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. 2017 Dec 15;5(1):e417.
doi: 10.1212/NXI.0000000000000417. eCollection 2018 Jan.

Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies

Ann Ranger  1 , Soma Ray  1 , Suzanne Szak  1 , Andrea Dearth  1 , Norm Allaire  1 , Ronald Murray  1 , Rebecca Gardner  1 , Diego Cadavid  1 , Sha Mi  1
Affiliations

Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies

Ann Ranger et al. Neurol Neuroimmunol Neuroinflamm. .

Abstract

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.

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Figures

Figure 1
Figure 1. Anti-LINGO-1 (Li81) has no effect on activated T-cell proliferation
(A) Western blot analysis with anti-LINGO-1 (3C11) shows that it was readily detected in neurons but not in activated human peripheral blood lymphocytes, rat splenocytes, or rat CD4+ T cells. (B and C) Stimulation with anti-CD3 antibody activated 3H thymidine incorporation into rat CD4+ T cells (B, left panel) and hPBMC (C, left panel), and in both cases, this was unaffected by the addition of anti-LINGO-1 (Li81) antibody at concentrations up to 30 μg/mL (B and C, right panels). CPM = counts per minute; hPBMC = human peripheral blood mononuclear cell; IgG = immunoglobulin G; NS = no stimulation.
Figure 2
Figure 2. Anti-LINGO-1 (Li81) does not affect cytokine production
Anti-LINGO-1 (Li81) does not affect cytokine production in the hPBMC, as determined by ELISA. Ab = antibody; hPBMC = human peripheral blood mononuclear cell; IFN = interferon; IgG = immunoglobulin G; IL = interleukin; TNF = tumor necrosis factor.
Figure 3
Figure 3. Gene expression in CSF cell pellets
Gene expression in CSF cell pellets reflecting (A.a–A.b) T cells, (B) B cells, (C.a–C.e) plasma cells, (D.a–D.b) myeloid cells, (E) T-cell activation, and (F) type I IFN response before and after opicinumab or placebo treatment. Each line connects the 2 time points of an individual patient. Patients from the 30-, 60-, and 100-mg/kg groups have been combined. Healthy range (shaded area) was determined by the minimum and maximum values of 5 healthy control patients evaluated. Ig = immunoglobulin; TCRα = T-cell receptor alpha.
Figure 4
Figure 4. Opicinumab does not affect the level of CXCL13 in CSF
Opicinumab does not affect the level of CXCL13 protein in CSF as measured by the CXCL13-Imperacer assay. aCorresponding day 0 (before dose) sample above the limit of quantification. bCorresponding day 0 sample not done. cDay 0 sample below the limit of quantification.
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