Vectorized factor xii antibodies and administration thereof
AssigneeREGENXBIO Inc.
InventorsJoseph Bruder, Ye Liu
Life of this patent
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Abstract
Compositions and methods are described for the delivery of a fully human post-translationally modified therapeutic monoclonal antibody that binds to factor XII to a human subject diagnosed with a disease or condition indicated for treatment with an anti-factor XII antibody. Such diseases include hereditary angioedema, as well as thrombosis and hypercoagulation.
Claims41
A pharmaceutical composition for treating hereditary angioedema, thrombosis, or hypercoagulation in a human subject in need thereof, comprising an adeno-associated virus (AAV) vector having:
- (a) a viral capsid that has a tropism for liver and/or muscle cells;
- and
- (b) an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITRs), wherein the expression cassette comprises a transgene encoding a heavy chain and a light chain of a substantially full-length or full-length anti-factor XII/XIIa mAb, operably linked to one or more regulatory sequences that promote expression of the transgene in human liver and/or muscle cells;
- wherein said AAV vector is formulated for systemic administration to said human subject.
A composition comprising an adeno-associated virus (AAV) vector having:
- a. a viral AAV capsid, that is optionally at least 95% identical to the amino acid sequence of AAV3B, AAV5, AAV7 (SEQ ID NO:198), AAV8 (SEQ ID NO:199), AAV9 (SEQ ID NO:200), AAVrh10 (SEQ ID NO:201), AAVrh46 (SEQ ID NO:202), AAVrh73 (SEQ ID NO:203), AAVS3 (SEQ ID NO:205), AAV-LK03 (SEQ ID NO:204), AAVrh8, AAV64R1, or AAVhu37;
- and
- b. an artificial genome comprising an expression cassette flanked by AAV inverted terminal repeats (ITRs), wherein the expression cassette comprises a transgene encoding a heavy and a light chain of a substantially full-length or full-length anti-factor XII mAb, operably linked to one or more regulatory sequences that promote expression of the transgene in human liver and/or muscle cells;
- c. wherein the transgene encodes a signal sequence at the N-terminus of the heavy chain and the light chain of said mAb that directs secretion and post translational modification of said mAb in liver and/or muscle cells.
A method of treating hereditary angioedema, thrombosis, or hypercoagulation in a human subject in need thereof, comprising intravenously administering to the subject a therapeutically effective amount of a composition comprising a recombinant AAV comprising a transgene encoding garadacimab, AB042/AB043, AB054, DX-4012, Ab26036, Ab26048, Ab260489, Ab26076, 559C-M0071-F06, 559C-M0179-D04, 559C-M0181-C02, 559C-M0180-G03, 559C-M0184-B04, 620I-X0173-A11, 620I-X0173-C07, 620I-X0173-E07, or 620I-X0173-G11, operably linked to one or more regulatory sequences that control expression of the transgene in liver and/or muscle cells, in an amount sufficient to result in expression from the transgene and secretion of garadacimab, AB042/AB043, AB054, DX-4012, Ab26036, Ab26048, Ab260489, Ab26076, 559C-M0071-F06, 559C-M0179-D04, 559C-M0181-C02, 559C-M0180-G03, 559C-M0184-B04, 620I-X0173-A11, 620I-X0173-C07, 620I-X0173-E07, or 620I-X0173-G11 into the bloodstream of the human subject.
A method of producing recombinant AAVs comprising:
- (a) culturing a host cell containing:
- (i) an artificial genome comprising a cis expression cassette flanked by AAV ITRs, wherein the cis expression cassette comprises comprising a transgene encoding a substantially full-length or full-length anti-factor XII mAb, operably linked to one or more regulatory sequences that promote expression of the transgene in human liver and/or muscle cells;
- (ii) a trans expression cassette lacking AAV ITRs, wherein the trans expression cassette encodes an AAV rep and an AAV capsid protein operably linked to expression control elements that drive expression of the AAV rep and the AAV capsid protein in the host cell in culture and supply the AAV rep and the AAV capsid protein in trans, wherein the capsid has liver and/or muscle tropism;
- (iii) sufficient adenovirus helper functions to permit replication and packaging of the artificial genome by the AAV capsid protein;
- and
- (b) recovering recombinant AAV encapsidating the artificial genome from the cell culture.
A host cell containing:
- a. an artificial genome comprising a cis expression cassette flanked by AAV ITRs, wherein the cis expression cassette comprises comprising a transgene encoding a substantially full-length or full-length anti-Factor XII mAb, operably linked to one or more regulatory sequences that promote expression of the transgene in human liver and/or muscle cells;
- b. a trans expression cassette lacking AAV ITRs, wherein the trans expression cassette encodes an AAV rep and an AAV capsid protein operably linked to expression control elements that drive expression of the AAV rep and the AAV capsid protein in the host cell in culture and supply the AAV rep and the AAV capsid protein in trans, wherein the capsid has liver and/or muscle tropism;
- c. sufficient adenovirus helper functions to permit replication and packaging of the artificial genome by the AAV capsid protein.
Dependencies are inferred from the claim text.