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Mol Cancer Ther. 2018 May;17(5):1024-1038. doi: 10.1158/1535-7163.MCT-17-0200. Epub 2018 Mar 15.

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.

Author information

1
Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
2
Department of Antibody Development and Protein Engineering, MedImmune, Gaithersburg, Maryland.
3
Translational Science, MedImmune, Gaithersburg, Maryland.
4
Department of Toxicology, MedImmune, Gaithersburg, Maryland.
5
Innovative Medicines, Oncology, AstraZeneca, Cambridge, United Kingdom.
6
Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon.
7
Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon.
8
AgonOx, Portland, Oregon.
9
Department of Oncology Research, MedImmune, Gaithersburg, Maryland. hammonds@medimmune.com.

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 (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB 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. Mol Cancer Ther; 17(5); 1024-38. ©2018 AACR.

PMID:
29545330
PMCID:
PMC5932227
DOI:
10.1158/1535-7163.MCT-17-0200
[Indexed for MEDLINE]
Free PMC Article

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