Selective Uptake of Cylindrical Poly(2‐Oxazoline) Brush‐AntiDEC205 Antibody‐OVA Antigen Conjugates into DEC‐Positive Dendritic Cells and Subsequent T‐Cell Activation

Abstract

To achieve specific cell targeting by various receptors for oligosaccharides or antibodies, a carrier must not be taken up by any of the very many different cells and needs functional groups prone to clean conjugation chemistry to derive well-defined structures with a high biological specificity. A polymeric nanocarrier is presented that consists of a cylindrical brush polymer with poly-2-oxazoline side chains carrying an azide functional group on each of the many side chain ends. After click conjugation of dye and an anti-DEC205 antibody to the periphery of the cylindrical brush polymer, antibody-mediated specific binding and uptake into DEC205(+) -positive mouse bone marrow-derived dendritic cells (BMDC) was observed, whereas binding and uptake by DEC205(-) negative BMDC and non-DC was essentially absent. Additional conjugation of an antigen peptide yielded a multifunctional polymer structure with a much stronger antigen-specific T-cell stimulatory capacity of pretreated BMDC than application of antigen or polymer-antigen conjugate.

Not Just for Tumor Targeting: Unmet Medical Needs and Opportunities for Nanomedicine

“…Bühler, Gietzen et al have recently synthesized poly(oxazoline) brushes conjugated with both monoclonal aDEC-205 antibodies and model antigen peptides derived from ovalbumin [53]. A much stronger antigen-specific T-cell maturation was found for the targeted antigen nanocarriers instead of applying a soluble antigen or antigen-brush conjugate [53]. However, co-delivery of immunostimulatory adjuvants was -so far -not possible.…”

“…Considering the numerous possibilities of functionalizing such HPMA carriers with further tumor-relevant antigens (e.g., MUC1-derived glycopeptide antigens as shown above) [33] cellular MUC1-derived antitumor response should be feasible too [52]. Bühler, Gietzen et al have recently synthesized poly(oxazoline) brushes conjugated with both monoclonal aDEC-205 antibodies and model antigen peptides derived from ovalbumin [53]. A much stronger antigen-specific T-cell maturation was found for the targeted antigen nanocarriers instead of applying a soluble antigen or antigen-brush conjugate [53].…”

Poly(2-oxazoline) molecular brushes by grafting through of poly(2-oxazoline)methacrylates with aqueous ATRP

“…31,47,48 Unfortunately, GTP is demanding with respect to the strict reaction conditions and the more robust RAFT has to be stopped at rather low conversions (usually ~50 %) in order to suppress side reactions. 57 As outlined above, the existing methods for the synthesis of POx molecular brushes are either experimentally demanding or uncontrolled and/or limited to rather short side chain or backbone lengths. 49 FRP of macromonomers results in molecular brushes with a very long backbone (P w ~ 1050) but a broad molar mass distribution.…”

A novel peptide targeting Clec9a on dendritic cell for cancer immunotherapy

“…To overcome this, researchers discovered a series of potential molecules on the surface of DCs, which could help DCs to recognize, uptake and process antigens. Among these molecules, C-type lectin members, such as DEC205[22–25], Clec9a [3–5, 15, 26] and Dectin-1 [8, 9, 27, 28] are extensively studied. Clec9a is selectively expressed on CD8a + DCs (mouse) and BDCA3 + DC (human), the subsets with the most strongest ability to the cross-presentation of antigens.…”