Mucin expression
and glycosylation patterns on cancer
cells differ
markedly from healthy cells. Mucin 1 (MUC1) is overexpressed in several
solid tumors and presents high levels of aberrant, truncated O-glycans
(e.g., Tn antigen). Dendritic cells (DCs) express lectins that bind
to these tumor-associated carbohydrate antigens (TACAs) to modulate
immune responses. Selectively targeting these receptors with synthetic
TACAs is a promising strategy to develop anticancer vaccines and to
overcome TACA tolerance. In this work, we prepared, via a solid phase
peptide synthesis approach, a modular tripartite vaccine candidate,
incorporating a high-affinity glycocluster based on a tetraphenylethylene
scaffold, to target the macrophage galactose-type lectin (MGL) on
antigen presenting cells. MGL is a C-type lectin receptor that binds
Tn antigens and can route them to human leukocyte antigen class II
or I, making it an attractive target for anticancer vaccines. Conjugation
of the glycocluster to a library of MUC1 glycopeptides bearing the
Tn antigen is shown to promote uptake and recognition of the TACA
by DCs via MGL. In vivo testing revealed that immunization with the
newly designed vaccine construct bearing the GalNAc glycocluster induced
a higher titer of anti-Tn-MUC1 antibodies compared to the TACAs alone.
Additionally, the antibodies obtained bind a library of tumor-associated
saccharide structures on MUC1 and MUC1-positive breast cancer cells.
Conjugation of a high-affinity ligand for MGL to tumor-associated
MUC1 glycopeptide antigens has a synergistic impact on antibody production.