(188bo) Engineering Bispecific Antibodies to Synergistically Inhibit Tumor Metastasis

Metastasis is responsible for 90% of deaths from solid tumors. However, many FDA cancer treatments are focused on preventing tumor cell proliferation rather than migration, and the mechanisms driving tumor metastasis remain unclear. Recently, a synergistic signaling pathway involving the interleukin-6 (IL-6) and IL-8 cytokines (IL-8) was reported to promote tumor metastasis, and inhibition of this pathway was demonstrated to prevent cancer cell migration. Recombinant antibodies serve as valuable therapeutic candidates due to their ability to specifically target their ligands with high potency, and bispecific antibodies offer the additional advantages of enhanced affinity and avidity and reduce the chances of secondary resistance due to mutational escape. We engineered a panel of bispecific antibody-based constructs that simultaneously block activation of the IL-6 and IL-8 receptors and tested their efficacy in blocking cell migration in highly metastatic cancer types including pancreatic ductal adenocarcinoma and triple negative breast cancer. Findings from 3-D cellular studies and mouse tumor models further informed the design and optimization of effective therapeutic antibodies targeting cancer metastasis.