Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein

• Published in: mAbs Vol. 7; no. 1; pp. 265 - 275
• Main Authors: Curtin, François, Perron, Hervé, Kromminga, Arno, Porchet, Hervé, Lang, Alois B
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2015
• Subjects: Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - immunology; Antibody Specificity; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Endogenous Retroviruses - immunology; Female; Gene Products, env - immunology; HEK293 Cells; Humans; Immunoglobulin G - administration & dosage; Immunoglobulin G - adverse effects; Immunoglobulin G - immunology; Male; Mice; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; HLA, human leukocyte antigen; AUC, area under the curve; Cmin, minimal concentration; HERV-W; HERV-W, human endogenous retrovirus type W; mAb, monoclonal antibody; MSRV; MSRV-Env, multiple sclerosis associated retrovirus envelope protein; Syncytin; neurotoxicity; MOG, myelin oligodendrocyte glycoprotein; MSRV, multiple sclerosis associated retrovirus; mu-GNbAC1, murine version of mAb GNbAC1; ADCC, antibody-dependent cell-mediated cytotoxicity; BLAST, Basic Local Alignment Search Tool; CDC, complement-dependent cytotoxicity; PBMC, peripheral blood mononuclear cell; AE, adverse events; SU, surface domain; toxicology; TLR4, Toll-like receptor 4; multiple sclerosis; drug safety; human endogenous retrovirus; ch-GNbAC1, chimeric version of mAb GNbAC1; SAE, serious adverse event; MS, multiple sclerosis; CDR, complementarity-determining regions; monoclonal antibody; Cmax, maximal concentration
• ISSN: 1942-0862; 1942-0870; 1942-0870
• DOI: 10.4161/19420862.2014.985021

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 (MSRV-Env) 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.