SAN DIEGO—A Toll-like receptor (TLR) antagonist can target B-cell lymphoma cells harboring the MYD88 L265P mutation, preclinical research suggests.
The compound, IMO-8400, decreased the viability of mutated diffuse large B-cell lymphoma (DLBCL) cells and Waldenström’s macroglobulinemia (WM) cells in vitro.
IMO-8400 also decreased tumor growth and prolonged survival in mice with MYD88 L265P-positive DLBCL.
Lakshmi Bhagat, PhD, and colleagues from the Cambridge, Massachusetts-based Idera Pharmaceuticals, Inc.—the company developing IMO-8400—presented these results at the AACR Annual Meeting 2014 (abstract 2570).
The researchers said their data provide additional evidence that the MYD88 L265P mutation results in over-activation of TLR7- and TLR9-mediated signaling, and blocking these TLRs leads to tumor cell death. IMO-8400 is an oligonucleotide-based antagonist of TLRs 7, 8, and 9.
In experiments with OCI‐Ly10 cells (DLBCL cells harboring the MYD88 L265P mutation), IMO-8400 prompted cell death and decreased proliferative cell signaling. But the compound did not produce these effects in SU-DHL-6 cells (DLBCL cells without the MYD88 L265P mutation).
In OCI‐Ly10 cells, IMO-8400 inhibited the IRAK-1, IRAK-4, BTK, STAT-3, Ik-Ba, and NF-κB pathways. The compound did not affect signaling pathways in SU-DHL-6 cells.
IMO-8400 also inhibited tumor growth in a mouse model of MYD88 L265P-positive, activated B-cell-like DLBCL. This inhibition was linked to the suppression of tumor-associated cytokines, including human IL-10, IL-2R, IP-10, and MIG.
Treated mice had significantly longer survival than controls, and the effect was dose-dependent. When IMO-8400 was given at 12.5 mg/kg, the P value was 0.0002. At 25 mg/kg, the P value was less than 0.0002. And at 50 mg/kg, the P value was less than 0.0001.
The researchers also found that IMO‐8400 inhibited cell viability, cytokine production, and signaling pathways in MYD88 L265P-positive WM cells. They observed these effects in the MWCL‐1 cell line and in cells from WM patients.
The team said these results provide a “strong foundation” for accelerating the clinical development of IMO-8400 in patients with B-cell lymphomas harboring the MYD88 L265P mutation.
To that end, Idera has opened enrollment in a phase 1/2 trial of IMO-8400 in WM patients who are refractory to prior therapies. The company has also submitted a protocol to the US Food and Drug Administration to conduct a phase 1/2 trial in patients with MYD88 L265P-positive DLBCL.
