Engineered Bispecific Antibodies for Targeted Inhibition of Tumor Metastasis

Description:
Unmet Need. In the United States, 40% of males and 38% of females will develop cancer in their lifetimes. Many types of cancers, including triple negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC), have devastatingly low five year survival rates, even after the removal of primary tumors. Poor prognoses for these cancer results from metastasis, the spread of cancer from the primary site to a distal site in the body via the circulatory or lymphatic system. Collectively, metastasis is responsible for 90% of all cancer-related deaths. It is often assumed that anti-cancer therapeutics designed to inhibit growth of the primary tumor will also inhibit metastasis, or that interrupting metastasis will not be necessary if primary tumor inhibition is sufficient. Thus, current clinical therapies do not directly address the process of metastasis, and in fact many approved anti-cancer therapies actually induce formation of metastases. Consequently, there is a critical unmet need for novel anti-cancer drugs that efficiently block metastasis to improve patient care and increase survival rates for a range of deadly cancers.
 
Technology Overview Johns Hopkins researchers have developed novel bispecific antibodies (BsAbs) that simultaneously bind interleukin (IL)-6 and IL-8 receptors to selectively target the synergistic IL-6/IL-8 pathway, which drives the migration of tumorigenic, metastatic cells. The bispecific strategy allows for enhanced binding to both the IL-6 and IL-8 receptors through avidity effects, thereby resulting in synergetic suppression of tumor cell metastasis, while also minimizing off-target effects by favoring interactions with tumor cells, which uniquely express both receptors. The bispecific approach also reduces the likelihood of acquired resistance through mutational escape, and addresses important downstream manufacturing concerns by eliminating the need for optimizing dosing ratios, which would be required for mixed-agent therapy. The researchers specifically designed these BsAbs to treat highly aggressive cancers, such as TNBC and PDAC, but they can be applied more broadly to other metastatic cancer types in the future.   
 
Stage of Development
The inventors have generated BsAbs specific for the IL-6 and IL-8 receptors to target a synergistic pathway involved in tumor cell migration and metastasis. In vitro testing has shown that these bispecific antibodies are capable of binding the IL-6 and IL-8 receptor and blocking their interaction with the cytokine. They have also demonstrated the ability of BsAbs to block 3D cell migration and metastasis of mouse TNBC tumors, even more effectively than monoclonal antibody therapy or antibody/small molecule combination treatments. Further research and development is required to test and optimize these bispecific antibodies in animal models of various metastatic cancer to advance this new technology into clinical studies.

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