NANOPARTICLE COMPOSITIONS AND METHODS FOR IMMUNOTHERAPY
The present invention provides compositions and methods for immunotherapy, which include shelf-stable pharmaceutical compositions for inducing antigen-specific T cells. Such compositions are employed as components of an artificial antigen presenting cell (aAPC), to provide a patient with complexes for presentation of an antigen (e.g., a tumor antigen) and/or a T cell co-stimulatory molecule.
1 . An artificial antigen presenting cell (aAPC) comprising a polymeric nanoparticle having attached polypeptide ligands for immune cell activation, the nanoparticle comprising:
a poly(lactic-co-glycolic acid) (PLGA) or polylactic acid (PLA) polymer core (PLGA/PLA), and
a hydrophilic shell formed of polyethylene glycol (PEG), wherein a portion of the PEG polymers have a terminal attachment of a polypeptide ligand.
2 . (canceled)
3 . The aAPC of claim 1 , wherein the polymer core is based on 1:0 to 1:1 Lactic Acid:Glycolic Acid ratio.
4 - 5 . (canceled)
6 . The aAPC of claim 1 , wherein the core polymer has a molecular weight of from about 10K to about 50K.
7 . The aAPC of claim 1 , wherein the polymeric nanoparticle comprises a PLGA or PLA polymer core, and PLGA-PEG and/or PLA-PEG block co-polymers, the PEG portion forming the hydrophilic shell.
8 . The aAPC of claim 7 , wherein the polypeptide ligands are attached through functional groups at the PEG terminus.
9 - 10 . (canceled)
11 . The aAPC of claim 1 , wherein the PLGA-PEG co-polymer contains a PLGA portion having a molecular weight of from about 10K to about 50K, and a PEG portion having molecular weight(s) of from about 2K to about 10K.
12 - 17 . (canceled)
18 . The aAPC of claim 1 , wherein the PLA-PEG co-polymer contains a PLA portion having a molecular weight of from about 10K to about 50K, and a PEG portion having molecular weight(s) of from about 2K to about 10K.
19 - 24 . (canceled)
25 . The aAPC of claim 1 , wherein the nanoparticles have a size in the range of about 20 to 200 nm.
26 . The aAPC of claim 1 , wherein the aAPC has a surface charge of about 0 to −20 mV.
27 . The aAPC of claim 26 , wherein the aAPC has a surface charge of from about −5 to about −10 mV.
28 . The aAPC of claim 1 , having less than about 200 ligands per particle.
29 . The aAPC of claim 1 , wherein the polypeptide ligands comprise peptide-HLA ligands, and one or more of anti-CD28 or anti-4-1BB ligands.
30 . The aAPC of claim 29 , comprising an anti-CD28 antibody ligand having a human IGHV4-59 germline framework optionally having from 5 to 15 murine framework residues, and a IGKV4-01 germline framework optionally having from 3 to 15 murine framework residues.
31 . The aAPC of claim 30 , wherein the anti-CD28 ligand comprises an antigen-binding antibody fragment or portion.
32 . (canceled)
33 . The aAPC of claim 29 , wherein the HLA ligand is dimeric.
34 . The aAPC of claim 33 , wherein the HLA is HLA-A*02:01.
35 . The aAPC of claim 33 , wherein the HLA comprises a fusion with immunoglobulin sequences.
36 . The aAPC of claim 35 , wherein the anti-CD28 antibody ligand and the HLA immunoglobulin fusion have an IgG4 constant region with mutations at S241 and L248, and an unpaired cysteine at codon 473.
37 - 39 . (canceled)
40 . A method for inducing the formation of antigen-specific cytotoxic T cells, comprising administering a composition comprising the aAPC of claim 1 .
41 . The method of claim 40 , wherein the patient is a cancer patient.
42 - 44 . (canceled)