ANTICOMPLEMENT ANTIBODIES AND VECTORIZED COMPLEMENT AGENTS AND THEIR ADMINISTRATION

Claims

Compositions and methods are described for the administration of a post-translationally modified, fully human therapeutic monoclonal antibody, or its antigen-binding fragment, that binds to C5, to a human subject for the treatment of an ocular indication, particularly AMD. The nucleotide sequence encoding the antibody is delivered in an rAAV vector that targets ocular tissue cells for transgene expression.

1. A recombinant adeno-associated virus (rAAV) vector comprising (a) an AAV capsid comprising viral capsid protein; wherein the viral capsid protein comprises a 7-amino-acid peptide inserted into an AAV3B or AAV8 capsid protein as the parental capsid protein and is AAV3B.455.DLMLPGS (SEQ ID No. 243), AAV3B.455.DVTPLLS (SEQ ID No. 244), AAV3B.455.LVSVSLP (SEQ ID No. 245), AAV8.456.RIQMGTK (SEQ ID No. 246), AAV8.456.RQKNAMV (SEQ ID No. 247), AAV8.590.GDNTTFRRA (SEQ ID No. 248) or AAV8.590.GRTIRGDLA (SEQ ID No. 249); and (b) an artificial genome comprising an expression cassette flanked by inverted terminal repeats (ITRs) of AAV, wherein the expression cassette comprises a transgene comprising a nucleotide sequence encoding C5-D-mab.ScFv.HL (SEQ ID No. 195 or 203), and wherein the transgene is operatively linked to one or more regulatory sequences that promote the expression of the transgene in human eye tissue cells; wherein the rAAV vector has an enhanced tropism towards eye tissue compared to an rAAV vector prepared from the parental capsid protein.

25. A pharmaceutical composition comprising the rAAV vector of any of claims 1 to 24 and a pharmaceutically acceptable carrier.

82. A method for producing recombinant AAV comprising: (a) culturing a host cell containing: (i) an artificial genome comprising an AAV ITR-flanked cis expression cassette, wherein the cis expression cassette comprises a transgene encoding C5-D-mab.ScFv.HL (SEQ ID No. 195 or 203), and wherein the transgene is operatively linked to one or more regulatory sequences that promote the expression of the transgene in human eye tissue cells; (ii) a trans expression cassette lacking ITR of AAV, wherein the trans expression cassette encodes an AAV rep and an AAV capsid protein operatively linked to expression control elements that drive expression of the AAV rep and the AAV capsid protein in the cultured host cell and supply the AAV rep and the AAV capsid protein in trans, wherein the capsid has eye tissue cell tropism; wherein the AAV capsid protein is AAV3B.455.DLMLPGS (SEQ ID No. 243), AAV3B.455.DVTPLLS (SEQ ID No. 244), AAV3B.455.LVSVSLP (SEQ ID No. 245), AAV8.456.RIQMGTK (SEQ ID No. 246), AAV8.456.RQKNAMV (SEQ ID No. 247), AAV8.590.GDNTTFRRA (SEQ ID No. 248) or AAV8.590.GRTIRGDLA (SEQ ID No. 249); (iii) sufficient adenovirus helper functions to allow replication and packaging of the artificial genome by the AAV capsid protein; and (b) recovering recombinant AAV encapsidizing the artificial genome from cell culture.

83. A host cell comprising: a plasmid comprising an AAV-flanked cis expression cassette, wherein the cis expression cassette comprises a transgene encoding C5-D-mab.ScFv.HL (SEQ ID No. 195 or 203), operatively linked to one or more regulatory sequences promoting expression of the transgene in human eye tissue cells.