ABSTRACT Metastatic castration resistance prostate cancer (mCRPC) is the advanced state of prostate cancer where majority of patients succumb to ineffective treatment perspectives like androgen deprivation alongside salvage therapies. mCRPC is predominantly orchestrated by androgen receptor (AR)‐dependent gene expression. On the account of AR being a “potentially attractive immunological target”, an immunoinformatics pipeline was built to identify and screen mutation‐independent, broad MHC covering, potential antigenic, non‐allergenic, non‐toxic and soluble epitopes. The filtered epitopes required assembly into a unified construct with interconnecting linkers and adjuvant and further TLR3‐docking. We chose TLR3 because of its pro‐apoptotic activity in prostate cancer, to check active immune response by the vaccine. Our study was not confined to the use of a conventional adjuvant like human beta defensin‐3 but it extended to the scope of utilization of a protein‐based TLR3‐specific agonist as an adjuvant for assembling the second composite construct. Our path was guided by the discovery of TLR3‐specific agonist minibinder 8.6 (a small, hyperstable protein) by Adams et al. An extensively comparative molecular dynamics study of the free state and bound states of the two constructs unveiled a more stable interaction, complex stability and immune response attributing to the specificity of the minibinder‐based construct towards TLR3. Our work circumscribes a multi‐headed approach beginning with peptide subunit multi‐epitope vaccine construct design for mitigating mCRPC; secondarily, endorsing the advocacy of TLR3‐agonizing minibinders as vaccine adjuvants for enhanced immunity and finally posing a comparative framework of minibinder 8.6 over HBD3, as a more potential adjuvant, apprehending wet‐lab proof.
Paul et al. (Fri,) studied this question.