Immunonanotherapeutics that provide IgG humoral response without T-cell antigen
The present invention provides compositions and systems for delivery of nanocarriers to cells of the immune system. The invention provides synthetic nanocarriers capable of eliciting an immune system response in the form of antibody production, wherein the nanocarriers lack any T cell antigens. In some embodiments, the invention provides nanocarriers that comprise an immunofeature surface, which provides high avidity binding of the nanocarriers to antigen presenting cells. The invention provides pharmaceutical compositions comprising inventive nanocarriers. The present invention provides methods of designing, manufacturing, and using inventive nanocarriers and pharmaceutical compositions thereof.
1. A composition comprising pharmaceutically acceptable synthetic nanocarriers comprising an immunofeature surface formed of a scaffold having bound thereto a plurality of B-cell antigen moieties, the immunofeature surface binding with high avidity and low affinity to antigen presenting cells, and an immunostimulatory or immunomodulatory agent to be delivered to the antigen presenting cells (APCs), wherein the nanocarriers contain less than 10 mol % of a T-helper antigen.
2. The composition of claim 1 , wherein the plurality of moieties are present in a density equal to or greater than the density required to obtain at least 10% of the maximal immobilization observed for a monoclonal antibody (MAb) in an antigen presenting cell (APC) binding assay, provided that, in the APC binding assay, the half maximal binding density for the plurality of moieties is at least twice the half maximal binding density for the MAb.
3. The composition of claim 2 , wherein the plurality of moieties are present in a density equal to or greater than the density required to obtain at least 20% of the maximal immobilization observed for a MAb in the APC binding assay.
4. The composition of claim 2 , wherein the half maximal binding density for the plurality of moieties is at least four times the half maximal binding density for the MAb.
5. The composition of claim 2 , wherein the APC binding assay comprises
(a) preparing a series of substrates having coatings of an functional moiety at a series of surface coating densities, wherein the functional moiety is capable of binding to a dendritic cell (DC) or subcapsular sinus macrophage surface receptors;
(b) exposing the series of substrates to single-cell suspensions of DCs or subcapsular sinus macrophages for a predetermined period of time;
(c) removing non-adhered APCs from the series of substrates, and fixing the adhered APCs to the series of substrates;
(d) quantifying the number of adhered APCs per unit surface area for each substrate in the series of substrates;
(e) plotting the result from (d) against the coating density of the functional moiety;
(f) obtaining a value for the maximal immobilization by determining the maximum number of adhered APCs per unit surface area for the series of substrates; and
(g) obtaining a value for half maximal binding density by determining the surface coating density that provides 50% of the maximum.
6. The composition of claim 2 , wherein the MAb is anti-CD1c (BDCA-1) Clone ADS-8E7 or rat anti-mouse CD169, clone 3D6.112, isotype IgG2a.
7. The composition of claim 1 , wherein the composition stimulates the production of anti-B-cell antigen IgG antibodies when administered to a human.
8. The composition of claim 1 , wherein the immunostimulatory agent is selected from the group consisting of an interleukin, an interferon, a cytokine, and an adjuvant.
9. The composition of claim 1 , wherein the B-cell antigen is selected from the group consisting of proteins, peptides, small molecules, and carbohydrates.
10. A method comprising administering to a subject the composition of claim 1 in an amount effective to induce the production of anti-B-cell antigen IgG antibodies such that the peak serum concentration of anti-B-cell antigen IgG antibodies is raised to greater than 100 ng/ml in the subject after the administration.
11. The method of claim 10 , further comprising administering at least one additional dose to the subject at a time after the initial dose.
12. The method of claim 11 , wherein the time after the initial dose is between 1 day and 1 year.