Organic & Biomolecular Chemistry, 2017, 15, 114 - 123
Herein, we report a new process that enables the gram-scale production of a fully synthetic anti-cancer
vaccine for human use. This therapeutic vaccine candidate, named MAG-Tn3, is a high-molecular-weight
tetrameric glycopeptide encompassing carbohydrate tumor-associated Tn antigen clusters and peptidic
CD4+ T-cell epitopes. The synthetic process involves (i) the stepwise solid-phase assembly of protected
amino acids, including the high value-added Tn building blocks with only 1.5 equivalents, (ii) a single iso-
lated intermediate, and (iii) the simultaneous deprotection of 36 hindered protective groups. The resulting
MAG-Tn3 was unambiguously characterized using a combination of techniques, including a structural
analysis by nuclear magnetic resonance spectroscopy. The four peptidic chains are flexible in solution,
with a more constrained but extended conformation at the Tn3 antigen motif. Finally, we demonstrate
that, when injected into HLA-DR1-expressing transgenic mice, this vaccine induces Tn-specific antibodies
that mediate the killing of human Tn-positive tumor cells. These studies led to a clinical batch of the
MAG-Tn3, currently investigated in breast cancer patients (phase I clinical trial). The current study demon-
strates the feasibility of the multigram-scale synthesis of a highly pure complex glycopeptide, and it opens
new avenues for the use of synthetic glycopeptides as drugs in humans.