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A multivalent CD44 glycoconjugate vaccine candidate for cancer immunotherapy

2024; Elsevier BV; Volume: 367; Linguagem: Inglês

10.1016/j.jconrel.2024.01.065

1873-4995

Rui Freitas, Andréia Miranda, Dylan Ferreira, Marta Relvas‐Santos, Flávia Castro, Eduardo Ferreira, Cristiana Gaiteiro, Janine Soares, Sofia Cotton, Martina Gonçalves, Mariana Eiras, Beatriz Santos, Carlos Palmeira, Margareta P. Correia, Maria José Oliveira, Bruno Sarmento, Andreia Peixoto, Lúcio Lara Santos, André M. N. Silva, José Alexandre Ferreira,

Peptidase Inhibition and Analysis

Cancer presents a high mortality rate due to ineffective treatments and tumour relapse with progression. Cancer vaccines hold tremendous potential due to their capability to eradicate tumour and prevent relapse. In this study, we present a novel glycovaccine for precise targeting and immunotherapy of aggressive solid tumours that overexpress CD44 standard isoform (CD44s) carrying immature Tn and sialyl-Tn (sTn) O-glycans. We describe an enzymatic method and an enrichment strategy to generate libraries of well-characterized cancer-specific CD44s-Tn and/or sTn glycoproteoforms, which mimic the heterogeneity found in tumours. We conjugated CD44-Tn-derived glycopeptides with carrier proteins making them more immunogenic, with further demonstration of the importance of this conjugation to overcome the glycopeptides' intrinsic toxicity. We have optimized the glycopeptide-protein maleimide-thiol conjugation chemistry to avoid undesirable cross-linking between carrier proteins and CD44s glycopeptides. The resulting glycovaccines candidates were well-tolerated in vivo, inducing both humoral and cellular immunity, including immunological memory. The generated antibodies exhibited specific reactivity against synthetic CD44s-Tn glycopeptides, CD44s-Tn glycoengineered cells, and human tumours. In summary, we present a promising prototype of a cancer glycovaccine for future therapeutical pre-clinical efficacy validation.