Pepinemab (VX15/2503) Neurology

Conclusions of the SIGNAL study in Huntington and implications for treatment of other slowly progressive neurodegenerative diseases
Clin Transl Med. 2023;13:e1169.
Zauderer M, Evans EE.
Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial
Nature Medicine, Aug 08,2022. doi: 10.1038/s41591-022-01919-8
Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, Mishra V, Manber R, Walters KA, Kowarski L, Oakes D, Siemers E, Kieburtz KD, Zauderer M, and the Huntington Study Group SIGNAL investigators.
Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity
J Neuroinflammation 19, 200 (2022).
Evans EE, Mishra V, Mallow C, Gersz EM, Balch L, Howell A, Reilly C, Smith ES, Fisher TL, Zauderer M.
Anti-Semaphorin 4D Rescues Motor, Cognitive, and Respiratory Phenotypes in a Rett Syndrome Mouse Model
Int. J. Mol. Sci. 2021, 22, 9465
Mao, Y.; Evans, E.E.; Mishra, V.; Balch, L.; Eberhardt, A.; Zauderer, M.; Gold, W.A.
Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial.
Neurol Neuroimmunol Neuroinflamm 2017. 4: e367.
LaGanke, C., L. Samkoff, K. Edwards, L. Jung Henson, P. Repovic, S. Lynch, L. Stone, D. Mattson, A. Galluzzi, T. L. Fisher, C. Reilly, L. A. Winter, J. E. Leonard, and M. Zauderer.
Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease.
Neurobiol Dis. 2015 Feb 3; 76:46–56.
Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, Jonason A, Felczak B, Zhang W, Kovalik V, Waltl S, Hall G, Pouladi MA, Smith ES, Bowers WJ, Zauderer M, Hayden MR.
SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.
Neurobiol Dis. 2014 Oct 18;73C:254-268. doi: 10.1016/j.nbd.2014.10.008.
Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, Klimatcheva E, Mallow C, Cornelius C, Leonard JE, Marchi N, Janigro D, Argaw AT, Pham T, Seils J, Bussler H, Torno S, Kirk R, Howell A, Evans EE, Paris M, Bowers WJ, John G, Zauderer M.

Other key neurology references:

FDG-PET in the Natural History of Huntington’s Disease

Tang CC, Feigin A, Ma Y, et al. Metabolic network as a progression biomarker of premanifest Huntington’s disease. J Clin Invest. 2013;123(9):4076-4088. doi:10.1172/JCI69411

Wilson H, De Micco R, Niccolini F, Politis M. Molecular Imaging Markers to Track Huntington’s Disease Pathology. Front Neurol. 2017;8:11. Published 2017 Jan 30. doi:10.3389/fneur.2017.00011

Correlation between Decline in FDG-PET and Cognitive Decline in Alzheimer’s Disease

Landau SM, Harvey D, Madison CM, et al. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol Aging. 2011;32(7):1207-1218. doi:10.1016/j.neurobiolaging.2009.07.002

Hanseeuw BJ, Betensky RA, Schultz AP, et al. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann Neurol. 2017;81(4):583-596. doi:10.1002/ana.24910

Khosravi M, Peter J, Wintering NA, et al. 18F-FDG Is a Superior Indicator of Cognitive Performance Compared to 18F-Florbetapir in Alzheimer’s Disease and Mild Cognitive Impairment Evaluation: A Global Quantitative Analysis. J Alzheimers Dis. 2019;70(4):1197-1207. doi:10.3233/JAD-190220

Cognitive and Biological Change During Natural Progression of Huntington’s

Stout JC, Queller S, Baker KN, et al. HD-CAB: a cognitive assessment battery for clinical trials in Huntington’s disease 1,2,3. Mov Disord. 2014;29(10):1281-1288. doi:10.1002/mds.25964

Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol. 2013;12(7):637-649. doi:10.1016/S1474-4422(13)70088-7

Role of Astrocytes in Huntington’s Disease

Khakh BS, Beaumont V, Cachope R, Munoz-Sanjuan I, Goldman SA, Grantyn R. Unravelling and Exploiting Astrocyte Dysfunction in Huntington’s Disease. Trends Neurosci. 2017;40(7):422-437. doi:10.1016/j.tins.2017.05.002

Osipovitch M, Asenjo Martinez A, Mariani JN, et al. Human ESC-Derived Chimeric Mouse Models of Huntington’s Disease Reveal Cell-Intrinsic Defects in Glial Progenitor Cell Differentiation. Cell Stem Cell. 2019;24(1):107-122.e7. doi:10.1016/j.stem.2018.11.010

Diaz-Castro B, Gangwani MR, Yu X, Coppola G, Khakh BS.Astrocyte molecular signatures in Huntington’s disease. Sci Transl Med. 2019;11(514):eaaw8546. doi:10.1126/scitranslmed.aaw8546

Role of Astrocytes in Alzheimer’s Disease

Cai Z, Wan CQ, Liu Z. Astrocyte and Alzheimer’s disease. J Neurol. 2017;264(10):2068-2074. doi:10.1007/s00415-017-8593-x

Habib N, McCabe C, Medina S, et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat Neurosci. 2020;23(6):701-706. doi:10.1038/s41593-020-0624-8

