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

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.

journal_name

Mol Cancer Ther

authors

Oberst MD,Augé 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 AJ,Park H,Sylwester A,Axthelm MK,Picker L,Morris NP,Weinberg A,Hammond SA

doi

10.1158/1535-7163.MCT-17-0200

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

1024-1038

issue

5

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-17-0200

journal_volume

17

pub_type

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