CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells
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ORIGINAL ARTICLE
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
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Received: 2 April 2012 / Accepted: 30 July 2012 / Published online: 25 August 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com
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 Catherine J. Wu and Gordon J. Freeman contributed equally.
Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1331-4) contains supplementary material, which is available to authorized users. M. Naito U. Hainz U. E. Burkhardt D. Ahove M. Rajasagi A. Alonso E. Witten J. S. Duke-Cohan C. J. Wu Cancer Vaccine Center, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA, USA M. Naito U. Hainz U. E. Burkhardt B. Fu D. Ahove M. Rajasagi B. Zhu A. Alonso E. Witten K. Matsuoka J. S. Duke-Cohan C. J. Wu G. J. Freeman Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA K. E. Stevenson D. Neuberg Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA J. S. Duke-Cohan C. J. Wu G. J. Freeman (&) Department of Medicine, Harvard Medical School, Boston, MA, USA e-mail: [email protected] C. J. Wu e-mail: [email protected]
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. Keywords CD40 CD40L B lymphocytes Immunotherapy Antigen-presenting cell
Introduction The CD40:CD40Ligand (CD40L) pathway provides
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