oncolytic adenovirus ORCA-010

A replication competent, oncolytic adenovirus serotype 5 (Ad5) that has been modified with a delta24 (d24) deletion, an incorporation of an RGD-4C motif in the Ad fiber protein, and an insertion of the T1 mutation in E3/19K gene, with potential oncolytic activity. Upon administration, oncolytic adenovirus ORCA-010 binds to specific Ad3 receptors that are highly expressed on certain tumor cells. This results in the replication of oncolytic adenovirus Ad5/3-delta24 in tumor cells and induces tumor cell lysis which may potentially result in the activation of a systemic immune response against tumor-associated antigens (TAAs). The Ad5/3-delta24 has a 24 base pair deletion in constant region 2 of the E1A gene which allows for selective replication in cells that are defective in the retinoblastoma gene (Rb) or cyclin-dependent kinase inhibitor-2A (CDKN2A or p16INK4a). As most tumor cells are defective in the Rb/p16 pathway, this virus selectively replicates in these cells. The RGD-4C motif is a 9-amino acid peptide that binds to various and enhances viral-cell receptor binding by allowing for a Coxsackie-adenovirus receptor (CAR)-independent infection of tumor cells, which is the natural route of viral binding, as CAR expression is often deficient on cancer cells. As integrins are often overexpressed on tumor cell surfaces, integrin receptor binding enhances tumor cells binding and infection by the Ad. The T1 mutation enhances the Ad5 release from tumor cells and promotes spreading throughout the tumor, thereby enhancing anti-tumor activity. The T1 mutation, a single Adenine insertion at position 445 of the nucleotide sequence of the E3/19K gene of Adenovirus, creates a truncated E3/19K protein that is relocated to the plasma membrane due to the disruption of its ER retention signal. This increases plasma membrane permeability and enhances the release of Ad5.