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 journalArticle

14 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
Externally publishedYes

Fingerprint

CD40 Ligand
B-Lymphocytes
Antigen-Presenting Cells
Peptides
Aptitude
Viral Tumor Antigens
Human Influenza
Cluster Analysis
Healthy Volunteers
T-Lymphocytes
Antigens

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Naito, M., Hainz, U., Burkhardt, U. E., Fu, B., Ahove, D., Stevenson, K. E., ... Freeman, G. J. (2013). CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunology, Immunotherapy, 62(2), 347-357. https://doi.org/10.1007/s00262-012-1331-4

CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. / Naito, Masayasu; Hainz, Ursula; Burkhardt, Ute E.; Fu, Buyin; Ahove, Deborah; Stevenson, Kristen E.; Rajasagi, Mohini; Zhu, Baogong; Alonso, Anselmo; Witten, Elizabeth; Matsuoka, Ken-ichi; Neuberg, Donna; Duke-Cohan, Jonathan S.; Wu, Catherine J.; Freeman, Gordon J.

In: Cancer Immunology, Immunotherapy, Vol. 62, No. 2, 02.2013, p. 347-357.

Research output: Contribution to journalArticle

Naito, M, Hainz, U, Burkhardt, UE, Fu, B, Ahove, D, Stevenson, KE, Rajasagi, M, Zhu, B, Alonso, A, Witten, E, Matsuoka, K, Neuberg, D, Duke-Cohan, JS, Wu, CJ & Freeman, GJ 2013, 'CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells', Cancer Immunology, Immunotherapy, vol. 62, no. 2, pp. 347-357. https://doi.org/10.1007/s00262-012-1331-4
Naito, Masayasu ; Hainz, Ursula ; Burkhardt, Ute E. ; Fu, Buyin ; Ahove, Deborah ; Stevenson, Kristen E. ; Rajasagi, Mohini ; Zhu, Baogong ; Alonso, Anselmo ; Witten, Elizabeth ; Matsuoka, Ken-ichi ; Neuberg, Donna ; Duke-Cohan, Jonathan S. ; Wu, Catherine J. ; Freeman, Gordon J. / CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. In: Cancer Immunology, Immunotherapy. 2013 ; Vol. 62, No. 2. pp. 347-357.
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