Triple-negative breast cancers (TNBCs) account for ~25% of breast cancer deaths and lack targeted therapies. We identified the non-essential, cell surface protein ADAM8 as an important target on TNBC. ADAM8 is present in 34% of primary TNBCs, and 48% of all breast cancer patient-derived metastases, but absent in normal breast tissues. High ADAM8 mRNA levels correlate with poor patient outcome. The ADAM8 Metalloproteinase (MP) and Disintegrin (DI) domains drive tumor growth and metastasis through release of pro-angiogenic factors and activation of ?1-integrin on cancer cells, respectively. A research-only anti-ADAM8 mouse monoclonal antibody (mAb) that inhibits the MP and DI domains decreased TNBC tumor growth and metastasis, validating ADAM8 as a therapeutic target. A PCT patent application (US14/37857) was filed May 13, 2014 by Drs. Sonenshein, Mineva and Romagnoli, and Tufts University, with claims to target the ADAM8 MP + DI domains (dual antagonist antibody) for treatment of breast and other ADAM8-driven cancers (e.g., gastric, lung, pancreatic). In October 2014, Adecto Pharmaceuticals, Inc. (AP) was founded by the 3 inventors to develop ADAM8 antibody-based therapies for aggressive cancers. Successful completion of the aims of our Phase I STTR has led to: i) generation of anti-human ADAM8 mouse mAbs (termed ADPs) that inhibit both the MP and DI domains, and ii) identification of two lead candidates (ADP2/ADP13) that decrease growth and dissemination of TNBC cell line-derived (CLD) tumors and improve mouse survival. We propose ADAM8 dual antagonist antibody therapy will become a new component of TNBC care. Through discussions with oncologists, we identified recurrent brain metastasis-free TNBC as our first indication and a combination of humanized ADP (hADP) + Standard-of-Care (SoC) chemotherapy (CT) as the treatment regimen. Preliminary results with ADP13 + Nab-Paclitaxel (N-PAC) demonstrate robust reduction in tumor regrowth compared to N- PAC alone in support of this approach. Immunohistochemistry of 30 normal human tissues detected ADAM8 primarily in gastrointestinal neuroendocrine cells (NECs) and occasionally in stomach and lung inflammatory immune cells. This limited expression pattern suggests targeting ADAM8 carries a low risk of side effects. Our 3 aims are to: (1) Identify the most effective SoC CT (e.g., N-PAC/Cisplatin) + ADP combination using CLD and patient-derived xenograft models; (2) Generate humanized (hADP2/hADP13) variants by CDR grafting, identify a functional lead for each in cell-based assays and confirm activity in humanized mice; (3) Perform early safety studies (determine effects of ADAM8 inhibition on primary PBMCs and NECs; confirm hADP lack of immunogenicity & tissue cross-reactivity). These studies will identify a lead hADP with early safety data and an entry path to the clinic. Guidance from GLP & GMP consultants will ensure AP is ready to transition to IND studies and allow us to attract investors/strategic partners and Phase 2b funding for continued development and commercialization of a novel treatment for TNBC patients, who currently lack targeted therapies.
We have identified a protein called ADAM8 on the surface of Triple-Negative Breast Cancer (TNBC) tumors, which lack targeted therapies and account for more than 25% of the 500,000 breast cancer deaths yearly worldwide, and validated it as a target for treatment. As proposed in our Phase I STTR grant, we successfully isolated and characterized highly specific inhibitory mouse monoclonal anti-ADAM8 antibodies (termed ADPs) and identified the top two inhibitors which reduced TNBC tumor growth and spread in mice and improved overall survival. In this Phase II SBIR grant, aims are proposed to identify a first-line chemotherapy that works more effectively in combination with an ADP, humanize our top two antibodies, and perform early safety studies to allow us to select a lead for further development and entry into the clinic, which could revolutionize treatment of TNBC by providing a more effective intervention that improves survival of patients with these very aggressive tumors.
