Development of Novel Cancer Immunotherapeutics Utilizing Cell-Targeting Peptides




Diaz, Tracy Montie

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Cancer immunotherapy is an emerging treatment option that offers high tumor specificity and efficacy. Immune therapies for cancer can be divided into two main types: active and passive. Active therapy strives to achieve a long term protective immunity against a tumor antigen while passive therapy supplies exogenous immunological reagents for anti-tumor effector functions. Both immunotherapies can be improved by utilizing cell targeting peptides.

Dendritic Cell Targeting Peptides: Cancer vaccines can elicit immune responses against tumor antigens. Antigen-pulsed in vitro matured dendritic cells (DCs) are used for higher efficacy. However, this method does not provide a significant therapeutic immune response. A more robust anti-tumor immune response could potentially be achieved through in vivo DC targeting of tumor antigens. Through phage-displayed peptide library panning protocol, four different DC-targeting phage clones were isolated. Of those, XS52.1 and XS52.3 bind specifically to the XS52 immature dendritic cells. The XS52.3 phage clone also binds bone-marrow dendritic cells (BMDCs) from Balb/c and C57BL/J6 mice. Each phage clone elicited heightened anti-phage antibody production in both mouse strains. Potential future studies will determine if these peptides can be used to target antigen to DCs for in vivo cancer vaccines.

Peptide-Antibody Targeting: Monoclonal antibodies directed against tumor antigens have been successful in clinics, but problems remain with identifying and validating new targets. Modification of the antibody scaffold for distinct applications can also be problematic. Using our phage display panning protocol, we have identified ligands of high affinity and specificity against a panel of human non-small cell lung cancer (NSCLC) cell lines. Furthermore, these peptide-targeting ligands can be chemically synthesized and easily modified for different uses. In my studies, synthetic-peptide ligands have been used to redirect antibody targeting by using biotinylated-tetrameric peptides and anti-biotin antibodies. These results suggest that peptide-antibody conjugates utilizing isolated peptides can be used to redirect antibody targeting. This methodology would increase the antibody repertoire available for therapy.