Adecto Pharmaceuticals is developing an antibody-based therapy against ADAM8-expressing cancers with triple-negative breast cancer (TNBC) as the initial focus. TNBC is a highly aggressive form of breast cancer that currently lacks targeted therapies. Patient treatment is restricted to surgery, chemotherapy and radiation. Unfortunately, one third of patients recur and progress to metastasis within 1-3 years. Thus, TNBC accounts for over 125,000 deaths yearly worldwide and represents a large unmet medical need.
Fig.1: ADAM8 mechanisms of action
We have identified the cell surface protein ADAM8 as an important driver of TNBC growth and spread and validated it as a target for treatment (Romagnoli 2014). High levels of ADAM8 are expressed in 34% of TNBC patient samples and 48% of all breast cancer-derived metastases. This expression is an independent predictor of poor prognosis.
Our studies indicate that ADAM8 has multiple roles in cancer. As a tumor grows, it reaches a size that cannot be supported by the existing vasculature. The ensuing lack of oxygen and nutrients lead to the induction of ADAM8. The Metalloprotease (MP) domain of ADAM8 promotes: 1) degradation of the extracellular matrix surrounding the tumor, which creates a growth and invasion permissive microenvironment; and 2) release of pro-angiogenic factors from the cancer cell surface, leading to the formation of new blood vessels around the tumor (angiogenesis) that support continued growth and offer access to distant sites (Fig. 1). The Disintegrin (DI) domain of ADAM8 also modifies the cancer cell surface. Specifically, the DI activity leads to: 1) activation of signaling which promotes resistance to chemotherapy; and 2) increased cell motility and invasion into the blood stream (Fig. 1). Once in the circulation, the presence of ADAM8 on the cancer cell surface is critical for its attachment to distant sites (colonization) and the formation of metastases. Thus, ADAM8 mediates a cascade of events that drive disease progression.
Adecto's technology is based on our discovery that both the extracellular MP and DI domains of ADAM8 drive its multiple cancer promoting functions (Figure 1) and therefore must both be inactivated for an effective therapeutic response. Using a proprietary method, we have generated a panel of highly specific, dual antagonist monoclonal anti-ADAM8 antibodies; each antibody can simultaneously inhibit the MP and DI activities. Our two lead therapeutic candidates, ADP2 and ADP13, significantly reduce tumor growth and metastasis and improve survival in TNBC mouse models when given as monotherapies. These antibodies also dramatically enhance treatment response when added to chemotherapy. ADP2 and ADP13 are currently in preclinical development.
ADAM8 is similarly expressed in many other solid malignancies beyond TNBC, including stomach, colon, lung, liver and pancreatic cancers. In each of these tumors, high ADAM8 levels are associated with poor prognosis, higher grade and/or a highly metastatic disease (Ishikawa 2004; Zhang 2013; Huang; Valkovskaya 2007). In the future, we plan to expand to other ADAM8-driven oncology indications beyond TNBC.
Romagnoli M, Mineva ND, Polmear M, Conrad C, Srinivasan S, Loussouarn D, Barille-Nion S, Georgakoudi I, Dagg A, McDermott EW, Duffy MJ, McGowan PM, Schlomann U, Parsons M, Bartsch JW, Sonenshein GE: ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO Mol Med 2014, 6(2):278-294.
Ishikawa N, Daigo Y, Yasui W, Inai K, Nishimura H, Tsuchiya E, Kohno N, Nakamura Y: ADAM8 as a novel serological and histochemical marker for lung cancer. Clin Cancer Res 2004, 10(24):8363-8370.
Zhang Y, Zha TZ, Hu BS, Jiang C, Ge ZJ, Zhang K, Tan YF: High expression of ADAM8 correlates with poor prognosis in hepatocellular carcinoma. Surgeon 2013, 11(2):67-71.
Huang J, Bai Y, Huo L, Xiao J, Fan X, Yang Z, Chen H, Yang Z: Upregulation of a disintegrin and metalloprotease 8 is associated with progression and prognosis of patients with gastric cancer. Transl Res 2015, 166(6):602-613.
Valkovskaya N, Kayed H, Felix K, Hartmann D, Giese NA, Osinsky SP, Friess H, Kleeff J: ADAM8 expression is associated with increased invasiveness and reduced patient survival in pancreatic cancer. Journal of cellular and molecular medicine 2007, 11(5):1162-1174.