Immunotherapy for Acute Myeloid Leukemia
University of Pittsburgh and Fred Hutch Cancer Center scientists have identified a therapeutic target protein for Acute Myeloid Leukemia (AML) and discovered fully human antibodies to selectively target this protein. C-type lectin domain family 2 member A (CLEC2A), a type 2 transmembrane glycoprotein expressed on keratinocytes, has several essential immune functions and is expressed on AML blasts in bone marrow and peripheral blood. Using antibodies to target AML blasts could be a novel strategy to treat AML while limiting side effects from off-target interactions.
Description
AML is the most common form of leukemia in adults, generally uncommon before the age of 45. While immunotherapy in other leukemias has shown promise, successful immunotherapy has yet to be developed for AML. Patients found to express the cell surface protein CLEC2A have significantly worse outcomes compared with patients without CLEC2A expression. Developing antibodies to specifically target this protein could lead to the development of antibody-mediated cytotoxic therapies targeting the most high-risk patients.Applications
• Acute myeloid leukemia• Other conditions found to overexpress CLEC2A
Advantages
Developing immunotherapy for AML has been hindered by the significant overlap of antigens expressed in AML and normal hematopoietic cells. Identifying antigens specific to AML as targets is necessary to develop immunotherapy.Through identification of genetic aberrations, CLEC2A was detected in 18% of AML patients. In patients with deadly subtype KMR2A rearrangements (KMT2A-r) CLEC2A is highly enriched in nearly half of all patients with this subtype. Targeting CLEC2A positive AML cells would allow for selective delivery of therapeutics to these cells avoiding normal healthy hematopoietic cells, reducing the risk of off target effects. These novel antibodies are unlike existing commercially available antibodies and demonstrate high affinity and specificity to CLEC2A. Given these antibodies are small, they are ideal for use with a variety of therapeutic modalities. Additionally, these antibodies are fully human unlike commercially available animal-derived antibodies, reducing the risk of immunogenicity in treatment.