Phosphoserine containing compositions for immune tolerance induction

Abstract

Compositions and methods for inducing immune tolerance to proteins and subsequence administration of the proteins are disclosed. Compositions comprise proteins complexed with liposomes comprising PS and PC, wherein at least part of the PS is present as lyso-PS.

What is claimed is: 
     
         1 . A composition comprising a plurality of liposomes, wherein the liposomes comprise phosphatidylcholine (PC) and lysophosphatidylserine (lyso-PS), wherein the ratio of PC to lyso-PS is from 90:10 to 60:40, and wherein the acyl chain of the lyso-PS has 16-20 carbon atoms and at least one double bond. 
     
     
         2 . The composition of  claim 1 , wherein the ratio of PC to lyso-PS is from 85:15 to 70:30. 
     
     
         3 . The composition of  claim 1 , wherein the PC is present as dimyristoyl-sn-glycero-3 phosphatidylcholine (DMPC). 
     
     
         4 . The composition of  claim 1 , wherein the size of the liposomes is from 80 to 150 nm. 
     
     
         5 . The composition of  claim 1 , wherein the zeta potential of the liposomes is from −10 to −15. 
     
     
         6 . The composition of  claim 1 , wherein the liposomes are complexed to an antigenic polypeptide. 
     
     
         7 . The composition of  claim 1 , wherein PC and lyso-PS are the only phospholipids present in the bilayer of the liposome. 
     
     
         8 . The composition of  claim 1 , further comprising retinoic acid wherein the ratio of PC, PS, and retinoic acid is 70:20:10 to 70:29:1. 
     
     
         9 . The composition of  claim 1  further comprising rapamycin wherein the ratio of PC, PS, and rapamycin is 70:20:10 to 70:29:1. 
     
     
         10 . The composition of  claim 1 , wherein 99% of the liposomes have a diameter of less than 250 nm and 90% have a diameter of less than 160 nm. 
     
     
         11 . The composition of  claim 11 , wherein 90% of the liposomes have a diameter of from 50 to 150 nm. 
     
     
         12 . The composition of  claim 1 , wherein the liposomes are complexed to a therapeutic protein, a diagnostic protein, a self-antigen, a neo-antigen, or an allergen. 
     
     
         13 . The composition of  claim 12 , wherein the target protein is FVIII, insulin, acid alpha glucosidase (GAA), myelin oligodendrocyte glycoprotein (MOG) peptide (35-55), ovalbumin (OVA), gliadin, collagen, or adeno associated virus (AAV) capsid protein. 
     
     
         14 . The composition of  claim 1 , wherein 90% of the liposomes have a diameter of from 50 to 150 nm and a zeta potential of from −10 to −17. 
     
     
         15 . The composition of  claim 14 , wherein the protein lipid molar ratio is 1:1,000 to 1:5,000. 
     
     
         16 . A method for inducing immune tolerance to a target protein in an individual comprising:
 a) providing to the individual a first regimen of multiple administrations of a first composition over a period of time, said composition comprising the liposomes of  claim 1  complexed to the target protein; and   b) providing to the individual a second regimen of one or more administrations of a second composition comprising the antigen free of liposomes.