Mogamulizumab, an anti-CCR4 antibody, targets human T-lymphotropic virus type 1-infected CD8+ and CD4+ T cells to treat associated myelopathy

  • J Infect Dis. 2015 Jan 15;211(2):238-48. doi: 10.1093/infdis/jiu438.
Junji Yamauchi  1 ,  Ariella Coler-Reilly  2 ,  Tomoo Sato  2 ,  Natsumi Araya  2 ,  Naoko Yagishita  2 ,  Hitoshi Ando  2 ,  Yasuo Kunitomo  2 ,  Katsunori Takahashi  2 ,  Yuetsu Tanaka  3 ,  Yugo Shibagaki  4 ,  Kusuki Nishioka  5 ,  Toshihiro Nakajima  5 ,  Yasuhiro Hasegawa  6 ,  Atae Utsunomiya  7 ,  Kenjiro Kimura  4 ,  Yoshihisa Yamano  2
Affiliations
  • 1. Department of Rare Diseases Research, Institute of Medical Science Division of Nephrology and Hypertension.
  • 2. Department of Rare Diseases Research, Institute of Medical Science.
  • 3. Department of Immunology, Graduate School of Medicine, University of the Ryukyus, Okinawa.
  • 4. Division of Nephrology and Hypertension.
  • 5. Institute of Medical Science, Tokyo Medical University.
  • 6. Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki.
  • 7. Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
PMID: 25104771 DOI: 10.1093/infdis/jiu438
Abstract

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.

Keywords
CCR4; CD8; HAM/TSP; HTLV-1; mogamulizumab.
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