Immune Responses and Antitumor Effect through Delivering to Antigen Presenting Cells by Optimized Conjugates Consisting of CpG-DNA and Antigenic Peptide,Bioconjugate Chemistry

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Immune Responses and Antitumor Effect through Delivering to Antigen Presenting Cells by Optimized Conjugates Consisting of CpG-DNA and Antigenic Peptide
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-11-05 , DOI: 10.1021/acs.bioconjchem.0c00523
Hitomi Irie ₁ , Koji Morita ₂ , Makoto Koizumi ₂ , Shinichi Mochizuki ₁

Affiliation

Immunotherapy using antigen-specific cytotoxic T lymphocytes (CTLs) has become one of the most attractive strategies for cancer treatment. For the induction of antigen-specific CTLs in vivo, the co-delivery of CpG-DNAs and antigens to the same antigen-presenting cells (APCs) is a promising strategy. In this study, we prepared conjugates consisting of 40mer of CpG-DNA (CpG40) and antigenic peptide (OVA_257–264), which have the following distinctive features: (1) multiple CpG motifs in a molecule; (2) cleavage in the cytosol because of the disulfide bonding via cysteine residue between peptide and CpG-DNA; (3) conjugation designed to induce antigen presentation on MHC class I molecules. Immunization with the conjugate CpG40-C-OVA_257–264 at the mouse tail base induced strong CTL activity at a very low peptide dose of 20 ng/head. It was found that the conjugates were internalized into C-type mannose receptor 1 (MRC1)-expressing cells in inguinal lymph nodes, indicating that the CpG portion in the conjugate acts as not only an adjuvant for the activation of TLR9 but also a carrier to APCs expressing MRC1. In a tumor-bearing mice model, mice immunized with CpG40-C-OVA_257–264 conjugates exhibited long delays in tumor growth compared with those treated with PBS, OVA_257–264 alone, or a mixture of CpG40 and OVA_257–264. Therefore, CpG-C-peptide conjugates could be a new and effective platform for peptide vaccine for the treatment of cancers and infectious diseases.

中文翻译：

通过优化的CpG-DNA和抗原肽结合物传递给抗原呈递细胞的免疫应答和抗肿瘤作用

使用抗原特异性细胞毒性T淋巴细胞（CTL）的免疫疗法已成为治疗癌症的最有吸引力的策略之一。为了在体内诱导抗原特异性CTL ，将CpG-DNA和抗原共同递送至相同的抗原呈递细胞（APC）是一种有前途的策略。在这项研究中，我们制备了由40mer CpG-DNA（CpG40）和抗原肽（OVA _257-264）组成的结合物，它们具有以下独特特征：（1）分子中有多个CpG基序；（2）由于肽和CpG-DNA之间通过半胱氨酸残基的二硫键而在细胞质中裂解；（3）设计用于诱导I类MHC分子上抗原呈递的偶联。使用结合物CpG40-C-OVA _{257-264进行免疫}小鼠尾巴中的α-肽以非常低的20 ng /头的肽剂量诱导了强大的CTL活性。发现缀合物被内化到腹股沟淋巴结中表达C型甘露糖受体1（MRC1）的细胞中，表明缀合物中的CpG部分不仅充当TLR9活化的佐剂，而且还充当表达MRC1的APC。在荷瘤小鼠模型中，与单独用PBS，OVA _257-264或CpG40和OVA _257-264混合治疗的小鼠相比，用CpG40-C-OVA _257-264缀合物免疫的小鼠表现出长期的肿瘤生长延迟。因此，CpG-C-肽结合物可以成为治疗癌症和传染病的肽疫苗的新的有效平台。

更新日期：2020-11-18

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