To this end, we have constructed CLN-049, a FLT3xCD3 T cell-engaging bsAb, based on an Fc-silenced hIgG1 anti-FLT3 antibody with anti-CD3 single-chain antibodies (scFvs) fused to the C-termini of the heavy chains. However, for leukemia patients with higher disease burden, more potent treatment modalities are needed. FLYSYN showed promising safety and preliminary efficacy in AML patients with minimal residual disease 21 (, NCT02789254). We recently developed an Fc-optimized monoclonal antibody (mAb) targeting FLT3, FLYSYN, which potently induces antibody-dependent cellular cytotoxicity. Unlike kinase inhibitors that are specific to a particular FLT3 mutational context, antibody-based therapies that target the extracellular domain of FLT3 are independent of FLT3 mutations, allowing for treatment of a broader patient population. 18 Its essential role in disease progression has been validated by the clinical benefit of tyrosine kinase inhibitors that target mutant FLT3. 15–17 FLT3 is a proto-oncogene that plays a key role in promoting leukemic cell proliferation and survival, and expression is preserved in AML after relapse. The receptor tyrosine kinase FLT3 is an attractive AML target with frequent expression on both blasts and leukemic stem cells, whereas expression on healthy myeloid cells is low and limited to myeloid DCs and HSCs.
12 Finally, CLEC12A is also expressed on normal myeloid cells including granulocytes, monocytes, macrophages, and DCs as well as granulocyte-macrophage progenitors.
10 11 CD123 is also expressed on many healthy cells such as myeloid progenitors, plasmacytoid dendritic cells (pDCs), monocytes, and basophils. 9 CD33 is expressed on approximately 30% of healthy bone marrow (BM) myeloid progenitors. 8 However, beyond their well-documented expression on malignant cells, these targets are also found at similar levels on normal myeloid cells and hematopoietic stem cells (HSCs), raising concerns regarding a narrow therapeutic window. Antibody-based therapeutics currently in development for AML focus primarily on CD33, CD123 and CLEC12A as target antigens. 5–7 However, T cell engaging strategies for myeloid-derived neoplasias like AML are not yet clinically established.Ī major challenge in AML is target selection. Strategies to mobilize T cells against tumor cells via bispecific antibodies (bsAbs) or directly engineering T cells to express chimeric antigen receptors have achieved remarkable success in lymphoid malignancies, including acute lymphoid leukemia (B-ALL) and multiple myeloma. Accordingly, prognosis of AML remains dismal with overall 5-year survival rates below 15%. In addition, remission-inducing chemotherapy and HSCT are associated with substantial treatment-associated morbidity and mortality, and many patients experience a subsequent relapse. However, more than 50% of patients are not eligible for the intensive pre-treatment chemotherapy regimens. 1 2 While several new treatments have recently been approved, including hypomethylating agents, the antibody drug conjugate gemtuzumab ozogamicin and various small molecule kinase inhibitors, 3 induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) remains the most widely used curative treatment approach. Correspondence to Dr Jennifer S Michaelson Īcute myeloid leukemia (AML) is the most frequent form of acute leukemia in adults, affecting 4–5 per 100 000 population.6 Image-Guided and Functional Instructed Tumor Therapy, Eberhard Karls Universitat Tubingen, Tubingen, Germany.5 Immunology, Ludwig-Maximilians-Universitat Munchen, Munchen, Germany.4 Internal Medicine, Eberhard Karls Universitat Tubingen, Tubingen, Germany.3 Clinical Collaboration Unit Translational Immunology, University Hospitals Tubingen, Tubingen, Germany.2 Immunology, Eberhard Karls Universitat Tubingen, Tubingen, Germany.1 Cullinan Florentine Corp, Cambridge, Massachusetts, USA.
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