Therapeutic antibodies are one of the most successful therapeutics for patients with solid tumors. However, the abnormal physiological properties of tumor tissue, such as the incomplete blood vessels and extracellular matrix components, limit the penetration of mAbs from blood. In addition, the intrinsic properties of mAbs, containing the relatively large size and high-affinity antigen binding, also limit vascular extravasation and transport within tumor tissue. Although various approaches have attempt to enhance tumor penetration of mAb, promising promoter agent has been developed not yet. Besides limitation of tumor penetration, therapeutic mAbs exhibit low response rate in the treatment of cancer patients because of intrinsic or acquired resistance. Therefore, I conducted a study to increase the efficacy of mAbs by overcoming these limitations.
In chapter 2, I report the development of immunoglobulin Fc-fused, neuropilin-1-specific peptide, which enhance tumor tissue penetration. An immunoglobulin Fc-fused peptide, Fc-TPP11, specifically binds to the VEGF-binding site of neuropilin-1 (NRP1) and increases the tumor penetration of co-injected anti-cancer drug or antibody. This is showing that Fc-TPP11 can be used as a tumor penetration-promoting agent.
In chapter 3, I identified resistance mechanism to cetuximab (Ctx), anti-EGFR mAb, in pancreatic ductal adenocarcinoma cells (PDADs). Also, to overcome resistance, I generated EGFR and NRP1 dual targeting antibody, Ctx-TPP11. Ctx-TPP11 efficiently suppressed the growth of cetuximab-resistant PDACs, in vitro and in vivo.
In chapter 4, I demonstrated that strategy for co-targeting of EGFR and NRP1 can overcome resistance to the five EGFR-targeted antibodies, including cetuximab, in non-small cell lung cancer (NSCLCs), too. Moreover, I found that resistance mechanism to cetuximab different from PDACs is integrin β3-driven bypass signaling in NSCLCs harboring Ras mutation. I validated that suppression of integrin β3-mediated signaling by targeting NRP1, while inhibiting EGFR signaling, restores cetuximab resistance in vitro.
My conclusion is that the solid tumor-penetrating peptide (TPP) platform technology using peptide TPP11, targeting NRP1, can easily apply to anti-cancer drugs or antibodies and a strategy for co-targeting EGFR and NRP1 can be effective therapeutic strategy in PDACs and NSCLCs. Therefore, it will provided new insights into NRP1 biology and next generation therapeutic antibody.
