Chimeric antigens for breaking host tolerance to foreign antigens
View Patent ↗Disclosed herein are compositions and methods for eliciting immune responses against antigens. In particular, the compounds and methods elicit immune responses against foreign antigens that are otherwise recognized by the host as “self” antigens, thus breaking host tolerance to those antigens. Presenting the host immune system with a chimeric antigen comprising an immune response domain and a target binding domain, wherein the target binding domain comprises an antibody fragment, enhances the immune response against the foreign or tolerated antigen. Antigen presenting cells take up, process, and present the chimeric antigen, eliciting both a humoral and cellular immune response against the desired antigen.
1. A purified chimeric antigen for eliciting an immune response against Hepatitis B virus (HBV) in a host, wherein the chimeric antigen comprises:
a polypeptide immune response domain, wherein the immune response domain comprises at least one antigenic portion of an HBV protein selected from the group consisting of HBV S1/S2, HBV S1/S2/S, HBV Core, HBV Core ctm and HBV polymerase;
a polypeptide target binding domain, wherein the target binding domain consists of a hinge region, at least a portion of a C H 1 region and a xenotypic Fc antibody fragment comprising at least part of a C H 2 and C H 3 domain;
wherein the immune response domain and the target binding domain are linked by peptide linkage; and
wherein the chimeric antigen is non-mammalian glycoslyated.
2. The chimeric antigen of claim 1 , wherein the chimeric antigen comprises more than one immune response domain.
3. The chimeric antigen of claim 1 , wherein the target binding domain is capable of binding to an antigen presenting cell.
4. The chimeric antigen of claim 1 , wherein the linkage is a covalent peptide linkage.
5. The chimeric antigen of claim 1 , which elicits a multi-epitopic immune response.
6. The chimeric antigen of claim 1 , which elicits an immune response to at least one epitope of the immune response domain.
7. The chimeric antigen of claim 1 , which elicits a humoral immune response.
8. The chimeric antigen of claim 1 , which elicits a cellular immune response.
9. The chimeric antigen of claim 1 , which elicits a Th1 immune response, a Th2 immune response, a CTL response, or a combination thereof.
10. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a chimeric antigen of claim 1 .
11. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition is formulated for parenteral administration.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated for transdermal, intradermal, intravenous, subcutaneous, intramuscular, nasal, pulmonary or oral administration.
13. An article of manufacture comprising a chimeric antigen of claim 1 and instructions for administering the chimeric antigen to a subject in need thereof.
14. The chimeric antigen of claim 1 , which is recombinantly produced.
15. The chimeric antigen of claim 1 , wherein the immune response domain and the target binding domain are produced separately.
16. The chimeric antigen of claim 1 , wherein the immune response elicited is greater than that elicited by the immune response domain alone.
17. The chimeric antigen of claim 1 , wherein the non-mammalian glycosylation comprises mannose glycosylation.
18. The chimeric antigen of claim 17 , wherein the mannose glycosylation comprises high mannose glycosylation.
19. The chimeric antigen of claim 17 , wherein the glycosylation comprises pauci mannose glycosylation.
20. The chimeric antigen of claim 1 , wherein the non-mammalian glycosylation is an insect cell generated post-translational modification that is capable of binding to a member of the C-type lectin family of endocytic receptors to increase immunogenicity in the host.
21. The chimeric antigen of claim 3 , wherein the antigen presenting cell is a dendritic cell.
22. The chimeric antigen of claim 1 , wherein the chimeric antigen is capable of binding to an Fc receptor.
23. The chimeric antigen of claim 22 , wherein the Fc receptor is selected from the group consisting of CD16, CD32, and CD64.
24. The composition of claim 10 , further comprising a nanoparticle.
25. The composition of claim 10 , further comprising a nanosphere.
26. The chimeric antigen of claim 1 , comprising a monomer comprising:
a polypeptide immune response domain wherein the immune response domain comprises at least one antigenic portion of an HBV protein selected from the group consisting of HBV S1/S2, HBV S1/S2/S, HBV Core, HBV Core ctm and HBV polymerase;
and a polypeptide target binding domain, wherein the target binding domain consists of a hinge region, at least a portion of a C H 1 region and a xenotypic Fc antibody fragment comprising at least part of a C H 2 and C H 3 domain.
27. The chimeric antigen of claim 1 , comprising a dimer of a monomer comprising:
a polypeptide immune response domain wherein the immune response domain comprises at least one antigenic portion of an HBV protein selected from the group consisting of HBV S1/S2, HBV S1/S2/S, HBV Core, HBV Core ctm and HBV polymerase;
and a polypeptide target binding domain, wherein the target binding domain consists of a hinge region, at least a portion of a C H 1 region and a xenotypic Fc antibody fragment comprising at least part of a C H 2 and C H 3 domain.
28. The chimeric antigen of claim 20 , wherein the member of the C-type lectin family of endocytic receptors is a macrophage mannose receptor.
29. The chimeric antigen of claim 1 , wherein at least one of the immune response domain and target binding domain are non-mammalian glycosylated.