Methods and compositions for engineering immunity
Inventors
Holmes, Michael C. • Riley, Brigit E.
Assignees
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Publication Number
US-11793888-B2
Publication Date
2023-10-24
Expiration Date
Abstract
Nucleases and methods of using these nucleases for expressing an antibody from a safe harbor locus in a secretory tissue, and clones and animals derived therefrom.
Core Innovation
The disclosed method concerns expressing an antibody that binds a protein expressed in the subject's brain through transgene integration at the endogenous albumin locus. The antibody comprises a single chain fragment variable with a C-terminal blood-brain barrier targeting motif. An isolated stem or liver cell comprises the integrated transgene, enabling the cell to produce and secrete the brain-protein-binding antibody.
The approach utilizes zinc finger nucleases targeting the endogenous albumin gene and an adeno-associated viral vector carrying the antibody-encoding transgene; [procedural detail omitted for safety]. Administering the isolated antibody-secreting cell to the subject mediates antibody production, circulating levels, and central nervous system antibody activity against brain targets such as alpha-synuclein.
Claims Coverage
The provided claims identify one independent claim comprising three inventive features directed to brain-protein-binding antibody expression and secretion using an albumin-locus-integrated cell, along with dependent refinements.
Brain-protein-binding antibody
The antibody binds a protein expressed in the subject's brain and comprises a single chain fragment variable with a C-terminal blood brain barrier targeting motif.
Albumin-locus transgene integration
An antibody-encoding transgene is integrated into an isolated stem or liver cell at the endogenous albumin gene via zinc finger nuclease targeting; [procedural detail omitted for safety].
Cell administration and antibody secretion
The isolated stem or liver cell produces and secretes the antibody, and the cell is administered to the subject to effect antibody secretion.
Dependent expression and vector refinements
Dependent claims specify expression driven by the endogenous albumin promoter, fusion proteins containing amino acids from the transgene and albumin gene, and AAV2/6 or AAV2/8 vector variants.
The independent claim covers an engineered stem or liver cell harboring an albumin-locus-integrated transgene encoding a blood-brain barrier-targeted antibody and its administration to secrete the antibody in a subject.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Expression of an antibody in a subject wherein the antibody binds a protein expressed in the brain, including cancer antigens, cellular receptors, cytokines, growth factors, growth factor receptors, kinase inhibitors, integrins, alpha-synuclein, amyloid proteins, and complement proteins.
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