Improved immunogenicity of a self tumor antigen by covalent linkage to CD40 ligand

Hsing I. Huang, Ping Yi Wu, Chin Yee Teo, Min Nan Chen, Yi Chau Chen, Dmytro Silin, Mi Hua Tao*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

24 Scopus citations

Abstract

The interaction between the CD40 ligand (CD40L) and CD40 on antigen-presenting cells (APCs) is critical in promoting humoral and cellular immune responses. Agonistic anti-CD40 monoclonal antibody and soluble CD40L can act as powerful adjuvants to promote vaccination, but usually require repeated high-dose treatment. In this study, we demonstrate that the adjuvant effect of CD40L can be greatly improved by directly linking the antigen to CD40L. We constructed a fusion protein (Id-CD40L) consisting of the extracellular domain of CD40L and the idiotype (Id) protein, a weakly immunogenic tumor-specific antigen derived from the murine 38CI3 B-cell lymphoma. The soluble Id-CD40L fusion protein retained CD40 binding activity and stimulated CD80 and CD86 upregulation and interleukin (IL)-12 production by macrophages. Immunization of mice with Id-CD40L without adjuvants resulted in high titers of anti-Id Abs dominated by the IgGI isotype and protected the mice from subsequent lethal tumor challenge. In a dose-response study, we demonstrated that Id-CD40L elicited anti-Id antibody (Ab) responses in all immunized animals, even at a dose as low as 0.5 μg. Immunization with free Id and an IgG-CD40L fusion protein, which was identical in structure to Id-CD40L but lost the Id determinant, resulted in significant lower anti-Id responses, indicating that physical linkage between the tumor antigen and CD40L was required for the optimal immune response. These results demonstrate that fusing CD40L to a candidate antigen can greatly improve the adjuvant activity of CD40L. This approach may be useful in developing vaccines for a variety of malignant and infectious diseases.

Original languageEnglish
Pages (from-to)696-703
Number of pages8
JournalInternational Journal of Cancer
Volume108
Issue number5
DOIs
StatePublished - 20 02 2004
Externally publishedYes

Keywords

  • B-cell lymphoma
  • CD40 ligand
  • Idiotype
  • Tumor vaccine

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