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Org Biomol Chem ; 15(1): 114-123, 2016 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-27812586

RESUMO

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 isolated 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 demonstrates 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.


Assuntos
Vacinas Anticâncer/química , Dendrímeros/química , Glicopeptídeos/química , Neoplasias/prevenção & controle , Vacinas Sintéticas/química , Sequência de Aminoácidos , Animais , Antígenos Glicosídicos Associados a Tumores/química , Antígenos Glicosídicos Associados a Tumores/imunologia , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/síntese química , Vacinas Anticâncer/uso terapêutico , Dendrímeros/síntese química , Dendrímeros/uso terapêutico , Glicopeptídeos/síntese química , Glicopeptídeos/uso terapêutico , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias/imunologia , Vacinas Sintéticas/uso terapêutico
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