins from different organisms, but typically the signal sequence of the most abundant secreted protein of this cell type is used for protein expression. For example, the signal peptide of human albumin, the most abundant protein in plasma, was found to substantially increase the production yield of proteins in CHO cells. However, certain signal peptides may retain a function as a "post-targeting function" and exert an activity after being cleaved from the expressed protein. Thus, in a specific embodiment, the signal peptide is selected from the signal peptide of the most abundant protein secreted by the cell used for expression, avoiding the post-targeting function. In certain embodiments, signal sequences are fused to both the heavy and light chain sequences. An exemplary sequence is MYRMQLLLLIALSLALVTNS (SEQ ID NO: 161), which can be encoded by the nucleotide sequence of SEQ ID NO: 422 (see Table 2, Figures 2-19 and Figures 29A-29F). Alternatively, suitable signal sequences for expression of HuPTM mAb or HuPTM Fab or scFv in the eye (including the CNS), muscle or liver are provided in Tables 2, 3 and 4, respectively, below. JPEG0007672344000014.jpg127170JPEG0007672344000015.jpg116170JPEG0007672344000016.jpg174170

[0064] 5.1.5 Polycistronic messages: IRES and F2A linker and scFv constructs Internal ribosome entry site: A single construct can be engineered to encode both heavy and light chains separated by a cleavable linker or IRES, allowing transduced cells to express heavy and light chain polypeptides with separate heavy and light chain polypeptides. In certain embodiments, the viral vectors provided herein provide polycistronic (e.g., bicistronic) messages. For example, the viral constructs can encode heavy and light chains separated by an internal ribosome entry site (IRES) element (see, for example, Gurtu et al., 1996, Biochem. Biophys. Res. Comm. 229(1):295-8, which is incorporated herein by reference in its entirety, for an example of the use of IRES elements to create bicistronic vectors). The IRES element bypasses the ribosome scanning model and initiates translation at an internal site. The use of IRES in AAV is described, for example, in Furling et al., 2001, Gene Ther 8(11):854-73, which is incorporated herein by reference in its entirety.In certain embodiments, bicistronic message is contained in a viral vector that has restrictions on the size of the polynucleotide therein.In certain embodiments, bicistronic message is contained in an AAV virus-based vector (e.g., AAV8-based vector, AAV9-based vector, or AAVrhlO-based vector).

[0065] Furin-2A linker. In other embodiments, the viral vectors provided herein encode heavy and light chains separated by a cleavable linker, such as self-cleaving 2A and 2A-like peptides, with or without an upstream furin cleavage site, e.g., a Furin / 2A linker, such as a Furin / F2A (F / F2A) or Furin / T2A (F / T2A) linker (Fang et al., 2005, Nature Biotechnology 23:584-590, Fang, 2007, Mol Ther 15:1153-9, and Chang, J. et al, MAbs 2015, 7(2):403-412, each of which is incorporated herein by reference in its entirety). For example, a Furin / 2A linker is incorporated into the expression cassette to separate the heavy and light chain coding sequences, resulting in a vector having the structure: A construct with leader-heavy chain-furin site-2A site-leader-light chain-polyA can be generated. 2A sites or 2A-like sites, such as the F2A site containing the amino acid sequence RKRR(GSG)APVKQTLNFDLLKLAGDVESNPGP (SEQ ID NO:231) or the F2A site containing the amino acid sequence RKRR(GSG)EGRGSLLTCGDVEENPGP (SEQ ID NO:429), are self-processing, resulting in "cleavage" of the final G and P amino acid residues. Some linkers that may be used, with or without an upstream flexible Gly-Ser-Gly (GSG) linker 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: 230) (See also, e.g., Szymczak, et al., 2004, Nature Biotechnol 22(5):589-594, and Donnelly, et al., 2001, J Gen Virol, 82:1013-1025, each of which is incorporated herein by reference in its entirety.) Exemplary nucleotide sequences encoding different portions of the flexible linker are set forth in Table 1-1. JPEG0007672344000017.jpg55170

