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MGD006 (also known as 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 MGD006 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 MGD006. This study is designed to assess the safety and tolerability of MGD006 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 MGD006. 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 MGD006 at the 55th Annual Meeting of the American Society of Hematology (ASH). The pre-clinical data highlighted the ability of MGD006 to redirect T cells against CD123-positive AML blasts. (Learn More: 2013 ASH Presentation)
In May 2015, a nonclinical research paper on MGD006 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 MGD006 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, MGD006 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 MGD006 in the U.S., Canada, Mexico, Japan, South Korea and India. MacroGenics’ partner, Servier, has rights to MGD006 in all other countries. (Learn More: Servier DART Collaboration)