Mogamulizumab, an Anti-CCR4 Antibody, Targets Human T-Lymphotropic Virus Type 1-infected CD8⁺ and CD4⁺ T Cells to Treat Associated Myelopathy

• Published in: The Journal of infectious diseases 2015-01, Vol.211 (2), p.238-248
• Main Authors: Yamauchi, Junji, Coler-Reilly, Ariella, Sato, Tomoo, Araya, Natsumi, Yagishita, Naoko, Ando, Hitoshi, Kunitomo, Yasuo, Takahashi, Katsunori, Tanaka, Yuetsu, Shibagaki, Yugo, Nishioka, Kusuki, Nakajima, Toshihiro, Hasegawa, Yasuhiro, Utsunomiya, Atae, Kimura, Kenjiro, Yamano, Yoshihisa
• Format: Article
• Language: English
• Subjects: Aged; Antibodies, Monoclonal, Humanized - therapeutic use; CD4-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - drug effects; Female; Humans; Male; Middle Aged; Paraparesis, Tropical Spastic - therapy; Receptors, CCR4 - antagonists & inhibitors; Treatment Outcome; VIRUSES
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiu438

Background. Human T-lymphotropic virus type 1 (HTLV-1) can cause chronic spinal cord inflammation, known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Since CD4⁺ CCR4⁺ T cells are the main HTLV-1 reservoir, we evaluated the defucosylated humanized anti-CCR4 antibody mogamulizumab as a treatment for HAM/TSP. Methods. We assessed the effects of mogamulizumab on peripheral blood mononuclear cells from 11 patients with HAM/TSP. We also studied how CD8⁺ T cells, namely CD8⁺ CCR4⁺ T cells and cytotoxic T lymphocytes, are involved in HTLV-1 infection and HAM/TSP pathogenesis and how they would be affected by mogamulizumab. Results. Mogamulizumab effectively reduced the HTLV-1 proviral load (56.4% mean reduction at a minimum effective concentration of 0.01 μg/mL), spontaneous proliferation, and production of proinflammatory cytokines, including interferon γ (IFN-γ). Like CD4⁺ CCR4⁺ T cells, CD8⁺ CCR4⁺ T cells from patients with HAM/TSP exhibited high proviral loads and spontaneous IFN-γ production, unlike their CCR4⁻ counterparts. CD8⁺ CCR4⁺ T cells from patients with HAM/TSP contained more IFN-γ-expressing cells and fewer interleukin 4-expressing cells than those from healthy donors. Notably, Tax-specific cytotoxic T lymphocytes that may help control the HTLV-1 infection were overwhelmingly CCR4⁻. Conclusions. We determined that CD8⁺CCR4⁺ T cells and CD4⁺CCR4⁺ T cells are prime therapeutic targets for treating HAM/TSP and propose mogamulizumab as a new treatment.