Intrathecal monovalent fragments from two human monoclonal antibodies block tetanus neurotoxin in rodents

Tetanus is a life-threatening disease characterized by spastic paralysis caused by Tetanus Neurotoxin (TeNT). Spasticity arises after TeNT is retro-transported inside peripheral nerves and released into spinal interstitial fluids, where it intoxicates inhibitory interneurons, blocking GABA/Glycine release. The only approved treatment, intramuscular antisera, is ineffective once TeNT has entered peripheral nerves. Here, we show that the intrathecal injection of F(ab)₁ fragments from TT104 and TT110-two potent TeNT-neutralizing human monoclonal antibodies-intercepts the TeNT molecules escaping peripheral neutralization by intramuscular antisera, enhancing protection from tetanus in rodents. F(abs)₁ achieve efficacy at markedly lower quantities than those tested in previous clinical trials with intrathecal polyclonal antisera, indicating that targeting two epitopes essential for TeNT mechanism of action is sufficient for toxin neutralization in spinal interstitial fluids. These findings highlight TT-F(ab)₁-104 and TT-F(ab)₁-110 as valuable candidates for improving tetanus intrathecal therapy, where dosage is limited by cerebrospinal fluid protein tolerance.