Chimeric diphtheria toxin– <scp>CCL8</scp> cytotoxic peptide for breast cancer management

Deregulation of chemokine CCL8 expression is common in various malignancies and other pathologies and plays a causative role in disease progression. However, despite CCL8's acknowledged role in pathology, inhibition of its activity does not represent a strategy of choice for cancer management. This is because its function overlaps with that of the other structurally related chemokines, and its activity is mediated by more than one receptor. To overcome this limitation, we hypothesized that ablation of CCL8 cellular targets, as opposed to disruption of CCL8 activity, may be more advantageous. Therefore, we developed DTCCL8, a chimeric cytotoxic peptide that delivers diphtheria toxin into cells expressing CCL8 receptors which are overexpressed in both the cells of tumor microenvironment and the cancer cells. The specificity of this peptide was confirmed in vitro by testing the cytotoxic activity of breast cancer cells overexpressing CCR5, a major CCL8 receptor, and by a neutralizing anti-CCL8 antibody we developed. In vivo, DTCCL8 transiently reduced lymphocytes in blood, and its anticancer activity was confirmed in mouse breast cancers triggered by the polyoma middle T oncogene. These findings suggest that DTCCL8 can be used as a prototype for the development of a novel class of breast cancer therapeutics, targeting chemokine targets instead of inhibiting their activity. These cytotoxic peptides may also be useful for managing cancers and other immune system-associated pathologies.