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 Therjournal_title
Molecular cancer therapeuticsauthors
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 SAdoi
10.1158/1535-7163.MCT-17-0200subject
Has Abstractpub_date
2018-05-01 00:00:00pages
1024-1038issue
5eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-17-0200journal_volume
17pub_type
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journal_title:Molecular cancer therapeutics
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