Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple
sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently
developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting
immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRVEnv)
protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin,
expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the
differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of
GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of
GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because
the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological
program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk.
Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level
of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in
10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it
induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be
a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.