[0066] In certain embodiments, the incorporation of an additional proteolytic cleavage site, such as a furin cleavage site, into the expression construct adjacent to a self-processing cleavage site (e.g., a 2A or 2A-like sequence) provides a means for removing additional amino acids remaining after cleavage by the self-processing cleavage sequence. Without being bound to any one theory, when a ribosome encounters an F2A sequence in an open reading frame, a peptide bond is omitted, resulting in the termination of translation or the continued translation of the downstream sequence (light chain). This self-processing sequence results in a stretch of additional amino acids at the C-terminus of the heavy chain. However, these additional amino acids are then cleaved by the host cell's furin at the furin site located immediately before the 2A site and after the heavy chain sequence, and further cleaved by carboxypeptidase. The resulting heavy chain may have one, two, three or more additional amino acids included at the C-terminus, depending on the sequence of the Furin linker used and the carboxypeptidase that cleaves the linker in vivo (see, e.g., Fang et al., 17 April 2005, Nature Biotechnol. Advance Online Publication; Fang et al., 2007, Molecular Therapy 15(6):1153-1159; Luke, 2012, Innovations in Biotechnology, Ch. 8, 161-186). Furin linkers that may be used include a sequence of four basic amino acids, such as RKRR (SEQ ID NO: 222), RRRR (SEQ ID NO: 223), RRKR (SEQ ID NO: 224), or RKKR (SEQ ID NO: 225).When the linker is cleaved by a carboxypeptidase, additional amino acids may still remain, such that 0, 1, 2, 3, or 4 additional amino acids, e.g., 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), may still remain on the C-terminus of the heavy chain. In certain embodiments, one linker is cleaved by a carboxypeptidase and no additional amino acids remain. In certain embodiments, 0.5% to 1%, 1% to 2%, 5%, 10%, 15%, or 20% of the population of antibodies, e.g., antigen-binding fragments, produced by the constructs for use in the methods described herein have 1, 2, 3, or 4 amino acids remaining on the C-terminus of the heavy chain after cleavage. In certain embodiments, the Furin linker has the sequence RXK / RR, such that the additional amino acid on the C-terminus of the heavy chain is R, RX, RXK, RXR, RXKR, or RXRR, where X is any amino acid, e.g., alanine (A). In certain embodiments, no additional amino acids may remain on the C-terminus of the heavy chain.

[0067] Flexible peptide linkers: In some embodiments, a single construct can be engineered to encode both heavy and light chains (preferably heavy and light chain variable domains) separated by a flexible peptide linker, such as one encoding an scFv. The flexible peptide linker can be composed of flexible residues such as glycine and serine, allowing adjacent heavy and light chain domains to move freely relative to each other. The construct can be arranged such that the heavy chain variable domain is at the N-terminus of the scFv, followed by a linker, then the light chain variable domain. Alternatively, the construct can be arranged such that the light chain variable domain is at the N-terminus of the scFv, followed by a linker, then the heavy chain variable domain. That is, the components are NH 2 -V L -Linker-V H -COOH or NH2 -V H -Linker-V L It can be arranged as -COOH.

[0068] In certain embodiments, the expression cassettes described herein are contained within a viral vector with size constraints on the polynucleotides therein. In certain embodiments, the expression cassettes are contained within an AAV virus-based vector. Due to size constraints of certain vectors, the vectors may or may not be able to accommodate coding sequences for the complete heavy and light chains of a therapeutic antibody, but may be able to accommodate coding sequences for Fab or F(ab') 2 The coding sequences for the heavy and light chains of an antigen-binding fragment, such as the heavy and light chains of a fragment or scFv, can be accommodated. In particular, the AAV vector described herein can accommodate a transgene of about 4.7 kilobases. In a construct such as the construct in FIG. 1, which contains the CB7 promoter, chicken β-actin intron, rabbit β-globin polyA signal, and ITRs, the encoded therapeutic antibody can be about 752 amino acids. Substitution of smaller expression elements would allow the expression of larger protein products, such as full-length therapeutic antibodies.

[0069] 5.1.6 Untranslated Regions In certain embodiments, the viral vectors provided herein comprise one or more untranslated regions (UTRs), such as 3'UTR and / or 5'UTR. In certain embodiments, the UTRs are optimized for the desired level of protein expression. In certain embodiments, the UTRs are optimized for transgene mRNA half-life. In certain embodiments, the UTRs are optimized for transgene mRNA stability. In certain embodiments, the UTRs are optimized for transgene mRNA secondary structure.

[0070] 5.1.7 ITR(inverted terminal repeat) In certain embodiments, the viral vectors presented herein comprise one or more ITR (inverted terminal repeat) sequences. The ITR sequences can be used to package recombinant gene expression cassettes into the virions of the viral vector. In certain embodiments, the ITRs are derived from AAV, for example, AAV8 or AAV2 (see, for example, Yan et al., 2005, J. Virol., 79(1):364-379; U.S. Patent No. 7,282,199, U.S. Patent No. 7,790,449, U.S. Patent No. 8,318,480, U.S. Patent No. 8,962,332, and International Patent Application No. PCT / EP2014 / 076466, each of which is incorporated herein by reference in its entirety). In a preferred embodiment, the nucleotide sequence encoding the ITRs can comprise, for example, the nucleotide sequence of SEQ ID NO: 418 (5'-ITR) or 420 (3'-ITR). In certain embodiments, modified ITRs can be used to generate self-complementary vectors, e.g., scAAV (see, e.g., Wu, 2007, Human Gene Therapy, 18(2):171-82; McCarty et al, 2001, Gene Therapy, Vol 8, Number 16, Pages 1248-1254; and U.S. Patent Nos. 6,596,535; 7,125,717; and 7,456,683, each of which is incorporated herein by reference in its entirety). In a preferred embodiment, the nucleotide sequence encoding the modified ITR can include, for example, the nucleotide sequence of SEQ ID NO: 419 (5'-ITR) or 421 (3'-ITR).

