title: Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function.
abstract: Current cancer vaccines induce tumor-specific T cell responses without sustained tumor regression because immunosuppressive elements within the tumor induce exhaustion of effector T cells and infiltration of immune-suppressive regulatory T cells (Tregs). Therefore, much effort has been made to generate agonistic Abs targeting members of the TNFR superfamily, such as OX40, 4-1BB, and GITR, expressed on effector T cells and Tregs, to reinvigorate T cell effector function and block Treg-suppressive function. In this article, we describe the development of a panel of anti-human OX40 agonistic mouse mAbs that could promote effector CD4(+) and CD8(+) T cell proliferation, inhibit the induction of CD4(+) IL-10 -producing type 1 regulatory T cells, inhibit the expansion of ICOS(+)IL-10(+) Tregs, inhibit TGF-β-induced FOXP3 expression on naive CD4(+) T cells, and block natural Treg-suppressive function. We humanized two anti-human OX40 mAb clones, and they retained the potency of their parental clones. These Abs should provide broad opportunities for potential combination therapy to treat a wide realm of cancers and preventative vaccines against infectious diseases.
authors.affiliation: Department of Immunology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Kui S
authors.initials: KS
authors.lastname: Voo
authors.forename: Laura
authors.initials: L
authors.lastname: Bover
authors.forename: Megan L
authors.initials: ML
authors.lastname: Harline
authors.forename: Long T
authors.initials: LT
authors.lastname: Vien
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008253:Macaca mulatta; D051379:Mice; D011485:Protein Binding; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053262:Receptors, OX40