On June 3, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported research published in the journal Science Translational Medicine that describes a gene expression signature of the tumor microenvironment in patients with acute myeloid leukemia (AML) that is associated with resistance to chemotherapy and response to flotetuzumab, an investigational, bispecific CD123 x CD3 DART molecule currently in clinical development for the treatment of primary induction failure and early relapsed AML (Press release, MacroGenics, JUN 3, 2020, View Source [SID1234560791]). The research was led by Sergio Rutella, M.D., Ph.D., FRCPath, Professor of Cancer Immunotherapy, John van Geest Cancer Research Centre at Nottingham Trent University in the UK.

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The study analyzed several hundred primary bone marrow samples from independent cohorts of pediatric and adult AML patients to identify differences in immune gene expression in the bone marrow tumor microenvironment across age groups and molecular subtypes. The data indicated that an inflammatory signature related to INF-γ gene expression was predictive of resistance to chemotherapy and potential response to flotetuzumab immunotherapy in patients with primary refractory or early relapsed AML.

"Patients with AML who have failed primary induction therapy or relapsed early after an initial response represent a challenging patient population to treat," said Ezio Bonvini, M.D., Senior Vice President and Chief Scientific Officer of MacroGenics. "These data provide a molecular basis to understand why AML patients who are refractory to chemotherapy may be responsive to immunotherapy with flotetuzumab and offer a rationale for further development of the molecule in a planned pivotal study in this patient population with unmet medical needs."

About Acute Myeloid Leukemia

AML is a hematological malignancy characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic precursors that prevent normal bone marrow hematopoiesis. Nearly 20,000 new cases of AML are diagnosed in the U.S. each year, with a median age of 69 years at diagnosis. Approximately 40-50% of newly diagnosed patients fail to achieve a complete remission with intensive induction therapy (primary induction failure; PIF) or experience disease recurrence after a short remission duration (<6 months; early relapsed; ER). A very small number of these patients are expected to respond to salvage therapy. Although new targeted agents have been approved for the treatment of frontline or relapsed/refractory AML in recent years, approximately 50% of patients have no known targetable mutations. The discovery by the Rutella lab of an immunological gene signature in the AML tumor microenvironment forms the basis for a potential predictive biomarker for further clinical validation.

About Flotetuzumab

Flotetuzumab (also known as MGD006) is a clinical-stage bispecific DART molecule that recognizes both CD123 and CD3. CD123, the interleukin-3 receptor alpha chain, has been reported to be over-expressed on malignant cells in AML and other hematologic malignancies. The primary mechanism of action of flotetuzumab is believed to be 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 cells. Data from the Phase 1/2 clinical study of flotetuzumab in patients with PIF/ER AML were presented in December 2019 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. MacroGenics plans a single-arm, registration-enabling clinical study to evaluate flotetuzumab in up to 200 patients with PIF/ER AML, with complete remission (CR) and CR with partial hematological recovery (CRh) as the primary endpoint. The study will be conducted as a continuation of the ongoing Phase 1/2 study (NCT02152956; to be updated). The FDA has granted orphan drug designation to flotetuzumab for the treatment of AML.