Apelin (APLN) is the endogenous ligand of the G-protein-coupled receptor APJ (APLNR) and triggers a wide range of downstream signaling events, including downregulation of the production of forskolin-induced cAMP and phosphorylation of ERKs, Akt, and p70 S6 kinase. Several lines of evidence suggest that the apelin/APJ axis promotes tumor growth. First, apelin is a potent inducer of angiogenesis and cell proliferation, and its expression is upregulated in hypoxic conditions. Apelin is upregulated in several cancer types and can directly promote tumor growth by inducing cell proliferation through ERK and/or Akt activation. Second, Berta et al. (2010) reported that elevated apelin level correlated with increased microvessel densities and poor survival. Third, blocking APJ signaling reduced proliferation and inhibited tumor growth in human colon adenocarcinoma cell lines expressing high levels of apelin (Picault et al., 2014) and in patient-derived hepatocellular carcinoma cells (Muto et al., 2014). Fourth, although anti-VEGF therapies were developed to block tumor angiogenesis, tumors can acquire drug resistance by bypassing the VEGF pathway and initiating an alternative angiogenic pathway such as the apelin/APJ axis to support growth. Therefore, blocking apelin signaling may be an effective therapeutic strategy for various types of cancer. To block the apelin pathway in cancer therapy, we developed several monoclonal antibodies (mAbs) that bind to the apelin peptide and block apelin-APJ signaling. The antibodies bind to all the physiologically active forms of apelin, including apelin-13, -17, -36, and pyro-apelin-13. These antibodies bind to unique epitopes with an affinity in the picomolar range. The antibodies potently neutralized apelin activity in a cell-based assay with IC50 values in the low nanomolar range. Two antibodies were tested in a mouse oxygen-induced retinopathy (OIR) model to assess their inhibitory effect on angiogenesis. Humanization of the antibodies identified several potent leads that are being characterized for their effect in suppressing the proliferation of tumor cells overexpressing APJ. A search of PDX models found that apelin is overexpressed in specific tumor types including colorectal cancer, kidney cancer, and sarcomas. Remarkably, in PDX models of brain cancer, both apelin and APJ are overexpressed. Indeed, a recent report by Harford-Wright et al. (2017) identified the apelin-APJ system as a central regulator of expansion of patient-derived glioblastoma cells. For recurrent glioblastoma, current anti-VEGF therapies have little to no effect, making the apelin-APJ system an important and exciting target for treating this devastating disease. We will show the efficacy of our lead antibody in PDX models of brain cancer as well as data in support of using apelin-neutralizing mAbs as cancer therapies.

Citation Format: Arvin Tam, Ming Wang, Hui Zou. Apelin-blocking antibodies as potent therapeutics for oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5756.