Antigen-specific tolerance and compositions for induction of same
Peptides that specifically bind erythrocytes are described. These are provided as peptidic ligands having sequences that specifically bind, or as antibodies or fragments thereof that provide specific binding, to erythrocytes. The peptides may be prepared as molecular fusions with therapeutic agents, tolerizing antigens, or targeting peptides. Immunotolerance may be created by use of the fusions and choice of an antigen on a substance for which tolerance is desired.
1. A composition for immunomodulation to achieve antigen-specific tolerance, the composition comprising: an antigen to which tolerance is desired;
wherein the antigen is selected from the group consisting of high molecular weight glutenin, low molecular weight glutenin, gliadin, hordein, secalin, avenin, and immunogenic fragments thereof;
an erythrocyte-binding moiety,
wherein the erythrocyte-binding moiety comprises an antibody fragment that has the ability to non-covalently, specifically bind an exterior erythrocyte surface in situ in blood,
wherein the antigen to which tolerance is desired is recombinantly fused or chemically conjugated to the erythrocyte-binding moiety, and
wherein, upon administration to a human in which tolerance to the antigen is desired:
the composition binds to CD45 negative cells, but not to CD45 positive cells, and the composition reduces, fails to induce, or prevents inflammatory responses in antigen-specific T cells as compared to when the human is exposed to the antigen alone.
2. The composition of claim 1 , wherein the erythrocyte-binding moiety is derived from a 10F7 clone, wherein the antibody fragment is affinity matured, and wherein the composition reduces the number of resident lymph node and spleen cells expressing interferon-gamma (IFNγ), as compared to the number of resident lymph node and spleen cells expressing IFNγ when the human is exposed to the antigen alone.
3. The composition of claim 1 , wherein the antibody fragment is directed against glycophorin A.
4. The composition of claim 3 , wherein the erythrocyte-binding moiety is derived from a 10F7 clone.
5. The composition of claim 3 , wherein the antibody fragment is affinity matured.
6. The composition of claim 1 , wherein the erythrocyte-binding moiety is fused via a linker, to the N- or C-terminus of the antigen.
7. The composition of claim 1 , wherein the administration of the composition ameliorates celiac disease, and wherein the antigen comprises an immunogenic fragment of gliadin.
8. A composition for immunomodulation to achieve antigen-specific tolerance, the composition comprising:
an antigen recombinantly fused or chemically conjugated with an erythrocyte binding moiety;
said antigen being recognizable by an immune system of a subject, the immune system of the subject being able to respond to the antigen with an unwanted immune response;
wherein the antigen is selected from the group consisting of high molecular weight glutenin, low molecular weight glutenin, gliadin, hordein, secalin, avenin, and immunogenic fragments thereof;
wherein said erythrocyte-binding moiety comprises an antibody fragment directed to glycophorin A;
wherein upon administration of the composition, said erythrocyte-binding moiety non-covalently and specifically binds an erythrocyte in situ in blood and presents said antigen to the immune system of the subject;
wherein the erythrocyte-binding moiety does not specifically bind to other blood components, wherein the other blood components comprises blood proteins, albumin, fibronectin, platelets, and white blood cells; and
wherein said composition elicits a tolerogenic response upon administration to said subject.
9. The composition of claim 8 , wherein the antigen is a food antigen to which a subject develops an unwanted immune response, wherein the food antigen is associated with celiac disease, and wherein the food antigen is selected from the group consisting gliadin or an immunogenic fragment thereof.
10. The composition of claim 9 , wherein the erythrocyte-binding moiety is chemically conjugated to the antigen.
11. The composition of claim 9 , wherein the erythrocyte-binding moiety is fused to the antigen via recombinant DNA technology.
12. The composition of claim 9 , wherein the erythrocyte-binding moiety is fused, optionally via a linker, to the N- or C-terminus of the antigen.
13. The composition of claim 9 , wherein the erythrocyte-binding moiety comprises an antibody fragment, wherein the antibody fragment is derived from a 10F7 clone, and wherein the antibody fragment has undergone affinity maturation.
14. The composition of claim 12 , wherein the linker is a peptide, a polymer, an aptamer, a nucleic acid, or a particle.