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9 HD Insights, Vol. 12 Copyright © Huntington Study Group 2015. All rights reserved. Animal models of HD and human individuals with HD both exhibit immune dysregulation and increased inflammation in addition to the characteristic neuronal atrophy observed in the disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling protein implicated in several processes that may increase neuroinflammation, including glial cell activation, inhibition of oligodendrocyte and astrocyte migration, inhibition of neurodevelopment, and inducement of apoptosis. 2 Given the increased inflammatory response and chronic immune activation observed in HD, SEMA4D inhibition may slow the progression of neurodegenerative processes. SEMA4D has also been implicated in assisting in the abnormal growth of cancer cells because its high expression at the margins of invasive growths inhibits anti-tumor immune cells from entering the tumor. Strikingly, in metastatic processes, SEMA4D inhibition promotes inflammation and immune activity to encourage rejection of invasive growths, 3 in contrast to the inhibitory effect VX15/2503 exhibits on neuroinflammation in mouse models of HD. VX15/2503 was also recently evaluated by Vaccinex in a phase I study in adults with solid tumors. Vaccinex has developed the anti-SEMA4D monoclonal antibody VX15/2503 using their novel vaccinia virus − based platform for screening human antibodies as therapeutic targets. According to the company's website, other similar processes that use yeast and bacteriophages to express candidate proteins are limited because the proteins do not undergo the post-translational modifications typical of a mammalian cell, and therefore may be less consistent in their quality and biophysical properties. 4,5 In collaboration with the Huntington Study Group, Vaccinex is currently conducting a Phase II clinical trial of VX15/2503 in HD patients, called SIGNAL (NCT02481674), which is designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of this novel monoclonal antibody in late prodromal and early manifest HD. Secondary endpoints include a number of imaging and biomarker studies, including MRI and PET imaging, as well as measurements of SEMA4D activity in T-cells and in the circulation. Clinical features of HD will be measured using components of the UHDRS, as well as the quantitative motor (Qmotor) assessment system (see HD Insights, Vol. 6), HD-CAB (Cognitive Assessment Battery), and the Problem Behaviors Assessment. 6 VX15/2503 showed promise for neuropathology and cognitive symptoms of HD in the YAC12B mouse model, but did not demonstrate motor improvements. 2 The SIGNAL trial may help to determine whether SEMA4D inhibition in the early stages of human HD might have similar effects. Correction: An earlier version of this article stated that VX15/2503 had been evaluated in a phase I study in melanoma. The antibody was actually evaluated in adults with solid tumors. The above text has been corrected as of October 29, 2015. BY: Meredith A. Achey, BM MANUFACTURER: Vaccinex Inc. MOLECULAR FORMULA: Anti-semaphorin 4D (SEMA4D) monoclonal antibody MECHANISM OF ACTION: VX15/2503 may slow or prevent neurodegeneration in HD by inhibiting SEMA4D, a signaling protein shown to be important in neuroinflammatory processes. 1 MEET THE COMPOUND: VX15/2503 Image Source: Illustration of antibodies from shutterstock.com 1 Smith ES, Jonason A, Reilly C, et al. SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol. Dis. 2015;73:254-268. 2 Southwell AL, Franciosi S, Villanueva EB, et al. Anti- semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol. Dis. 2015;76:46-56. 3 Evans EE, Jonason AS, Bussler H, et al. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies. Cancer Immunol. Res. 2015;3(6):689-701. 4 Vaccinex Inc. Vaccinia Technology. [Web page]. 2015; vaccinex.com/activmab/vaccinia-technology/ 5 Smith ES, Zauderer M. Antibody library display on a mammalian virus vector: combining the advantages of both phage and yeast display into one technology. Curr Drug Discov Technol. 2014;11(1):48-55. 6 Kingma EM, van Duijn E, Timman R, van der Mast RC, Roos RA. Behavioural problems in Huntington's disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry. 2008;30(2): 155-161. H D I N S I G H T S