Potent immune modulation by medi6383, an engineered human ox40 ligand igg4p fc fusion protein

Michael D. Oberst, Catherine Auge, Chad Morris, Stacy Kentner, Kathy Mulgrew, Kelly McGlinchey, James Hair, Shino Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, Lolke de Haan, Andrew J. Pierce, Haesun Park, Andrew Sylwester, Michael K. Axthelm, Louis Picker, Nicholas P. MorrisAndrew Weinberg, Scott A. Hammond

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcgRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFkB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies.

Original languageEnglish (US)
Pages (from-to)1024-1038
Number of pages15
JournalMolecular cancer therapeutics
Volume17
Issue number5
DOIs
StatePublished - May 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Oberst, M. D., Auge, C., Morris, C., Kentner, S., Mulgrew, K., McGlinchey, K., Hair, J., Hanabuchi, S., Du, Q., Damschroder, M., Feng, H., Eck, S., Buss, N., de Haan, L., Pierce, A. J., Park, H., Sylwester, A., Axthelm, M. K., Picker, L., ... Hammond, S. A. (2018). Potent immune modulation by medi6383, an engineered human ox40 ligand igg4p fc fusion protein. Molecular cancer therapeutics, 17(5), 1024-1038. https://doi.org/10.1158/1535-7163.MCT-17-0200