Design, Synthesis, and Bioactivity Evaluation of a TF-Based Cancer Vaccine Candidate Using Lipid A Mimetics As a Built-In Adjuvant

• Published in: Journal of medicinal chemistry Vol. 67; no. 12; pp. 9976 - 9990
• Main Authors: Gao, Lingqiang, Li, Guiqi, Qiu, Cuiping, Ye, Yifan, Li, Xiaohui, Liao, Pan, Ming, Wenbo, Liu, Zhongqiu, Luo, Xiang, Liao, Guochao
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.06.2024; Amer Chemical Soc
• Subjects: Adjuvants, Immunologic - chemical synthesis; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - pharmacology; Animals; Cancer Vaccines - chemical synthesis; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; Cell Line, Tumor; Chemistry, Medicinal; Drug Design; Female; Humans; Life Sciences & Biomedicine; Lipid A - analogs & derivatives; Lipid A - chemistry; Lipid A - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Pharmacology & Pharmacy; Science & Technology; Toll-Like Receptor 4 - metabolism; GAMMA; CONJUGATE; A DERIVATIVES; ANTIGEN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00042

This study describes the design and synthesis of five TF-based cancer vaccine candidates using a lipid A mimetic as the carrier and a built-in adjuvant. All synthesized conjugates elicited robust and consistent TF-specific immune responses in mice without external adjuvants. Immunological studies subsequently conducted in wild-type and TLR4 knockout C57BL/6 mice demonstrated that the activation of TLR4 was the main reason that the synthesized lipid A mimetics increased the TF-specific immune responses. All antisera induced by these conjugates can specifically recognize, bind to, and induce the lysis of TF-positive cancer cells. Moreover, representative conjugates 2 and 3 could effectively reduce the growth of tumors and prolong the survival time of mice in vivo, and the efficacies were better than glycoprotein TF-CRM197 with alum adjuvant. Lipid A mimetics could therefore be a promising platform for the development of new carbohydrate-based vaccine carriers with self-adjuvanting properties for the treatment of cancer.