[0071] 5.1.8 Transgenes The transgene can be a full-length antibody or an antigen-binding fragment thereof, such as a Fab fragment (HuGlyFab) or F(ab') based on the therapeutic antibody disclosed herein. 2or as an scFv. In a specific embodiment, the HuPTM mAb or antigen-binding fragment, in particular HuGlyFab, is engineered to contain additional glycosylation sites on the Fab domain (see, e.g., Courtois et al., 2016, mAbs 8:99-112, which is incorporated by reference in its entirety for its description of hyperglycosylation sites on the Fab domain). Figure 20 presents an alignment of the Fab heavy and Fab light chains of the therapeutic antibodies disclosed herein, highlighting in green residues that may be substituted with asparagine or, in some cases, serine, resulting in hyperglycosylation. Additionally, in the case of HuPTM mAbs that include an Fc domain, the Fc domain can be engineered to alter the glycosylation site at N297 or prevent glycosylation at that site (e.g., substitution at N297 with another amino acid and / or substitution at T297 with a residue that is not T or S to knock out the glycosylation site). Such an Fc domain is "non-glycosylated."

[0072] In certain embodiments, the transgene encodes a full-length antibody or an antigen-binding fragment thereof, with coding sequences for the heavy and light chains. Such transgenes encoding full-length antibodies include a Fab portion and an Fc region. The Fc region is further discussed in Section 5.1.9. Exemplary sequences are provided in Figure 23 and Table 7.

[0073] In some embodiments, it is advantageous to use antigen-binding fragments. Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F present the amino acid sequences of the heavy and light chains of the Fab fragments and scFvs of therapeutic antibodies (see also Table 5, which presents the amino acid sequences of the heavy and light chains of therapeutic antibodies). In some embodiments, the transgene for expression of full-length antibodies may comprise nucleotide sequences encoding the heavy and light chain sequences, using nucleotide sequences encoding the Fab portion of the heavy chain plus the Fc polypeptide of the heavy chain, including the hinge region sequence, for the appropriate isotype, and the light chain, as further described herein. Nucleotide sequences encoding the Fab fragment portions of the heavy and light chains of the therapeutic antibodies disclosed herein are presented in Table 6. Some of these nucleotide sequences are codon optimized for expression in human cells. The sequences of the lanadelumab and adalimumab encoding transgenes are presented in Tables 8 and 17, respectively. The transgenes may encode Fab fragments using nucleotide sequences encoding the sequences presented in Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F, but without the portion of the hinge region on the heavy chain that forms the interchain disulfide bond (i.e., the portion containing the sequence CPPCPA (SEQ ID NO: 232)). Heavy chain variable domain sequences that do not contain the CPPCP (SEQ ID NO: 233) sequence of the hinge region at the C-terminus do not form intrachain disulfide bonds and therefore form Fab fragments with the corresponding light chain variable domain sequences, whereas heavy chain variable domain sequences with a portion of the hinge region at the C-terminus that contains the sequence CPPCP (SEQ ID NO: 233) form intrachain disulfide bonds and therefore form Fab2 fragments.For example, in some embodiments, the transgene may encode an scFv comprising a light chain variable domain and a heavy chain variable domain (in which case the heavy chain variable domain may be at the N-terminus or C-terminus of the scFv) connected by a flexible linker between them, and may optionally further comprise an Fc polypeptide (e.g., IgG1, IgG2, IgG3, or IgG4) on the C-terminus of the heavy chain. Alternatively, in other embodiments, the transgene comprises a F(ab') comprising nucleotide sequences encoding light and heavy chain sequences including at least the sequence CPPCA (SEQ ID NO:430) of the hinge region depicted in Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F, which depict various regions of the hinge region that may be included C-terminal to the heavy chain sequence. 2 The fragment may encode a nucleotide sequence that is a C-terminus of the IgG1 isotype. Existing anti-hinge antibodies (AHA) may cause immunogenicity and reduce efficacy. Thus, in certain embodiments, for IgG1 isotypes, C-terminus with D221, or C-terminus with mutation T225L, or C-terminus with L242 may reduce binding to AHA (see, for example, Brezski, 2008, J Immunol 181:3183-92; and Kim, 2016, 8:1536-1547). For IgG2, the hinge region of IgG2 is not susceptible to enzymatic cleavage, which is required to generate endogenous AHA, so the risk of AHA is small (see, for example, Brezski, 2011, MAbs 3:558-567).

