RT Journal Article
SR Electronic
T1 Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e417
DO 10.1212/NXI.0000000000000417
VO 5
IS 1
A1 Ranger, Ann
A1 Ray, Soma
A1 Szak, Suzanne
A1 Dearth, Andrea
A1 Allaire, Norm
A1 Murray, Ronald
A1 Gardner, Rebecca
A1 Cadavid, Diego
A1 Mi, Sha
YR 2018
UL http://nn.neurology.org/content/5/1/e417.abstract
AB Objective: To evaluate whether the anti-LINGO-1 antibody has immunomodulatory effects.Methods: Human peripheral blood mononuclear cells (hPBMCs), rat splenocytes, and rat CD4+ T cells were assessed to determine whether LINGO-1 was expressed and was inducible. Anti-LINGO-1 Li81 (0.1–30 μg/mL) effect on proliferation/cytokine production was assessed in purified rat CD4+ T cells and hPBMCs stimulated with antibodies to CD3 +/– CD28. In humans, the effect of 2 opicinumab (anti-LINGO-1/BIIB033; 30, 60, and 100 mg/kg) or placebo IV administrations was evaluated in RNA from blood and CSF samples taken before and after administration in phase 1 clinical trials; paired samples were assessed for differentially expressed genes by microarray. RNA from human CSF cell pellets was analyzed by quantitative real-time PCR for changes in transcripts representative of cell types, activation markers, and soluble proteins of the adaptive/innate immune systems. ELISA quantitated the levels of CXCL13 protein in human CSF supernatants.Results: LINGO-1 is not expressed in hPBMCs, rat splenocytes, or rat CD4+ T cells; LINGO-1 blockade with Li81 did not affect T-cell proliferation or cytokine production from purified rat CD4+ T cells or hPBMCs. LINGO-1 blockade with opicinumab resulted in neither significant changes in immune system gene expression in blood and CSF, nor changes in CXCL13 CSF protein levels (clinical studies).Conclusions: These data support the hypothesis that LINGO-1 blockade does not affect immune function.Classification of evidence: This study provides Class II evidence that in patients with MS, opicinumab does not have immunomodulatory effects detected by changes in immune gene transcript expression.EAE=experimental autoimmune encephalomyelitis; EDSS=Expanded Disability Status Scale; Gd+=gadolinium-enhancing; hPBMC=human peripheral blood mononuclear cell; IFN=interferon; IgG=immunoglobulin G; MAD=multiple ascending dose; MLR=mixed lymphocyte reaction; NA=not applicable; RRMS=relapsingremitting MS; SPMS=secondary progressive MS