Technology
Adecto Pharmaceuticals is developing an antibody-based therapy against ADAM8-expressing cancers and an immunohistochemistry (IHC)-based diagnostic to identify patients who can benefit from it.
Fig.1: ADAM8 mechanisms of action
Our primary focus is on breast cancer, the leading cause of cancer-related death of women worldwide (~700,000 annually). Our earliest focused indication is Triple-negative Breast Cancer (TNBC). Despite representing only 10-15% of breast cancer cases, TNBC accounts for >25% of the reported deaths worldwide (~175,000 annually). TNBC is a highly aggressive form of breast cancer that occurs preferentially in African-American and younger women and currently lacks effective targeted therapies. The standard-of-care is restricted to surgery, radiation and chemotherapy. Unfortunately, one third of TNBC patients recur within 1-3 years of initial diagnosis and progress rapidly to fatal disease. Recently approved treatments for advanced TNBC, including the antibody-drug conjugate Trodelvy and the immunotherapy Keytruda, have so far had limited success in treating this disease. Thus, there is great unmet need for new TNBC precision therapies and diagnostics.
We identified the cell surface protein ADAM8 as an important driver of TNBC growth, spread and poor patient survival, and validated it as a target for treatment (Romagnoli 2014). Our data indicate 1/3 of TNBC patients have ADAM8-positive tumors and could benefit from an ADAM8-targeted therapy. In the US alone, 525,000 women currently live with TNBC. This translates to 157,500 patients with ADAM8-positive disease that could be helped.
Our therapeutic technology is based on the discovery that the extracellular Metalloprotease (MP) and Disintegrin (DI) domains of ADAM8 have distinct cancer promoting functions (Fig. 1) and that both must be inactivated for an effective therapeutic response. The MP domain of ADAM8 promotes: 1) degradation of the extracellular matrix surrounding the tumor, which creates a growth permissive microenvironment; and 2) release of factors from the cancer cell surface, which stimulate the formation of new blood vessels around the tumor (angiogenesis) that support continued growth and provide access to distant sites (Fig. 1). The DI domain of ADAM8 promotes: 1) activation of signaling pathways that mediate cancer cell resistance to chemotherapy; and 2) increased cancer cell motility, local invasion and distant metastasis via the blood stream (Fig. 1). Our solution is a first-in-class, highly specific, mouse monoclonal, MP+DI dual antagonist ADAM8 antibody, called ADP2. As single agent in TNBC mouse models, ADP2 decreases primary tumor growth, reduces metastases and extends survival. When added to chemotherapy, it enhances treatment response. Following successful ADP2 humanization, a therapeutic lead, AD100, was selected for continued development. AD100 is undergoing efficacy and safety tests in humanized mice and human immune cells ahead of Investigational New Drug (IND)-enabling studies.
Our diagnostic uses IHC of tumor biopsies, a well-established technology performed routinely in clinical pathology laboratories worldwide. This ensures rapid adoption of the diagnostic and facilitates patient access to our therapy. In IHC, an antibody directed against a specific target is used to detect this target following tissue fixation in formalin and paraffin embedding. The innovation of our diagnostic is the selection of the original mouse monoclonal ADP2 as lead IHC antibody. ADP2 detects ADAM8 with high specificity and sensitivity under IHC conditions. It also shares the same epitope as AD100, a safety feature, which ensures only cancers confirmed to express this epitope will be treated. A prototype diagnostic assay based on ADP2 has been developed and is now undergoing extensive pre-clinical validation with breast cancer patient samples.
In the future, we plan on expanding beyond TNBC to all breast cancers and to other solid oncology indications driven by ADAM8, including stomach, colon, lung, liver and pancreatic cancers (Ishikawa 2004; Zhang 2013; Huang; Valkovskaya 2007).
REFERENCES:
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.