Targeting EGFL7 in AML

Treatment of blood cancer with anti-EGFL7 antibody.

The Need

Despite recent progress in understanding acute myeloid leukemia (AML) biology and the use of intensive treatments, the long-term overall survival is only 30-40% in younger (<60 years) and <10% in older adult AML patients. This highlights the urgent need for novel therapeutic approaches for adult AML patients.

The Background

Aberrant expression of EGFL7 has been shown to be involved in carcinogenesis and disease progression of several solid tumor types, including glioblastoma, liver, breast, lung, and pancreatic cancers. Indeed, it was originally identified as a critical regulator of endothelial cells, vascular integrity, and angiogenesis. Parsatuzumab, an anti-EGFL7 antibody, was developed and clinically tested by Genentech/Roche for certain solid tumor indications in combination with their other angiogenesis blockbuster, bevacizumab (Avastin). Unfortunately, phase II clinical studies revealed little to no efficacy of Parsatuzumab in non-small cell lung cancer and metastatic colorectal cancer. The program was eventually abandoned.

The Technology

Researchers at The Ohio State University led by Drs. Adrienne Dorrance, Ramiro Garzon, and Changxian Shen discovered a link between EGFL7 and hematopoesis. First, they demonstrated that among cytogenetically normal acute myeloid leukemia (CN-AML) cases, EGFL7 is highly expressed in a large cohort of patients and is associated with poor prognosis. In addition, AML blasts secrete EGFL7 protein. EGFL7 protein increases blast cell growth and data demonstrates that EGFL7 impacts leukemia stem cell (LSC) function by increasing LSC frequency and inducing quiescence. Mechanistically, it was determined that EGFL7 binds multiple components of key signal transduction pathways important for leukemia, including NOTCH.

The inventors identified a novel role of EGFL7 in the leukemic microenvironment. Data demonstrates that targeting primary AML blasts with an anti-EGFL7 antibody (Parsatuzumab) leads to decreased blast cell growth and increases in NOTCH target gene expression. It was also shown that Parsatuzumab synergizes with the FLT3 inhibitor (Gilteritinib) in primary AML cell lines from patients. Remarkably, treatment of healthy wild type (WT) mice with the highest reportable dose of Parsatuzumab did not display any significant hematopoietic defects, which is consistent with in vitro data showing no effect in CB CD34+ cells treated with Parsatuzumab. Furthermore, there have not been any reports of significant hematopoietic side effects in patients with solid tumors treated with Parsatuzumab in combination with chemotherapy. Thus, the data indicate that Parsatuzumab exhibits anti-leukemic effects without affecting normal hematopoiesis.

Benefits/Advantages

  • Parsatuzumab has been clinically validated for safety
  • Parsatuzumab showed efficacy in primary cultured AML cells
  • Multiple animal models of leukemia have demonstrated successful disease treatment using Parsatuzumab, including patient derived xenograft

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