(22d) Engineered Bispecific Antibodies for Targeted Inhibition of Cancer Metastasis

Metastasis, the spread of cancer from a primary site to a distal site through the circulatory or lymphatic systems, is responsible for 90% of all cancer-related deaths. However, current anti-cancer therapies are designed to inhibit or reverse growth of the primary tumor, and fail to address metastasis. In contrast with the conventional belief thattargeting tumor growth will also inhibit metastasis, many current clinical therapies actuallypromotemetastasis, leading to drug resistance or disease recurrence. Consequently, there is an urgent medical demand for a clinically relevant therapeutic approach that specifically and effectively targets cancer metastasis.

Recently, our team discovered a new biochemical pathway involving the interleukin-6 (IL-6) cytokine and the interleukin-8 (IL-8) chemokine that actively drives tumor cell migration. We further demonstrated that blocking signaling through both the IL-6 and IL-8 receptors using an antibody/small molecule combination therapy regimen significantly decreased tumor cell migration in vitroand also markedly suppressed cancer metastasis in vivo. However, translation of this combination therapy strategy into patients is complicated by logistical challenges, such as dosing ratio optimization, as well as increased regulatory hurdles. Moreover, small molecule drugs face significant clinical challenges in terms of specificity.

To overcome the logistical and regulatory limitations associated with antibody/small molecule combination therapy, we have engineered newbispecific antibodiesthat simultaneously engage the IL-6 and IL-8 receptors (IL-6R and IL‑8R). Compared to monoclonal antibodies, bispecific antibodies exhibit enhanced affinity, potency, and selectivity while reducing risk of drug resistance by concurrently blocking two different pathways.The novel antibodies we designed have vast clinical potential for treating a range of cancer types, particularly highly aggressive neoplasias such as triple negative breast cancer and pancreatic duct adenocarcimona. We have characterized the binding and competitive properties of our engineered bispecific antibodies, and demonstrated their efficacy in blocking tumor cell migration in 3D collagen matrices and inhibiting metastasis in mouse tumor xenograft models. Overall, these results present an exciting opportunity for targeted inhibition of cancer metastasis, which can also synergize with current clinical therapies targeting tumor growth.