Immunoadsorption
Upon administration of rAAV vectors the humoral immune response (neutralizing antibodies) is the first barrier that needs to be overcome. Surprisingly it was found that by using immunoadsorption for depletion of immunoglobulins from the blood (plasma), subjects can be highly efficiently treated with rAAV vectors, i.e. obtain highly efficient transduction after rAAV vector administration, in spite of the presence of high levels of nAb.
1. A method of administering a recombinant adeno-associated virus (rAAV) to a subject, comprising:
(a) depleting a subject's circulating immunoglobulins by contacting the subject's blood with an extracorporeal device for immunoadsorption, the device comprising a binding moiety attached to a matrix, wherein the binding moiety binds immunoglobulins, and
(b) subsequently administering a rAAV to the subject, wherein prior to depleting the subject's circulating immunoglobulins, the subject had neutralizing antibodies that bind to a capsid of the rAAV as a result of previously receiving a treatment comprising a rAAV vector.
2. The method of claim 1 , wherein the binding moiety is selective for one or more of IgA, IgD, IgE, IgG and/or IgM.
3. The method of claim 1 , wherein the binding moiety is selected from the group consisting of peptides, dextran sulfate, tryptophan, protein A, protein G, protein A/G, protein L, and anti-human immunoglobulin antibodies.
4. The method of claim 1 , wherein the binding moiety comprises a protein that binds anti-rAAV immunoglobulins.
5. The method of claim 4 , wherein the protein that binds anti-rAAV immunoglobulins binds to AAV VP1, AAV VP2, or AAV VP3.
6. The method of claim 1 , wherein the rAAV is administered intravenously.
7. A method of decreasing a humoral immune response in response to a recombinant adeno-associated virus (rAAV) gene therapy in a subject comprising,
(a) a first immunoadsorption step comprising contacting the subject's blood with a first extracorporeal device comprising a binding moiety that binds immunoglobulins, wherein the binding moiety is attached to a matrix,
(b) a second immunoadsorption step comprising contacting the subject's blood with a second extracorporeal device comprising a binding moiety that binds anti-rAAV immunoglobulins, wherein the binding moiety is attached to a matrix, and
(c) subsequently administering rAAV gene therapy to the subject, thereby decreasing the humoral immune response to the rAAV gene therapy;
wherein prior to depleting the subject's circulating immunoglobulins, the subject had neutralizing antibodies that bind to a capsid of the rAAV as a result of previously receiving a treatment comprising a rAAV vector.
8. The method of claim 7 , wherein the rAAV is administered intravenously.
9. The method of claim 7 , wherein the first and second immunoadsorption steps depletes the amount of neutralizing antibodies in the subject's blood by at least 90%.
10. The method of claim 7 , wherein the first and second immunoadsorption steps are performed at most 24 hours prior to administration of the rAAV.
11. The method of claim 7 , wherein the subject is administered a dose of rAAV that is the same as a dose for a subject not having neutralizing antibodies for a capsid of the rAAV.
12. The method of claim 7 , wherein a cellular response the rAAV is reduced.
13. A method for reducing an anti-rAAV immunoglobulin concentration in the blood of a subject, comprising:
a) obtaining blood from the subject, wherein the subject's blood comprises neutralizing antibodies that bind to a capsid of the rAAV as a result of previously receiving a treatment comprising a rAAV vector;
b) separating the blood into plasma components and cellular components;
c) contacting the plasma components with an extracorporeal immunoadsorption device, the device comprising a binding moiety attached to a matrix, wherein the binding moiety binds anti-rAAV immunoglobulins;
d) reconstituting the blood by combining the cellular components with the plasma components that were subjected to immunoadsorption; and
e) administering the reconstituted blood to the subject, thereby reducing the anti-rAAV immunoglobulin concentration in the subject's blood.
14. The method of claim 13 , further comprising administering an rAAV vector to the subject.
15. The method of claim 14 , wherein the rAAV vector is administered to the subject within 24 hours of administering the reconstituted blood to the subject.
16. The method of claim 13 , wherein the anti-rAAV immunoglobulin concentration in the subject's blood is depleted by at least 90%.