JP-2022530006-A5 -

Dates

Publication Date

20230501

Application Date

20200424

Description

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 may be codons optimized for expression in human cells, and the number of CpG dimers in the sequence may be reduced. Accordingly, a composition is provided comprising an AAV vector expressing a transgene encoding the full-length heavy chain (including the Fc domain) and light chain of a therapeutic antibody. Methods for administration and preparation 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 complex, and primary age-related tauopathy, Huntington's disease, juvenile Huntington's disease, Parkinson's disease, synucleinopathy, ALS, migraine, or cluster headache in human subjects requiring treatment for Alzheimer's disease (AD), frontotemporal dementia (FD), tauopathy, progressive supranuclear palsy, chronic traumatic encephalopathy, Pick complex, and primary age-related tauopathy, Huntington's disease, juvenile Huntington's disease, Parkinson's disease, synucleinopathy, ALS, migraine, or cluster headache, (a) Viral capsids that are at least 95% identical in amino acid sequence to AAV8 capsid (SEQ ID NO: 143), AAV9 capsid (SEQ ID NO: 144), AAVrh10 capsid (SEQ ID NO: 145), AAVrh20 capsid, AAVrh39 capsid or AAVcy5 capsid; and (b) an artificial genome comprising an expression cassette sandwiched between AAV ITRs (inverted terminal repeats), wherein the expression cassette comprises a trans gene, the trans gene operably linked to one or more regulatory sequences that control the expression of the trans gene in human CNS cells, human hepatocytes, and/or human muscle cells, and which encodes substantially the full length or full length mAb of an anti-amyloid β (anti-Aβ), anti-soltirin, anti-tau protein (anti-tau), anti-semaphorin 4D (anti-SEMA4D), anti-α-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; It contains an adeno-associated virus (AAV) vector having 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-soltirin mAb is AL-001; the anti-tau mAb is ABBV-8E12, UCSB-0107, or NI-105 (BIIB076); the anti-SEMA4D mAb is VX15/2503; the anti-SNCA mAb is pracinezumab, 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 The pharmaceutical composition according to item 1 or 2, which is a single-chain variable domain (scFv). 4. The full-length mAb or antigen-binding fragment comprises a heavy chain having the 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 the amino acid sequence of SEQ ID NO: 2; or a heavy chain having the 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 the amino acid sequence of SEQ ID NO: 4; or a heavy chain having the 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 the amino acid sequence of SEQ ID NO: 5 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: 6; also This includes a heavy chain having the amino acid sequence of SEQ ID NO: 7, and optionally an Fc polypeptide of the 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: 8; or a heavy chain having the amino acid sequence of SEQ ID NO: 9, and optionally an Fc polypeptide of the amino acid sequence of SEQ ID NO: 292, and a light chain having the amino acid sequence of SEQ ID NO: 10; or a heavy chain having the amino acid sequence of SEQ ID NO: 11, 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: 12; or a heavy chain having the amino acid sequence of SEQ ID NO: 13, and optionally an Fc polypeptide of the IgG4 isotype (e.g., the amino acid sequence of SEQ ID NO: 285), and the amino acid sequence of SEQ ID NO: 14 A light chain h