[0074] In certain embodiments, the viral vectors provided herein comprise the following elements in the following order: a) a constitutive promoter sequence or an inducible (e.g., hypoxia-inducible or rifamycin-inducible) promoter sequence or a tissue-specific promoter / regulatory region, such as one of the regulatory regions provided in Table 1, and b) a sequence encoding a transgene (e.g., HuGlyFab). In certain embodiments, the sequence encoding the transgene comprises multiple ORFs separated by an IRES element. In certain embodiments, the ORFs encode the heavy and light chain domains of HuGlyFab. In certain embodiments, the sequence encoding the transgene comprises multiple subunits within one ORF separated by an F / F2A sequence. In certain embodiments, the sequence comprising the transgene encodes the heavy and light chain domains of HuGlyFab separated by an F / F2A sequence. In certain embodiments, the sequence comprising the transgene encodes the heavy and light chain variable domains of HuGlyFab separated by a flexible peptide linker (as an scFv). In certain embodiments, the viral vectors provided herein comprise the following elements in the following order: a) a constitutive or inducible promoter sequence or a tissue-specific promoter, such as one of the promoters or regulatory regions in Table 1, and b) a sequence encoding a transgene (e.g., HuGlyFab), where the transgene comprises a nucleotide sequence encoding a signal peptide, a light chain Fab portion, and a heavy chain Fab portion, separated by an IRES element. In certain embodiments, the viral vectors provided herein comprise the following elements in the following order: a) a constitutive or hypoxia-inducible promoter sequence or a regulatory element listed in Table 1, and b) a sequence encoding a transgene, where the sequence comprises a signal peptide, a light chain sequence, and a heavy chain sequence, separated by a truncated F / F2A sequence (SEQ ID NO: 231) or F / T2A sequence (SEQ ID NO: 429) or a flexible peptide linker.

[0075] In certain embodiments, the viral vectors provided herein comprise the following elements in the following order: a) a first ITR sequence, b) a first linker sequence, c) a constitutive promoter sequence or an inducible promoter sequence or a tissue-specific promoter or a regulatory region, d) a second linker sequence, e) an intron sequence, f) a third linker sequence, g) a first UTR sequence, h) a sequence encoding a transgene (e.g., HuGlyFab), i) a second UTR sequence, j) a fourth linker sequence, k) a polyA sequence, l) a fifth linker sequence, and m) a second ITR sequence.

[0076] In certain embodiments, the viral vectors provided herein comprise the following elements in the following order: a) a first ITR sequence, b) a first linker sequence, c) a constitutive or inducible promoter sequence or a tissue-specific regulatory region, d) a second linker sequence, e) an intron sequence, f) a third linker sequence, g) a first UTR sequence, h) a sequence encoding a transgene (e.g., HuGlyFab), i) a second UTR sequence, j) a fourth linker sequence, k) a polyA sequence, l) a fifth linker sequence, and m) a second ITR sequence, where the transgene comprises a signal peptide and where the transgene encodes a light chain sequence and a heavy chain sequence separated by a truncated F / F2A sequence.

[0077] 5.1.9 Fc region modification In certain embodiments, the transgene encodes full-length or substantially full-length heavy and light chains that assemble to form a full-length or intact antibody. ("Substantially intact" or "substantially full-length" refers to a mAb having a heavy chain sequence that is at least 95% identical to a full-length heavy chain mAb amino acid sequence and a light chain sequence that is at least 95% identical to a full-length light chain mAb amino acid sequence.) Thus, the transgene includes nucleotide sequences that encode the light and heavy chains of a Fab fragment, e.g., of Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F, including the hinge region of the heavy chain and the C-terminus of the heavy chain of an Fc domain peptide that is a Fab fragment. Table 7 presents the amino acid sequences of the Fc polypeptides of some of the therapeutic antibodies described herein. Alternatively, IgG1, IgG2, or IgG4 Fc domains (sequences of which are presented in FIG. 23) may be utilized. As detailed, the transgene may comprise a nucleotide sequence encoding the Fc polypeptide of a therapeutic antibody linked to a nucleotide sequence encoding a heavy chain Fab fragment at the C-terminus of the hinge region presented in Table 6 (amino acid sequences presented in FIGS. 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F and Table 6).

