Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function

• Published in: The Journal of immunology (1950) Vol. 191; no. 7; pp. 3641 - 3650
• Main Authors: Voo, Kui S, Bover, Laura, Harline, Megan L, Vien, Long T, Facchinetti, Valeria, Arima, Kazuhiko, Kwak, Larry W, Liu, Yong J
• Format: Journal Article
• Language: English
• Published: United States 01-10-2013
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized - metabolism; Antibodies, Monoclonal, Humanized - pharmacology; Cell Line; Cell Proliferation - drug effects; Female; Humans; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Macaca mulatta; Mice; Protein Binding; Receptors, OX40 - antagonists & inhibitors; Receptors, OX40 - metabolism; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1202752

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.