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

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

Author information

1
Neurimmune AG, 8952 Schlieren, Switzerland.
2
Institute for Regenerative Medicine-IREM, University of Zurich, 8952 Schlieren, Switzerland.
3
ALS Therapy Development Institute, Cambridge, MA 02139, USA.
4
Interfaculty Institute of Biochemistry, University of Tübingen, 72076 Tübingen, Germany.
5
Muskelzentrum/ALS Clinic, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
6
Neurimmune AG, 8952 Schlieren, Switzerland. jan.grimm@neurimmune.com.

Abstract

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.

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