[0078] The term "Fc region" refers to a dimer of two "Fc polypeptides" (or "Fc domains"), each "Fc polypeptide" comprising the heavy chain constant region of an antibody excluding the first constant region immunoglobulin domain. In some embodiments, an "Fc region" comprises two Fc polypeptides linked by one or more disulfide bonds, chemical linkers, or peptide linkers. "Fc polypeptide" refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, or the last three constant region immunoglobulin domains of IgE and IgM, and may also include some or all of the flexible hinge N-terminal to these domains. For IgG, for example, an "Fc polypeptide" comprises immunoglobulin domains Cgamma2 (Cγ2, often referred to as CH2 domain) and Cgamma3 (Cγ3, also referred to as CH3 domain), and Cgamma1 (Cγ1, Cγ2, Cγ3, Cγ4, Cγ5, Cγ6, Cγ7, Cγ8, Cγ9, Cγ10, Cγ11, Cγ12, Cγ13, Cγ14, Cγ15, Cγ16, Cγ17, Cγ18, Cγ19, Cγ20, Cγ210, Cγ22, Cγ23, Cγ24, Cγ25, Cγ26, Cγ27, Cγ28, Cγ29, Cγ30, Cγ31, Cγ32, Cγ33, Cγ34, Cγ35, Cγ36, Cγ37, Cγ38, Cγ39, Cγ310, Cγ311, Cγ312, Cγ313, Cγ32, Cγ33, Cγ34, Cγ35, Cγ36, Cγ37, Cγ38, Cγ39, Cγ39, Cγ314, Cγ315, Cγ316, Cγ317, Cγ318, Cγ319, H The boundaries of an Fc polypeptide can vary, but a human IgG heavy chain Fc polypeptide is usually defined to include residues beginning at its carboxyl terminus with T223 or C226 or P230, numbering according to the EU index of Kabat et al. (1991, NIH Publication 91-3242, National Technical Information Services, Springfield, Va.). For IgA, an Fc polypeptide includes immunoglobulin domains Calpha2 (Cα2) and Calpha3 (Cα3), and can include the lower portion of the hinge between Calpha1 (Cα1) and Cα2.

[0079] In certain embodiments, the Fc polypeptide is that of a therapeutic antibody (see Table 7) or is an Fc polypeptide corresponding to the isotype of a therapeutic antibody (isotypes are shown in Figures 2A-2C, 3, 4A-4C, 5, 6A-6C, 7A-7B, 8A-8C, 9A-9C, 10A-10D, 11, 12A-12C, 13, 14A-14B, 15, 16A-16I, 17, 18, 19, and 29A-29F). In yet other embodiments, the Fc polypeptide is an IgG Fc polypeptide. The Fc polypeptide can be from an IgG1, IgG2, or IgG4 isotype (see Figure 23 for an alignment of IgG1, IgG2, and IgG4 Fc domain sequences, numbered according to EU numbering), or can be an IgG3 Fc domain, for example, depending on the desired effector activity of the therapeutic antibody. In some embodiments, the engineered heavy chain constant region (CH) containing the Fc domain is chimeric. Thus, the chimeric CH region combines CH domains from two or more immunoglobulin isotypes and / or subtypes. For example, the chimeric (or hybrid) CH region comprises part or all of the Fc region from IgG, IgA, and / or IgM. In other examples, the chimeric CH region comprises part or all of the CH2 domain from a human IgG1, human IgG2, or human IgG4 molecule combined with part or all of the CH3 domain from a human IgG1, human IgG2, or human IgG4 molecule. In other embodiments, the chimeric CH region contains a chimeric hinge region.

[0080] In some embodiments, the recombinant vector encodes a therapeutic antibody comprising an engineered (mutant) Fc region, e.g., an engineered Fc region of an IgG constant region. Modifications to an antibody constant region, Fc region, or Fc fragment of an IgG antibody may alter one or more effector functions, such as Fc receptor binding or fetal Fc receptor (FcRn) binding, and thus half-life, CDC activity, ADCC activity, and / or ADPC activity, compared to a wild-type IgG constant region, or a corresponding antibody having an IgG heavy chain constant region without the aforementioned modification(s). Thus, in some embodiments, an antibody may be engineered to provide an antibody constant region, Fc region, or Fc fragment of an IgG antibody that exhibits altered binding to one or more Fc receptors (e.g., FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA, FcγRIIIB, FcγRIV, or FcRn receptors) (compared to a reference or wild-type constant region without the aforementioned modification(s)). In some embodiments, the antibody constant region, Fc region, or Fc fragment of an IgG antibody exhibits altered one or more effector functions, such as altered CDC, ADCC, or ADCP activity, compared to a wild-type IgG constant region, or a corresponding antibody having an IgG constant region without the aforementioned modification(s).

[0081] "Effector function" refers to a biochemical event resulting from the interaction of the Fc region of an antibody with an Fc receptor or ligand. Effector functions include FcγR-mediated effector functions, such as ADCC and ADCP, and complement-mediated effector functions, such as CDC.

[0082] "Effector cell" refers to a cell of the immune system that expresses one or more Fc receptors and mediates one or more effector functions. Effector cells include, but are not limited to, monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, and T cells, and may be from any organism, including, but not limited to, human, mouse, rat, rabbit, and monkey.

