Merus Selects Clinical Candidate for the Treatment of Acute Myeloid Leukemia (AML)
Published: Jan 07, 2013
MCLA-117 is a human, full-length IgG bispecific antibody, which activates the patient’s own immune system by simultaneously binding to the CLEC12A molecule expressed by AML tumor cells and the CD3 molecule expressed by T cells. MCLA-117-mediated co-engagement of CLEC12A and CD3 results in the potent killing of cancerous AML cells and their malignant precursors. Merus intends to start phase I clinical trials with MCLA-117 in 2014.
The antibody is based on Merus' Biclonics™ ENGAGE platform. Human bispecific antibodies from this platform can be manufactured and administered like conventional, full-length IgG molecules, thereby providing for high yield, good stability and a long serum half life. In addition, bispecific antibodies from the Biclonics™ ENGAGE platform have a modified constant region to abrogate unwanted clinical cytokine release.
"We are excited about this clinical candidate because MCLA-117 selectively targets the burden of the leukemia load as well as the leukemia-initiating stem cells. It is designed to provide a therapy that more efficiently eradicates the cancer cells and prevents relapse," said Setareh van Driel Shamsili, Chief Medical Officer of Merus. "AML is a disease with limited treatment options, so there is a significant need for targeted therapies with potent mechanisms of action that attack the tumor at its roots."
Prof. Gert Ossenkoppele from the department of hematology at the Free University Medical Centre in Amsterdam, The Netherlands, added: “CLEC12A has been identified by my lab as a leukemic stem cell-specific antigen. In vitro data with MCLA-117 have confirmed killing of leukemic cells by targeting this molecule. Therefore, the clinical development of a T cell redirecting treatment by a bispecific antibody against the CLEC12A target could offer great opportunities and be of extreme importance to potentially cure this disease.”
Prof. Ossenkoppele will be the lead investigator of the first MCLA-117 Phase I study.
About Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. It is the most common type of acute leukemia in adults, with 54% of AML patients diagnosed at age 65 or older. It is estimated that every year, more than 13,000 new cases of AML occur in the United States and more than 10,000 patients die from the disease. In Europe, the annual mortality rate is 4-6 cases per 100,000 individuals. At present, standard treatments for AML include chemotherapy, radiation therapy and stem cell transplants. Targeted therapies, such as monoclonal antibodies, are also being evaluated in clinical trials. AML is generally associated with a poor prognosis. Despite of initial complete remissions with available therapies (60-80% in patients younger than 60 years and 40-55% in older patients), the long-term disease survival is only about 20-30 % (see footnotes 1,2,3).
MCLA-117 is based on Merus´ proprietary Biclonics™ ENGAGE platform. Biclonics™ are full-length, human, bispecific IgG antibodies with a common light chain (cLC) and two different heavy chains. Panels of cLC human antibodies are obtained from MeMo®, a transgenic mouse engineered to generate antibody diversity using a single light chain and diversified heavy chains. Using a proprietary CH3 dimerization technology, the two different heavy chains and the cLC encoding two different specificities are expressed in a single cell to efficiently and stably assemble into Biclonics™. Biclonics™ ENGAGE antibodies bridge T cells and tumor cells through simultaneous binding of CD3 and a tumor associated antigen, thereby inducing potent T cell-mediated tumor cell killing. Bispecific antibodies based on the Biclonics™ ENGAGE platform have IgG constant regions with modified CH2 domains to prevent undesirable cytokine release during therapeutic application.
About Merus B.V.
Merus is a biotechnology company building a pipeline of innovative, human bispecific antibodies (Biclonics™) and single cell-derived combinations of antibodies (Oligoclonics®) for cancer therapy. Through the use of a common antibody light chain and CH3 heterodimerization technology, these full-length IgG antibody therapeutics can be robustly produced at high yields from a single clonal manufacturing cell line using standard approaches. Biclonics™ and Oligoclonics® bind to multiple disease-associated targets, such as growth factor receptors expressed by tumor cells. Synergy is achieved by addressing multiple pathways/mechanisms simultaneously, thereby eliminating tumor cells more efficiently and preventing treatment escape. In the Biclonics™-ENGAGE approach, full-length, human, bispecific IgG antibodies are used to induce the cytotoxic activity of T cells to kill cancer cells.
Merus meets a significant need in the oncology field: the discovery and development of bispecific antibodies and single-cell derived antibody combinations with improved clinical efficacy to address the limited potency of conventional antibodies. For further information, please visit Merus´ website at www.merus.nl
1- National Cancer Institute. General Information About Adult Acute Myeloid Leukemia.
http://www.cancer.gov/cancertopics/pdq/treatment/adultAML. Accessed January 2, 2013.
2- NCCN clinical guidelines, Acute Myeloid Leukemia. v.2, 2012, www.NCCN.com
3- ESMO clinical practice guidelines- Acute Myeloblastic Leukemia- M. F. Fey& M. Dreyling, Annals of Oncology 21 (Supplement 5): v158–v161, 2010.
Dr. Ludger Wess or Ines-Regina Buth
Tel. +49 (0)40 88 16 59 64 / +49 (0)30 2363 2768
S. Margetson - s.margetson(at)merus.nl
3584CH Utrecht, The Netherlands