Mechanism of Action of Glycoprotein D (gD)
Herpes simplex virus gD is a genetically encoded checkpoint modifier adjuvant. It works at the site of T cell induction, promoting enhanced CD8+ T cell responses and broadened responses by recognizing subdominant epitopes that generally fail to reach the threshold for T cell activation. We believe that inducing potent, prolonged, broad, and highly functional CD8+ T cell responses can translate into novel, adaptable, and accessible therapies to fight disease, alone or in combination with other treatments.
Herpes Simplex Virus gD – The Genetically Encoded Checkpoint Modifier Adjuvant
Anti-PD-1 Monoclonal Antibody Plus gD-containing Combination Demonstrated Delayed Tumor Growth
In the preclinical melanoma (Melapoly) model, anti-PD-1 monoclonal antibody plus gD-containing combination demonstrated delayed tumor growth1,5
Benefits of gD’s Mechanism of Action
Preclinical studies in HIV, HBV, HCV, malaria, COVID-19, ebola, and in certain cancers (i.e. melanoma) have demonstrated the safety and immunogenic benefits of gD.6–10 This includes data demonstrating that gD amplifies and broadens CD8+ T cell responses to different disease-specific antigens.6–10 gD has shown promising preclinical efficacy, not only in our anti-HBV immunotherapy (VRON-0200), but also in cancers associated with HPV and melanoma.1,2,11,12 It is believed to have lower risk of “off target” side effects.
Checkpoint modification by gD lowers the CD8+ T cell activation threshold.
Checkpoint Modification (gD): Amplifies CD8+ T cell Responses
Checkpoint Modification (gD): Broadens CD8+ T cell Responses
Checkpoint Modification (gD): Improved Efficacy
AdC, chimpanzee adenovirus serotype 68; AdC6, heterologous chimpanzee adenoviral viral vector of serotype 6; Ad, adenovirus; Ag, antigen; ANOVA, analysis of variance; APC, antigen presenting cell; BL, baseline; BTLA, B-and T-lymphocyte attenuator; CD, cluster of differentiation; E7, HPV E7 oncoprotein; gD, glycoprotein D; HBV2, HBV core & pol; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPV, human papillomavirus; hTrp, human tyrosinase-related protein; HVEM, herpes virus entry mediator; IFN, interferon; IL, interleukin; I.P., intraperitoneal injection; IV, intravenous; LIGHT, lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes; Melapoly, melanoma antigens (Trp-1, Trp-2, gp100, mutated BRAFV600E); MHC, major histocompatibility complex; mTrp, mouse tyrosinase-related protein; PD-1, programmed cell death protein-1; PolN, N terminus of polymerase; SEM, standard error of mean; TCR, T cell receptor; tet, tetramer; TNF, tumor necrosis factor; Trp, tyrosinase-related protein; VRON-0200, gD fused to HBV core & pol.
- Luber A, et al. ESMO TAT 2021:Abstract 143.
- Xiang ZQ, et al. ASCO-SITC Clinical Immuno-Oncology Symposium 2020:Abstract 71.
- Stiles KM, et al. J Virol. 2010;84:11646–60.
- Virion Therapeutics. Data on file.
- Zhang Y, et al. Cancer Cell. 2017;32:377–91.
- Barnes E, et al. Sci Transl Med. 2012;4:115ra1.
- Ledgerwood JE, et al. N Engl J Med. 2014; 376:928–38.
- Hayton E-J, et al. PLoS One. 2014;9:e101591.
- Tiono AB, et al. PLoS One. 2018;13:e0208328.
- Guo J, et al. Hum Vaccin Immunother. 2018;14:1679–85.
- Zhang Y and Ertl HCJ. J Immunol. 2014;193:1836–46.
- Hasanpourghadi M, et al. EASL 2021:Abstract OS-2478.
- Hasanpourghadi M, et al. Virol J. 2021;18:242.
- Novikov M, et al. BioRxiv. Published online January 1, 2022. DOI: 10.1101/2022.02.23.481620.
- Lasaro M, et al. Mol Ther. 2011;19:1727–36.