[0083] "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated reaction in which non-specific cytotoxic cells expressing FcγR recognize bound antibody on a target cell and subsequently cause lysis of the target cell.

[0084] "ADCP" or "antibody-dependent cell-mediated phagocytosis" refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0085] "CDC" or "complement dependent cytotoxicity" refers to a reaction in which one or more complement protein components recognize bound antibody on a target cell, resulting in the subsequent lysis of the target cell.

[0086] In some embodiments, modifications of the Fc domain include, but are not limited to, the following modifications and combinations thereof based on the EU numbering of the IgG constant region (see FIG. 23): 233, 234, 235, 236, 237, 238, 239, 248, 249, 250, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 297, 298, 301, 303, 305, 307, 308, 309, 311, 312, 315, 318, 320, 322, 324, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 340, 342, 344, 356, 358, 359, 360, 361, 362, 373, 375, 376, 378, 380, 382, ​​383, 384, 386, 388, 389, 398, 414, 416, 419, 428, 430, 433, 434, 435, 437, 438, and 439.

[0087] In certain embodiments, the Fc region comprises one or more amino acid additions, deletions, or substitutions of amino acid residues 251-256, 285-290, 308-314, 385-389, and 428-436 of IgG. In some embodiments, 251-256, 285-290, 308-314, 385-389, and 428-436 (Kabat EU numbering; see FIG. 23) are substituted with histidine, arginine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, or glutamine. In some embodiments, a non-histidine residue is substituted with a histidine residue. In some embodiments, a histidine residue is substituted with a non-histidine residue.

[0088] Enhanced FcRn binding by antibodies with engineered Fc results in preferential binding of the affinity-enhanced antibody to FcRn compared to antibodies with wild-type Fc, leading to a net enhanced recycling of the FcRn affinity-enhanced antibody, resulting in a further increase in antibody half-life. The enhanced recycling approach allows for more effective targeting and clearance of antigens, e.g., "high titer" circulating antigens such as C5, cytokines, or bacterial or viral antigens.

[0089] In certain embodiments, modified constant regions, Fc regions, or Fc fragments of IgG antibodies are provided that have enhanced binding to FcRn in serum compared to wild-type Fc regions (without engineered modifications). In some cases, the antibodies, e.g., IgG antibodies, are engineered to bind to FcRn at neutral pH, e.g., pH 7.4 or higher, enhancing the pH-dependence of binding to FcRn compared to wild-type Fc regions (without engineered modifications). In some cases, the antibodies, e.g., IgG antibodies, are engineered to exhibit enhanced binding (e.g., increased affinity or KD) to FcRn in endosomes (e.g., at acidic pH, e.g., pH 6.0 or lower) compared to wild-type IgG and / or reference antibody binding to FcRn at acidic pH and compared to binding to FcRn in serum (e.g., at neutral pH, e.g., pH 7.4 or higher). Antibodies are provided having engineered antibody constant regions, Fc regions or Fc fragments of an IgG antibody that exhibit improved serum or resident tissue half-life compared to a corresponding antibody having a wild-type IgG constant region or an IgG constant region without the aforementioned modification(s).

[0090] Non-limiting examples of such Fc modifications include, for example, modifications at positions 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., LN / Y / W or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T); or modifications at positions 428 and / or 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., H / F or Y); or modifications at positions 250 and / or 428; or modifications at positions 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modifications are 250Q and 428L modifications (e.g., T250Q and M428L); and 307 and / or 308 modifications (e.g., 308F or 308P) (EU numbering; see Figure 23).

[0091] In some embodiments, the Fc region can be a mutant, such as hIgG1 Fc, that includes M252 mutations, e.g., M252Y and S254T and T256E ("YTE mutations"), that exhibit enhanced affinity for human FcRn (Dall'Acqua, et al., 2002, J Immunol 169:5171-5180), and the crystal structure of this mutant antibody bound to hFcRn subsequently results in the formation of two salt bridges (Oganesyan, et al. 2014, JBC 289(11):7812-7824). Antibodies with YTE mutations have been administered to monkeys and humans with significantly improved pharmacokinetic properties (Haraya, et al., 2019, Drug Metabolism and Pharmacokinetics, 34(1):25-41).

[0092] In some embodiments, modifications to one or more amin...

