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<p>Immunotoxin (ITX)-mediated cell targeting enables selective elimination of neuronal types of interest from a complex neural network. In this technology, human interleukin-2 receptor α-subunit or CD25 (hCD25) is expressed in specific cell types in transgenic rodents, and then the animals are treated with a recombinant ITX composed of monoclonal antibody variable regions for hCD25 fused to a <i>Pseudomonas</i> exotoxin fragment (PE38), resulting in the ablation of hCD25-expressing cells. However, there is a critical issue on the cross-reactivity of the recombinant ITX for endogenous CD25 in non-human primates (NHPs), leading to off-target effects. Here we generated a mouse CD25 (mCD25)-specific recombinant ITX, termed anti-mCD25-PE38, based on variable regions of a rabbit monoclonal antibody that specifically reacts to mCD25, but not to hCD25. Anti-mCD25-PE38 showed high-affinity binding to mCD25 and cytotoxic activity toward mCD25-expressing cells. Injection of anti-mCD25-PE38 into the ventral midbrain of common marmosets, in which the mCD25 transgene was expressed in dopamine neurons by a lentiviral vector for retrograde gene transfer, induced a significant loss of midbrain dopamine neurons. Therefore, anti-mCD25-PE38 provides a useful strategy for selective targeting of neuronal types to study the behavioral and neurological functions of these neurons in the NHP brain.</p>

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Targeting of specific neuronal types in the non-human primate brain by using a murine CD25-specific recombinant immunotoxin

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Tomoko Kobayashi,
  • Shigeki Kato,
  • Shingo Kimura,
  • Masateru Sugawara,
  • Kanichiro Ihara,
  • Tatsuhiko Ozawa,
  • Ken-ichi Inoue,
  • Masahiko Takada,
  • Masanori Onda,
  • Kazuto Kobayashi

摘要

Immunotoxin (ITX)-mediated cell targeting enables selective elimination of neuronal types of interest from a complex neural network. In this technology, human interleukin-2 receptor α-subunit or CD25 (hCD25) is expressed in specific cell types in transgenic rodents, and then the animals are treated with a recombinant ITX composed of monoclonal antibody variable regions for hCD25 fused to a Pseudomonas exotoxin fragment (PE38), resulting in the ablation of hCD25-expressing cells. However, there is a critical issue on the cross-reactivity of the recombinant ITX for endogenous CD25 in non-human primates (NHPs), leading to off-target effects. Here we generated a mouse CD25 (mCD25)-specific recombinant ITX, termed anti-mCD25-PE38, based on variable regions of a rabbit monoclonal antibody that specifically reacts to mCD25, but not to hCD25. Anti-mCD25-PE38 showed high-affinity binding to mCD25 and cytotoxic activity toward mCD25-expressing cells. Injection of anti-mCD25-PE38 into the ventral midbrain of common marmosets, in which the mCD25 transgene was expressed in dopamine neurons by a lentiviral vector for retrograde gene transfer, induced a significant loss of midbrain dopamine neurons. Therefore, anti-mCD25-PE38 provides a useful strategy for selective targeting of neuronal types to study the behavioral and neurological functions of these neurons in the NHP brain.