TY - JOUR
T1 - Site-Specific Modification of Virus-Like Particles for Exogenous Tumor Antigen Display and Minimizing Preexisting Immunity
AU - Cheng, Keman
AU - Ma, Nana
AU - Liang, Jie
AU - Ma, Xiaotu
AU - Feng, Qingqing
AU - Liu, Guangna
AU - Xu, Chen
AU - Tang, Ming
AU - Zhang, Lizhuo
AU - Gao, Xiaoyu
AU - Xu, Jiaqi
AU - Wang, Chufan
AU - Zhu, Fei
AU - Wang, Xinwei
AU - Li, Xiang
AU - Zhao, Xiao
AU - Nie, Guangjun
N1 - Publisher Copyright:
© 2023 Wiley-VCH GmbH.
PY - 2023/6/7
Y1 - 2023/6/7
N2 - The widespread preexisting immunity against virus-like particles (VLPs) seriously limits the applications of VLPs as vaccine vectors. Enabling technology for exogenous antigen display should not only ensure the assembly ability of VLPs and site-specific modification, but also consider the effect of preexisting immunity on the behavior of VLPs in vivo. Here, combining genetic code expansion technique and synthetic biology strategy, a site-specific modification method for hepatitis B core (HBc) VLPs via incorporating azido-phenylalanine into the desired positions is described. Through modification position screening, it is found that HBc VLPs incorporated with azido-phenylalanine at the main immune region can effectively assemble and rapidly conjugate with the dibenzocycolctyne-modified tumor-associated antigens, mucin-1 (MUC1). The site-specific modification of HBc VLPs not only improves the immunogenicity of MUC1 antigens but also shields the immunogenicity of HBc VLPs themselves, thereby activating a strong and persistent anti-MUC1 immune response even in the presence of preexisting anti-HBc immunity, which results in the efficient tumor elimination in a lung metastatic mouse model. Together, these results demonstrate the site-specific modification strategy enabled HBc VLPs behave as a potent antitumor vaccine and this strategy to manipulate immunogenicity of VLPs may be suitable for other VLP-based vaccine vectors.
AB - The widespread preexisting immunity against virus-like particles (VLPs) seriously limits the applications of VLPs as vaccine vectors. Enabling technology for exogenous antigen display should not only ensure the assembly ability of VLPs and site-specific modification, but also consider the effect of preexisting immunity on the behavior of VLPs in vivo. Here, combining genetic code expansion technique and synthetic biology strategy, a site-specific modification method for hepatitis B core (HBc) VLPs via incorporating azido-phenylalanine into the desired positions is described. Through modification position screening, it is found that HBc VLPs incorporated with azido-phenylalanine at the main immune region can effectively assemble and rapidly conjugate with the dibenzocycolctyne-modified tumor-associated antigens, mucin-1 (MUC1). The site-specific modification of HBc VLPs not only improves the immunogenicity of MUC1 antigens but also shields the immunogenicity of HBc VLPs themselves, thereby activating a strong and persistent anti-MUC1 immune response even in the presence of preexisting anti-HBc immunity, which results in the efficient tumor elimination in a lung metastatic mouse model. Together, these results demonstrate the site-specific modification strategy enabled HBc VLPs behave as a potent antitumor vaccine and this strategy to manipulate immunogenicity of VLPs may be suitable for other VLP-based vaccine vectors.
KW - immunogenicity manipulation
KW - preexisting immunity
KW - site-specific modification
KW - tumor vaccines
KW - virus-like particles (VLPs)
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U2 - 10.1002/smll.202300125
DO - 10.1002/smll.202300125
M3 - Article
AN - SCOPUS:85149293187
SN - 1613-6810
VL - 19
JO - Small
JF - Small
IS - 23
M1 - 2300125
ER -