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ACS Nano. 2019 Mar 26;13(3):2936-2947. doi: 10.1021/acsnano.8b07241. Epub 2019 Mar 11.

Biomimetic Glyconanoparticle Vaccine for Cancer Immunotherapy.

Author information

1
Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences , Tel Aviv University , Tel Aviv 69978 , Israel.
2
Department of Chemistry , University of California , Davis , California 95616 , United States.
3
Avantea , Laboratory of Reproductive Technologies , Via Porcellasco 7/F , 26100 Cremona , Italy.
4
Institut de Transplantation-Urologie-Néphrologie , INSERM Unité Mixte de Recherche 1064, Centre Hospitalo Universitaire de Nantes , Nantes 44000 , France.
5
FondazioneAvantea Cremona , Via Cabrini, 12 , 26100 Cremona , Italy.

Abstract

Cancer immunotherapy aims to harness the immune system to combat malignant processes. Transformed cells harbor diverse modifications that lead to formation of neoantigens, including aberrantly expressed cell surface carbohydrates. Targeting tumor-associated carbohydrate antigens (TACA) hold great potential for cancer immunotherapy. N-glycolylneuraminic acid (Neu5Gc) is a dietary non-human immunogenic carbohydrate that accumulates on human cancer cells, thereby generating neoantigens. In mice, passive immunotherapy with anti-Neu5Gc antibodies inhibits growth of Neu5Gc-positive tumors. Here, we designed an active cancer vaccine immunotherapy strategy to target Neu5Gc-positive tumors. We generated biomimetic glyconanoparticles using engineered αGal knockout porcine red blood cells to form nanoghosts (NGs) that either express (NGpos) or lack expression (NGneg) of Neu5Gc-glycoconjugates in their natural context. We demonstrated that optimized immunization of "human-like" Neu5Gc-deficient Cmah-/- mice with NGpos glyconanoparticles induce a strong, diverse and persistent anti-Neu5Gc IgG immune response. The resulting anti-Neu5Gc IgG antibodies were also detected within Neu5Gc-positive tumors and inhibited tumor growth in vivo. Using detailed glycan microarray analysis, we further demonstrate that the kinetics and quality of the immune responses influence the efficacy of the vaccine. These findings reinforce the potential of TACA neoantigens and the dietary non-human sialic acid Neu5Gc, in particular, as immunotherapy targets.

KEYWORDS:

N-glycolylneuraminic acid; biomimetic; cancer immunotherapy; glycan microarray; glyconanoparticle; neoantigen; sialic acid

PMID:
30840433
DOI:
10.1021/acsnano.8b07241

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