CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells

Masayasu Naito, Ursula Hainz, Ute E. Burkhardt, Buyin Fu, Deborah Ahove, Kristen E. Stevenson, Mohini Rajasagi, Baogong Zhu, Anselmo Alonso, Elizabeth Witten, Ken Ichi Matsuoka, Donna Neuberg, Jonathan S. Duke-Cohan, Catherine J. Wu, Gordon J. Freeman

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

CD40L has a well-established role in enhancing the immunostimulatory capacity of normal and malignant B cells, but a formulation suitable for clinical use has not been widely available. Like other TNF family members, in vivo and in vitro activity of CD40L requires a homotrimeric configuration, and growing evidence suggests that bioactivity depends on higher-order clustering of CD40. We generated a novel formulation of human recombinant CD40L (CD40L-Tri) in which the CD40L extracellular domain and a trimerization motif are connected by a long flexible peptide linker. We demonstrate that CD40L-Tri significantly expands normal CD19+ B cells by over 20- to 30-fold over 14 days and induces B cells to become highly immunostimulatory antigen-presenting cells (APCs). Consistent with these results, CD40L-Tri-activated B cells could effectively stimulate antigen-specific T responses (against the influenza M1 peptide) from normal volunteers. In addition, CD40L-Tri could induce malignant B cells to become effective APCs, such that tumor-directed immune responses could be probed. Together, our studies demonstrate the potent immune-stimulatory effects of CD40L-Tri on B cells that enable their expansion of antigen-specific human T cells. The potent bioactivity of CD40L-Tri is related to its ability to self-multimerize, which may be facilitated by its long peptide linker.

Original languageEnglish
Pages (from-to)347-357
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume62
Issue number2
DOIs
Publication statusPublished - Feb 2013

Keywords

  • Antigen-presenting cell
  • B lymphocytes
  • CD40
  • CD40L
  • Immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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