PT  - JOURNAL ARTICLE
AU  - Ranger, Ann
AU  - Ray, Soma
AU  - Szak, Suzanne
AU  - Dearth, Andrea
AU  - Allaire, Norm
AU  - Murray, Ronald
AU  - Gardner, Rebecca
AU  - Cadavid, Diego
AU  - Mi, Sha
TI  - Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies
AID  - 10.1212/NXI.0000000000000417
DP  - 2018 Jan 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e417
VI  - 5
IP  - 1
4099  - http://nn.neurology.org/content/5/1/e417.short
4100  - http://nn.neurology.org/content/5/1/e417.full
SO  - Neurol Neuroimmunol Neuroinflamm2018 Jan 01; 5
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