Development of therapeutic chemokine-based formulations

National Institute On Aging

Investigators

Linked publications & trials

Abstract

1) We have developed two novel technologies for depletion of unwanted subsets of cells at will. The strategy is based on the nature of chemokines to deliver antigens to the cytosol of cells expressing respective chemokine receptors. One technology designated chemotoxin, a chimeric chemokine fused with toxic moieties, can specifically kill cells expressing respective chemokine receptors. TARC-chemotoxin efficiently eradicates established leukemia (CEM cells) generating almost 100% tumor- free mice . We propose that the strategy may be applied for treatment of human T cell malignant diseases when patients immune system is severely immunocompromised. The results of this study have been recently published (Baatar et al, 2008a). We have also utilized this technology to specifically deplete Tregs in mice to augment immune responses to cancer vaccines. Part one of this ongoing project demonstrates that TARC-chemotoxin-mediated depletion of Tregs enhance CD8+ T cell responses to melanoma antigen gp100. This is an encouraging result, although its clinical significance remains to be evaluated. [unreadable] [unreadable] 2) Despite significant potency and attractiveness of siRNA and shRNA-mediated gene silencing methods, the technology can not be efficiently used in vivo. The major problem is that there is almost no practical way that delivers/targets oligonucleotides to cells of interest. To solve this, we aimed to develop chemokine-based technology for the delivery of siRNA to cells expressing the respective chemokine receptors. We have hypothesized that this can be achieved by generating modified chemokines that contain RNA binding domains (RBD). The technology designated chemoarp is still under development. However, we have successfully demonstrated proof of principle by delivering siRNA to tumor cells that express CCR4. For example, TARC-Arp (TARC fused with RBD) was able to specifically bind siRNA when mixed in PBS. Importantly, chemoarp delivered siRNA into cells expressing CCR4 and disabled/silenced expression of the gene of interest.