University of Pittsburgh researchers have developed novel, efficient oncolytic herpes simplex viral vectors (oHSVs). Using retargeting, where herpes simplex viral vectors can be engineered to selectively target only cancer cells and promote oncolysis, these novel oHSVs have the potential to revolutionize therapy in oncology.
Description
Using oHSVs is a safe and effective approach to induce tumor cell death. Vital in this approach is retargeting the viral vector to selectively target cells expressing tumor-associated cell surface receptors to facilitate cell infection and subsequent cell death. Typically, this is done through modifications to the N-terminus of glycoprotein D (gD) using a single-chain antibody (scFv). In this novel approach, VHH antibodies (nanobodies) were used at different positions on the N-terminus of gD leading to more efficacious oHSVs. These novel retargeted oHSVs could lead to the development of more cancer-cell-specific oHSVs, reducing the risk of off-target side effects and improving outcomes in patients.
Applications
1. Targeted oncology treatment
Advantages
Retargeting of oHSVs could be achieved through modification of the viral envelope glycoprotein D (gD) to eliminate recognition by the entry receptors nectin-1 and herpesvirus entry mediator (HVEM). While HVEM recognition can be abolished by various amino acid substitutions, deletions, or insertions roughly extending to residue 30 of the N-terminal region of gD, modifications to impair virus entry through nectin-1 are more challenging. Residue 38 is critical to nectin-1 binding. This novel approach aims to remove residue 38 and use various single domain (VHH/SD) antibodies to target a tumor-specific epidermal growth factor receptor (EGFR) variant EGFRvIII to facilitate tumor cell infection. These novel oHSVs would be more selective to tumor cells allowing for more targeted treatment of cancer cells.
Invention Readiness
Previous efforts to insert a point mutation at residue 38 (Y38C) along with a scFv to target the EGFRvIII between gD residues 1 and 25 led to efficient EGFR-dependent infection. However, position 38 reverted to tyrosine (Y) in nectin-expressing cells removing selectivity and reducing EGFR-dependent virus entry. To overcome this, residue 38 was completely deleted from the N-terminus of gD (gDD38) and three more compact VHH/SD antibodies (7D12, EgA1, and 9G8), known EGFR inhibitors, were inserted at varying positions in gDD38. In vitro testing in a U251 flank tumor model found these single-domain-based oHSVs could selectively infect tumor cells via EGFR dependent virus entry and demonstrated lateral spread compared to scFv-based oHSVs, while minimally infecting other cells. Further work is required to test these oHSVs in animals.
IP Status
https://patents.google.com/patent/WO2024151990A1
