Cancer immunosurveillance-stimulatory effects of ACBP/DBI neutralization

Objective

Acyl CoA binding protien (ACBP, encoded by diazepam binding inhibitor, DBI) is a novel glucocorticoid-induced tissue hormone that contributes to tissue aging. In still health individuals, the plasma concentrations of ACBP/DBI protein increase before cancer diagnosis. ACBP/DBI mediates immunosuppressive effects, meaning that its neutralization improves cancer immunosurveillance. Therefore, ACBP/DBI might be considered as an immune checkpoint. Thus far, we have demonstrated the immunostimulatory and cancer immunotherapeutic effects of ACBP/DBI inhibition by the inducible knockout of the Dbi gene or by means of a tool antibody recognizing mouse (but not human) ACBP/DBI protein. Here, we propose the validation of an interspecies cross-reactive monoclonal antibody (mAb) recognizing an epitope that is shared among human and mouse ACBP/DBI. We plan to test this new (unpublished) antibody in three experimental settings: (i) the neutralization of human recombinant ACBP/DBI protein, abolishing its capacity to elict chloride fluxes via the GABAA receptor expressed by human cells; (ii) the reversal of the immunosuppressive effects of human recombinant ACBP/DBI protein or glucocorticoids (which transcriptionally induce ACBP/DBI) on primary human peripheral blood mononuclear cells; and (iii) the improvement of immunosurveillance and the reversal of immunosuppression by glucocorticoids in mouse models of non-small cell lung cancer, fibrosarcoma and breast cancer. Altogether, these results should allow to file a composition-of-matter patent describing a therapeutically useful anti-ACBP/DBI mAb. Moreover, such data will increase the interest of potential investors in a yet-to-be-financed biotech company developing therapeutic anti-ACBP/DBI mAbs for the treatment of cancer and other age-related diseases.