Project: Development of a fully human bispecific therapeutic antibody for T cell mediated eradication of Acute Myeloid Leukemia

Approximately 30.000 patients are diagnosed each year with acute myeloid leukemia (AML) in Europe and the US. The majority of these patients are 60 years of age or older. Older age is a major negative determinant of outcome in AML and long-term survival (at 5 years) of intensively treated older AML patients is approximately 10%. In patients that receive intensive chemotherapy for induction of remission, the complete response (CR) rate is in the range of 40% to 50%. In almost all patients that have gone in remission, disease progression is observed within 3 years. It is necessary to develop more active therapeutic regimens for the induction of remission as well as for the elimination of residual leukemia during remission and thereby stabilize these remissions more effectively. Current post-remission treatment has shown limited, if any, value in older patients with AML. Therefore, a significant load of residual resistant leukemia reCOs, and the surviving subpopulation of drug-resistant leukemic cells rapidly generates recurrence. Novel types of drugs with entirely different modes of action are needed to target these chemotherapy non-responsive AML tumor cells in efforts to induce and sustain complete remissions._x000D_T cell mediated lysis of AML tumor cells induced by bispecific IgG antibodies that engage both T cells and AML tumors cells could be such a mechanism of action that can evade acquired drug resistance. Bispecific IgG-induced simultaneous targeting of the CD3 protein expressed on T lymphocytes, and a tumor cell associated cell surface target on AML blasts, could result in efficient T cell mediated tumor cell killing (irrespective of MHC-restriction or co-stimulation). This approach has been clinically validated using an anti-CD3xanti-Epcam bispecific IgG of rat/mouse origin for epithelial abdominal tumors, resulting in market approval of Removab (catumaxomab) in Europe in 2009. _x000D_BlyMAT assembles a consortium of expertise in antibody discovery and development, AML biology, access to patient materials as well as clinical know how. Jointly, the consortium aims to provide a novel therapeutic option for a currently unmet clinical need by T lymphocyte mediated targeting of AML with a fully human bispecific IgG antibody. Merus will apply its unique single VL antibody technologies to generate and produce the bispecific anti-CD3xanti-AML IgG and aims to demonstrate pre-clinical proof of concept for the lead bispecific IgG. Therapeomic will apply its novel formulation development technologies to generate a bispecific antibody platform formulation that can support clinical evaluation and subsequent development of the product leads. As a direct result of this program, a pre-clinical candidate bispecific IgG will be generated and formulated that can rapidly progress to non-clinical safety evaluation and subsequent clinical efficacy evaluation in AML. Successful implementation of the program could result in co-development or licensing of a product with annual revenues of 300-500 million €. The format of fully human, single VL bispecific IgG antibodies for T lymphocyte-mediated tumor cell lysis could also be applied to other hematologic and solid tumor oncology indications. Furthermore, efficient protein formulation strategies will result from this program that in addition to their direct application to the bispecific IgG T cell recruitment product leads could also be applied more broadly for the efficient generation of better and safer protein therapeutics. _x000D_An efficacious bispecific IgG for AML potentially provides a therapeutic option for a large patient segment for which there is currently no alternative treatment available. In addition to providing a means to achieve durable remissions, this treatment modality could also have curative potential for AML when applied during remission in a minimal residual disease setting._x000D__x000D_

Acronym BlyMAT (Reference Number: 6960)
Duration 01/03/2012 - 28/02/2015
Project Topic Development of bispecific IgG antibodies that induce killing of Acute Myeloid Leukemia by the patient’s own T cells. By targeting AML tumor stem cells it is aimed: 1) To treat AML patients with chemotherapy resistant tumors and 2) To prevent AML relapse by tumor stem cell therapy during remission.
Project Results
(after finalisation)
The BlyMAT program has generated pivotal proof of concept data demonstrating that a full length human bispecific IgG targeting CD3 and CLEC12A can efficiently induce the AML patients T cells to kill their own AML tumor cells in primary bone marrow samples. In addition, a product lead has been defined, MCLA-117, that includes an engineered bispecific IgG format in which the non-specific interactions with Fc receptors have been abrogated. A liquid formulation for MCLA-117 has been developed by the P Therapeomic that supports the iv administration in patients. Furthermore, a CHO producer cell line has been generated by subcontractor Boehringer Ingelheim, from which representative MCLA-117 product has been purified. Using this MCLA-117 material initial non-clinical safety data has been generated to support the clinical evaluation of MCLA-117 in patients.
Network Eurostars
Call Eurostars Cut-Off 7

Project partner

Number Name Role Country
2 Therapeomic Inc. Partner Switzerland
2 MERUS BV Coordinator Netherlands