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Flotetuzumab (also known as MGD006 or S80880) is a humanized, Dual-Affinity Re-Targeting, or DART®, molecule that recognizes both CD123 and CD3. CD123, the Interleukin-3 receptor alpha chain, has been reported to be over-expressed on cancer cells in a wide range of hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). AML and MDS are thought to arise in and be perpetuated by a small population of leukemic stem cells (LSCs) that generally resist conventional chemotherapeutic agents. LSCs are characterized by high levels of CD123 expression that is low or absent in the corresponding hematopoietic progenitors and stem cell populations in normal human bone marrow.
The primary mechanism of action of flotetuzumab is its ability to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cancer cells.
In 2014, we initiated a Phase 1 dose-escalation study with flotetuzumab. This study is designed to assess the safety and tolerability of flotetuzumab in patients with relapsed/refractory acute myeloid leukemia (AML). In addition to the primary safety endpoint, secondary endpoints of pharmacokinetics and activity will be evaluated, as will a number of translational endpoints examining the immunobiology of flotetuzumab. MacroGenics continues to enroll patients in the Phase 1 study.
In November 2013, one of our academic investigators presented data from a pre-clinical study of flotetuzumab at the 55th Annual Meeting of the American Society of Hematology (ASH). The pre-clinical data highlighted the ability of flotetuzumab to redirect T cells against CD123-positive AML blasts. (Learn More: 2013 ASH Presentation)
In May 2015, a nonclinical research paper on flotetuzumab was published in Science Translational Medicine. This published research shows anticancer activity in vitro and in mouse models together with favorable pharmacodynamic and safety profile in nonhuman primates. In this paper, MacroGenics’ scientists demonstrated that flotetuzumab can arm T cells from AML patients to reduce blast counts in vitro and is effective in eliminating AML cells implanted in mice in the presence of human effector cells. Furthermore, flotetuzumab administered to cynomolgus monkeys demonstrated potent pharmacodynamic activity in the form of near complete elimination of circulating CD123-positive cells at doses that were safe and well tolerated.
Under the terms of a collaboration, MacroGenics retains full development and commercialization rights to flotetuzumab in the U.S., Canada, Mexico, Japan, South Korea and India. MacroGenics’ partner, Servier, has rights to flotetuzumab in all other countries. (Learn More: Servier DART Collaboration)