Effective Cancer Immunotherapy through Bi-Functional Molecules
Until recently, cancer immunotherapies have relied primarily on strategies leading to direct immune stimulation, by pressing on a variety of "gas pedals" of the immune system to initiate antitumor attack. The efficacy of this approach is diminished by a countervailing force of the tumor microenvironment, which engages multiple "brakes" limiting the immune cell action. To overcome this complex blockade, our drugs are designed to both press the “gas pedal” while releasing the brakes simultaneously. This dual effect results from the combination of a CpG DNA-based immunoadjuvant with oligonucleotide-based STAT3 inhibitor, resulting in a potent synergistic effect which has already shown promising results against tumor models in mice.
Lead Candidate: CSI-2B
A CpG based immunoadjuvant conjugated to a competitive inhibitor of STAT3
CSI-2B (CpG-STAT3 Inhibitor-2B) consists of two functional oligonucleotide parts, a CpG immunoadjuvant and a competitive inhibitor of STAT3, which act synergistically to achieve maximum level of immunostimulation. The first part is a short single-stranded DNA sequence with unmethylated CpG motif (mimicking bacterial DNA) to allow for spontaneous uptake into target cells and stimulating immunity. The second part of the molecule comprises of high affinity STAT3-binding DNA sequence, which acts as a competitive STAT3 inhibitor. The CSI-2B conjugate is quickly internalized by target cells, leading to suppression of STAT3 signaling both in vitro and in vivo. In tumor-bearing mice, CSI-2B has potently inhibited STAT3 and reduced the expression of survival genes and upregulation of antigen-presenting machinery and immunostimulatory mediators. Altogether, bi-functional CSI-2B molecule unleashes potent antitumor immune responses leading to tumor growth inhibition and regression with long-term protective effect preventing cancer relapse.