Pepinemab (VX15/2503) Oncology

A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non–Small Cell Lung Cancer
Clinical Cancer Research, 2021 DOI: 10.1158/1078-0432.CCR-20-4792
Shafique MR, Fisher TL, Evans EE et al.
Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function.
Cancer Immunol Res. 2019;7(2):282-291. doi:10.1158/2326-6066.CIR-18-0156
Clavijo PE, Friedman J, Robbins Y, et al.
Antibody blockade of semaphorin 4D promotes immune infiltration into tumor and enhances response to other immunomodulatory therapies.
Cancer Immunol Res. 2015 Jun;3(6): 689-701.
Evans EE, Jonason AS Jr, Bussler H, Torno S, Veeraraghavan J, Reilly C, Doherty MA, Seils J, Winter LA, Mallow C, Kirk R, Howell A, Giralico S, Scrivens M, Klimatcheva K, Fisher TL, Bowers WJ, Paris M, Smith ES, Zauderer M.
Immunomodulation of the tumor microenvironment by neutralization of Semaphorin 4D.
Invited “Author’s View”. OncoImmunology, 2015. 4:12, e1054599, DOI: 10.1080/2162402X.2015.1054599
Evans EE, Paris M, Smith ES, Zauderer M.
Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors.
Clin Cancer Res. 2016;22(4):827-836. doi:10.1158/1078-0432.CCR-15-0431
Amita Patnaik, Glen J. Weiss, John E. Leonard, Drew Warren Rasco, Jasgit C. Sachdev, Terrence L. Fisher, Christine Reilly, Laurie A. Winter, Robert B. Parker, Danielle Mutz, Lisa Blaydorn, Anthony W. Tolcher, Maurice Zauderer and Ramesh K. Ramanathan.

Pepinemab (VX15/2503) Nonclinical and Bioanalytical

Nonclinical Safety Evaluation of VX15/2503; a Humanized IgG4 Anti-SEMA4D Antibody.
Mol Cancer Ther. 2015;14(4):964-972. doi:10.1158/1535-7163.MCT-14-0924
Leonard JE, Fisher TL2 Winter LA, Cornelius CA, Reilly C, Smith ES, Zauderer M.
Generation and preclinical characterization of an antibody specific for SEMA4D.
MAbs. 2016;8(1):150-162. doi:10.1080/19420862.2015.1102813
Fisher TL, Reilly CA, Winter LA, Pandina T, Jonason A, Scrivens M, Balch L, Bussler H, Torno S, Seils J, Mueller L, Huang H, Klimatcheva E, Howell A, Kirk R, Evans E, Paris M, Leonard JE, Smith ES, Zauderer M.
Saturation monitoring of VX15/2503, a novel semaphorin 4D-specific antibody, in clinical trials.
Cytometry B Clin Cytom. 2016;90(2):199-208. doi:10.1002/cyto.b.21338
Fisher, T. L., J. Seils, C. Reilly, V. Litwin, L. Green, J. Salkowitz-Bokal, R. Walsh, S. Harville, J. E. Leonard, E. Smith, and M. Zauderer.


Use of poxvirus display to select antibodies specific for complex membrane antigens
mAbs, 15:1 (2023)
Smith ES, Balch LA, Scrivens M et al.
A Vaccinia-based system for directed evolution of GPCRs in mammalian cells
Nat Commun 14, 1770 (2023).
Klenk, C., Scrivens, M., Niederer, A. et al.
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 Mar;11(1):48-55 – March 2014
Smith ES, Zauderer M.
Antibody Selection from Immunoglobulin Libraries Expressed in Mammalian Cells.
In Therapeutic Antibodies: From Bench to Clinic. Edited by Zhiqiang An. 2009 p283-307. – January 2009
Smith ES, Zauderer M.
In vitro generation of tumor specific T cells that recognize a shared antigen of AML: molecular characterization of TCR genes.
Leuk Res. 2007;31(2):195-202. doi:10.1016/j.leukres.2006.04.007
Coppage M, Belanger T, Zauderer M, Sahasrabudhe D.
Construction of cDNA Libraries in Vaccinia Virus
Methods Mol Biol. 2004;269:65-76. doi:10.1385/1-59259-789-0:065
Smith, E.S., S. Shi, and M. Zauderer
Lethality-Based Selection of Recombinant Genes in Mammalian Cells: Application to Identifying Tumor Antigens
Nat Med. 2001;7(8):967-972. doi:10.1038/91017
Smith, E S.., A. Mandokhot, E. Evans, L. Mueller, M.A. Borrello, D. Sahasrabudhe, and M. Zauderer.
Construction and characterization of vaccinia direct ligation vectors.
Virology. 1997;238(2):444-451. doi:10.1006/viro.1997.8828
Merchlinsky M, Eckert D, Smith E, Zauderer M.


CXCL13 antibody for the treatment of autoimmune disorders.
BMC Immunol. 2015;16(1):6. Published 2015 Feb 12. doi:10.1186/s12865-015-0068-1
Klimatcheva E, Pandina T, Reilly C, et al.
Anti-CXCL13 antibody can inhibit the formation of gastric lymphoid follicles induced by Helicobacter infection.
Mucosal Immunol. 2014;7(5):1244-1254. doi:10.1038/mi.2014.14
Yamamoto K, Nishiumi S, Yang L, et al.


CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses.
Cancer Immunol Immunother. 2013;62(4):747-760. doi:10.1007/s00262-012-1381-7
Corgnac S, Perret R, Derré L, et al.
Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice.
J Clin Invest. 2008;118(3):994-1005. doi:10.1172/JCI33249
Stirnemann K, Romero JF, Baldi L, et al.