Claims

1. 1. A pharmaceutical composition for treating non-infectious uveitis in a human subject in need thereof, comprising: (a) a viral capsid that is at least 95% identical to the amino acid sequence of AAV2.7m8 (SEQ ID NO: 142), an AAV8 capsid (SEQ ID NO: 143), or an AAV9 capsid (SEQ ID NO: 144); and (b) an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITRs), the expression cassette comprising a transgene, the transgene encoding a substantially full-length or full-length anti-tumor necrosis factor alpha (anti-TNFα), anti-complement component 5 (anti-C5), or anti-interleukin-6 receptor (IL-6R) monoclonal antibody (mAb), or an antigen-binding fragment thereof, the transgene being operably linked to one or more regulatory sequences that control expression of the transgene in a human retinal cell; The AAV vector comprises the transgene comprises a nucleotide sequence encoding a heavy chain and a nucleotide sequence encoding a light chain, the nucleotide sequence encoding the heavy chain and the nucleotide sequence encoding the light chain being separated by a nucleotide sequence encoding a Furin / T2A linker; The pharmaceutical composition, wherein the AAV vector is formulated for subretinal, intravitreal, intranasal, or suprachoroidal administration to the subject.

2. 2. The pharmaceutical composition of claim 1, wherein the anti-TNFα mAb is adalimumab, infliximab, or golimumab; the anti-C5 mAb is tesidolumab or ravulizumab; the anti-IL-6 mAb is siltuximab, clazakimuzumab, sirukumab, olokizumab, or gerilimuzumab; or the anti-IL-6R mAb is satralizumab, sarilumab, or tocilizumab.

3. The pharmaceutical composition of claim 2, wherein the antigen-binding fragment is Fab, F(ab') 2 , or scFv. Claim 4: A full length mAb or antigen-binding fragment comprising a heavy chain having the amino acid sequence of SEQ ID NO:45, and optionally, 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 a heavy chain having the amino acid sequence of SEQ ID NO:47, and optionally, 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 a heavy chain having 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 a light chain having the amino acid sequence of SEQ ID NO:

50. a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:39, and optionally an amino acid sequence of SEQ ID NO:301, and a light chain having an amino acid sequence of SEQ ID NO:40; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:362, and optionally an amino acid sequence of SEQ ID NO:393, and a light chain having an amino acid sequence of SEQ ID NO:363; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:331, and optionally an amino acid sequence of SEQ ID NO:355, and a light chain having an amino acid sequence of SEQ ID NO:332; an amino acid sequence of SEQ ID NO:333, and optionally an Fc polypeptide having the amino acid sequence of SEQ ID NO:

335. Optionally, 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:334; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:335 and, optionally, the amino acid sequence of SEQ ID NO:357 and a light chain having the amino acid sequence of SEQ ID NO:336; a heavy chain having an Fc polypeptide having the amino acid sequence of SEQ ID NO:337 and, optionally, the amino acid sequence of SEQ ID NO:358 and a light chain having the amino acid sequence of SEQ ID NO:338; a light chain having the amino acid sequence of SEQ ID NO:339 and the amino acid sequence of SEQ ID NO:

340.

3. The pharmaceutical composition of claim 2, comprising: a heavy chain having an amino acid sequence of SEQ ID NO:59, and optionally 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; a heavy chain having an amino acid sequence of SEQ ID NO:61, and optionally 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; and a heavy chain having an amino acid sequence of SEQ ID NO:341, and optionally 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.

5. The transgene comprises a nucleotide sequence of SEQ ID NO:115 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:116 encoding a light chain; or a nucleotide sequence of SEQ ID NO:117 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:118 encoding a light chain; a nucleotide sequence of SEQ ID NO:119 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:120 encoding a light chain; a nucleotide sequence of SEQ ID NO:109 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:110 encoding a light chain; or a nucleotide sequence of SEQ ID NO:378 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:379 encoding a light chain; a nucleotide sequence of SEQ ID NO:343 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:344 encoding a light chain; a nucleotide sequence of SEQ ID NO:345 encoding a heavy chain and a nucleotide sequence of SEQ ID NO:346 encoding a light chain.

5. The pharmaceutical composition of claim 4, comprising a nucleotide sequence of SEQ ID NO: 346 encoding the heavy chain; a nucleotide sequence of SEQ ID NO: 347 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 348 encoding the light chain; a nucleotide sequence of SEQ ID NO: 349 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 350 encoding the light chain; a nucleotide sequence of SEQ ID NO: 351 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 352 encoding the light chain; a nucleotide sequence of SEQ ID NO: 129 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 130 encoding the light chain; a nucleotide sequence of SEQ ID NO: 131 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 132 encoding the light chain; or a nucleotide sequence of SEQ ID NO: 353 encoding the heavy chain and a nucleotide sequence of SEQ ID NO: 354 encoding the light chain.

