The present invention provides multi-armed high MW polymers containing hydrophilic groups conjugated to Factor VIII, and methods of preparing such polymers.

The present invention provides multi-armed high MW polymers containing hydrophilic groups conjugated to Factor VIII, and methods of preparing such polymers.

An optimized coding sequence of human blood clotting factor eight (VIII) and a promoter may be used in vectors, such as rAAV, for introduction of factor VIII, and/or other blood clotting factors and transgenes. Exemplary of these factors and transgenes arc alpha-1-antitrypsin, as well as those involved in the coagulation cascade, hepatocye biology, lysosomal storage, urea cycle disorders, and lipid storage diseases. Cells, vectors, proteins, and glycoproteins produced by cells transformed by the vectors and sequence, may be used in treatment.

An optimized coding sequence of human blood clotting factor eight (VIII) and a promoter may be used in vectors, such as rAAV, for introduction of factor VIII, and/or other blood clotting factors and transgenes. Exemplary of these factors and transgenes arc alpha-1-antitrypsin, as well as those involved in the coagulation cascade, hepatocye biology, lysosomal storage, urea cycle disorders, and lipid storage diseases. Cells, vectors, proteins, and glycoproteins produced by cells transformed by the vectors and sequence, may be used in treatment.

The invention relates to a molecular complex comprising at least one polylysine conjugate (PLL), comprising a main PLL straight chain and at least one molecule F having an average molecular weight of between 50 daltons and 1000 daltons that is covalently bonded to said main chain, and at least one molecule M that is unstable in solution, the conjugate(s) and the molecule(s) M being bonded by means of a non-covalent bond. The invention also relates to a composition comprising a complex of this kind, to a method for obtaining said composition and use thereof, and to the use of one or more PLL-based conjugates for improving the hydrophilicity, the effectiveness, and the activity of a molecule that is unstable in solution, over a time period that is compatible with the use of said molecule. The invention also relates to a method for identifying a PLL-based conjugate or a combination of a plurality of PLL-based conjugates that makes it possible to improve the hydrophilicity, the effectiveness, and the activity of a molecule that is unstable in solution, and to a kit for implementing said method.

The invention relates to a molecular complex comprising at least one polylysine conjugate (PLL), comprising a main PLL straight chain and at least one molecule F having an average molecular weight of between 50 daltons and 1000 daltons that is covalently bonded to said main chain, and at least one molecule M that is unstable in solution, the conjugate(s) and the molecule(s) M being bonded by means of a non-covalent bond. The invention also relates to a composition comprising a complex of this kind, to a method for obtaining said composition and use thereof, and to the use of one or more PLL-based conjugates for improving the hydrophilicity, the effectiveness, and the activity of a molecule that is unstable in solution, over a time period that is compatible with the use of said molecule. The invention also relates to a method for identifying a PLL-based conjugate or a combination of a plurality of PLL-based conjugates that makes it possible to improve the hydrophilicity, the effectiveness, and the activity of a molecule that is unstable in solution, and to a kit for implementing said method.

The present disclosure provides methods of administering chimeric and hybrid Factor VIII (FVIII) polypeptides comprising FVIII and Fc to subjects at risk of developing inhibitory FVIII immune responses, including anti-FVIII antibodies and/or cell-mediated immunity. The administration is sufficient to promote coagulation and to induce immune tolerance to FVIII. The chimeric polypeptide can comprise full-length FVIII or a FVIII polypeptide containing a deletion, e.g., a full or partial deletion of the B domain.

The present disclosure provides methods of administering chimeric and hybrid Factor VIII (FVIII) polypeptides comprising FVIII and Fc to subjects at risk of developing inhibitory FVIII immune responses, including anti-FVIII antibodies and/or cell-mediated immunity. The administration is sufficient to promote coagulation and to induce immune tolerance to FVIII. The chimeric polypeptide can comprise full-length FVIII or a FVIII polypeptide containing a deletion, e.g., a full or partial deletion of the B domain.

Embodiments provide devices, preparations and methods for delivering therapeutic agents (TAs) such as clotting factors (CFs, e.g., Factor 8) within the GI tract. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations configured to be contained within the capsule, advanced from the capsule into the IW and/or surrounding tissue (ST) and degrade to release the TA into the bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW or ST (e.g., the peritoneal cavity). Embodiments are particularly useful for delivery of CFs for treatment of clotting disorders (e.g., hemophilia) where such CFs are poorly absorbed and/or degraded within the GI tract.

Embodiments provide devices, preparations and methods for delivering therapeutic agents (TAs) such as clotting factors (CFs, e.g., Factor 8) within the GI tract. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations configured to be contained within the capsule, advanced from the capsule into the IW and/or surrounding tissue (ST) and degrade to release the TA into the bloodstream to produce a therapeutic effect (e.g., improved clotting). The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW or ST (e.g., the peritoneal cavity). Embodiments are particularly useful for delivery of CFs for treatment of clotting disorders (e.g., hemophilia) where such CFs are poorly absorbed and/or degraded within the GI tract.