A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis

Sci Transl Med. 2018 Dec 5;10(470):eaah3924. doi: 10.1126/scitranslmed.aah3924.


Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (α-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, α-miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the α-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1G37R or SOD1G93A mutations, treatment with the α-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether α-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of α-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Antibodies / administration & dosage
  • Antibodies / pharmacology
  • Antibodies / therapeutic use*
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Inflammation / pathology
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Mice, Transgenic
  • Motor Activity* / drug effects
  • Protein Folding / drug effects*
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Superoxide Dismutase-1 / chemistry*
  • Superoxide Dismutase-1 / metabolism*
  • Survival Analysis


  • Antibodies
  • Recombinant Proteins
  • Superoxide Dismutase-1