6. The pharmaceutical composition described in claim 1, wherein the transgene encodes signal sequences at the N-terminus of the heavy chain and the N-terminus of the light chain of the antibody or antigen-binding fragment, the signal sequences directing secretion and post-translational modification in the human retinal cells. [0023] The signal sequence is selected from the group consisting of MYRMQLLLLIALSLALVTNS (SEQ ID NO: 146), MNFLLSWVHWSLALLLYLHHAKWSQA (SEQ ID NO: 147), MERAAPSRRVPLPLLLLLGGLALLAAGVDA (SEQ ID NO: 148), MAPLRPLLIALLALLAWVALA (SEQ ID NO: 149), MRLLAKIICLMLWAICVA (SEQ ID NO: 150), MRLLAFLSLLALVLQETGT (SEQ ID NO: 151), MKWVTFISLLFLFSSAYS (SEQ ID NO: 152), MAFLWLSCWALLGTTF G (SEQ ID NO: 153), MYRMQLLSCIALILLALVTNS (SEQ ID NO: 154), MNLLLILTFVAAAVA (SEQ ID NO: 155), MRAWIFFLLCLAGRALA (SEQ ID NO: 156), MFSFVDLRLLLLLLAATALLTHG (SEQ ID NO: 157), MKLVFLVLLFLGALGLCLA (SEQ ID NO: 158), MGPTSGPSLLLLLLLTHLPLALG (SEQ ID NO: 159), MSLSAFTLFLALIGGTSG (SEQ ID NO: 160), MAPHRPAPALLCALSLALCALSLPVRA (SEQ ID NO: 161), 161), MWATLPLLCAGAWLLGVPVCGA (SEQ ID NO: 162), MQALVLLLCIGALLGHSSC (SEQ ID NO: 163), MQMSPALTCLVLGLALVFGEGSA (SEQ ID NO: 164), MQPSSLLPLALCLLAAPASA (SEQ ID NO: 165), MAPFEPLASGILLLLWLIAPSRA (SEQ ID NO: 166), MLRGPGPGLLLLLAVQCLGTAVPSTGAS KSKR (SEQ ID NO: 167), MWCIVLFSLLAWVYA (SEQ ID NO: 168), MNPTLILAAFCLGIASA ( SEQ ID NO: 169), MWQLWASLCCLLVLANA (SEQ ID NO: 170), MLLILLSVALLAFSSA (SEQ ID NO: 171), MWKRWLALALALVAVAWVRA (SEQ ID NO: 172), MKWVTFISLLFLFSSAYS (SEQ ID NO: 173), MPSSVSWGILLLAGLCCLVPVSLA (SEQ ID NO: 174), MKAAVLTLAVLFLTGSQA (SEQ ID NO: 175), MKLLAATVLLLTICSLEG (SEQ ID NO: 176), MDPRPALLALLALPALLLLLLLAGARA (SEQ ID NO: 177),MQRVNMIMAESPGLITICLLGYLLSAEC (SEQ ID NO: 178), MGPLMVLFCLLFLYPGLADS (SEQ ID NO: 179), MWLLVSVILISRISSVGG (SEQ ID NO: 180), MLLLFSVILISWVSTVGG (SEQ ID NO: 181), MFSMRIVCLVLSVVGTAWT (SEQ ID NO: 182), MKRMVSWSFHKLKTMKHLLLLLLCVFLVKS (SEQ ID NO: 183), MSWSLHPRNLILYFYALLFLSSTCVA (SEQ ID NO: 184), MKSLVLLLCLAQLWGCHS (SEQ ID NO: 185), MARVLGAPVALGL WSLCWSLAIA (SEQ ID NO: 186), MKLITILFLCSRLLLSLT (SEQ ID NO: 187), MSLFPSLPLLLLSMVAASYS (SEQ ID NO: 188), MEHKEVVLLLLLLFLKSGQG (SEQ ID NO: 189), MAHVRGLQLPGCLALAALCSLVHS (SEQ ID NO: 190), MISRMEKMTMMMKILIMFALGMNYWSCSG (SEQ ID NO: 191), MYSNVIGTVTSGKRKVYLLSLLLIGFWDCVTC (SEQ ID NO: 192), or MRLAVGALLVCAVLGLCLA (SEQ ID NO: 193).

8. The pharmaceutical composition described in claim 2, wherein the viral capsid is an AAV8 capsid.

9. The pharmaceutical composition of claim 2, wherein the anti-TNFα mAb is adalimumab, the heavy chain is encoded by a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO:115, SEQ ID NO:444, or SEQ ID NO:445, and the light chain is encoded by a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO:116, SEQ ID NO:448, or SEQ ID NO:

449.

10. The pharmaceutical composition described in claim 9, wherein the heavy chain, the light chain, and the Furin / T2A linker are encoded by the nucleotide sequence of SEQ ID NO:452 or SEQ ID NO:

454.

11. The pharmaceutical composition of claim 9, wherein the one or more regulatory sequences include a CAG, EF-1α, or mU1a promoter.

12. The pharmaceutical composition described in claim 9, wherein the expression cassette comprises a nucleotide sequence of SEQ ID NO:451 or SEQ ID NO:453.

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