SYNTHETIC MEMBRANE-RECEIVER COMPLEXES
Compositions comprising synthetic membrane-receiver complexes, methods of generating synthetic membrane-receiver complexes, and methods of treating or preventing diseases, disorders or conditions therewith.
1 . A pharmaceutical composition formulated as a liquid suspension for intravenous administration to the circulatory system of a mammalian subject, comprising: a population of synthetic membrane-receiver polypeptide complexes which comprise:
a receiver polypeptide capable of interacting with a target, and
a membrane comprising a second polypeptide,
wherein the synthetic membrane-receiver polypeptide complex has catalytic activity independent of the receiver, and wherein the receiver polypeptide is capable of binding to and thereby reducing the circulatory concentration of the target.
2 . The pharmaceutical composition of claim 1 , whereupon administration of the composition into a circulatory system of a subject, the receiver polypeptide is present for substantially the duration of the synthetic membrane-receiver polypeptide complex in the circulatory system of the subject.
3 . The pharmaceutical composition of claim 1 , wherein the receiver polypeptide comprises at least one of an S domain, an A domain or a U domain, wherein the S domain is a surface domain exposed to the environment around the synthetic membrane-receiver polypeptide complex, wherein the A domain is an anchor, and wherein the U domain faces the unexposed side of the synthetic membrane-receiver polypeptide complex.
4 . The pharmaceutical composition of claim 1 , wherein interacting with a target comprises binding, degrading, cleaving and/or sequestering the target.
5 . The pharmaceutical composition of claim 1 , wherein the target is a self-antibody, a complement cascade factor, a clotting cascade factor, an immune complex, a serum amyloid protein, a metabolite or a toxin.
6 . The pharmaceutical composition of claim 1 , wherein the receiver polypeptide is encoded by an exogenous nucleic acid and a) the exogenous nucleic acid is not retained by the synthetic membrane-receiver polypeptide complex or b) the synthetic membrane-receiver complex is substantially incapable of self-replication.
7 . The pharmaceutical composition of claim 1 , wherein the synthetic membrane-receiver polypeptide complex comprises at least 1,000 copies of the receiver polypeptide.
8 . The pharmaceutical composition of claim 1 comprising at least 1×10 5 synthetic membrane-receiver complexes provided in a volume of between 10 nl and 500 ml.
9 . A method of reducing the circulatory concentration of a target self-antibody, the method comprising: administering to a human subject suffering from or at risk of developing a self-antibody mediated disease, disorder or condition, a pharmaceutical composition comprising a synthetic membrane-receiver polypeptide complex, wherein the pharmaceutical composition is administered in an amount effective to substantially reduce the circulatory concentration of the target self-antibody.
10 . The method of claim 9 , wherein the half-life in circulation of a receiver polypeptide in or on the synthetic membrane-receiver polypeptide complex is increased by at least 1.5-fold when compared to an unmodified polypeptide.
11 . The method of claim 9 , wherein the synthetic membrane-receiver polypeptide complex has a volume of distribution equal to the plasma volume of the subject.
12 . The method of claim 9 comprising administering the pharmaceutical composition at least twice over a treatment period such that the self-antibody mediated disease, disorder or condition is treated, or a symptom thereof is decreased.
13 . The method of claim 12 , the circulatory concentration of the target self-antibody is decreased by at least about 5% during part or the entirety of the treatment period.
14 . The method of claim 9 , wherein the receiver polypeptide comprises complement receptor 1 (CR1) or a fragment thereof, or an antigenic polypeptide selected from the group consisting of glycoprotein (GP Ib-IX, IIb-IIIa, IV, or Ia-IIa), the NC1 domain of collagen α3 (IV), B2 glycoprotein-1, or phospholipase A2 receptor, or an antigenic fragment thereof.
15 . The method of claim 9 further comprising the step of selecting for treatment a subject suffering from or at risk of a self-antibody mediated disease, disorder or condition selected from the group consisting of: type I diabetes, multiple sclerosis, rheumatoid arthritis, ulcerative colitis, lupus, IgA nephropathy, immune thrombocytopenia purpura, warm antibody hemolytic anemia, cold agglutinin disease, Goodpasture syndrome, antiphospholipid antibody syndrome, and membranous glomerulonephritis.
16 . A method of generating an isolated population of erythroid cells comprising a receiver polypeptide, the method comprising: a) introducing into a cultured or freshly isolated erythroid cell precursor an exogenous nucleic acid encoding a receiver polypeptide, and b) expanding the erythroid cells comprising a receiver polypeptide by at least 20,000-fold in culture, wherein the population comprises at least 20% of enucleated erythroid cells comprising a receiver polypeptide, in the absence of: i) an enrichment step and ii) co-culturing with an adherent stromal cell layer.
17 . The method of claim 16 , wherein during enucleation the receiver polypeptide is retained by the erythroid cell whereas the exogenous nucleic acid is not retained by the erythroid cell.
18 . The method of claim 16 , wherein the population is cultured in a bioreactor.
19 . The method of claim 16 , wherein the resulting enucleated erythroid cell comprising a receiver polypeptide exhibits substantially the same osmotic fragility as an isolated, cultured or uncultured erythroid cell not comprising the polypeptide receiver.
20 . The method of claim 16 further comprising formulating the population as a sterile injectable suspension.