The evaluation of AXL-specific single domain antibodies as diagnostic tracer and therapeutic application in Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML), the most common form of acute leukemia in adults, is characterized by abnormal proliferation of immature myeloid cells and bone marrow failure. Despite major progress in understanding the biology of AML, treatment of elderly patients remains highly challenging, and relapse often occurs. The 5-year overall survival rate of adults older than 60 years is less than 10%, indicating the need for novel therapeutic approaches. Receptor tyrosine kinase AXL, a transmembrane protein, has been identified as a key regulator of cancer cell growth and therapy resistance in AML. AXL-targeting small molecule inhibitors showed pronounced therapeutic effects in AML, nonetheless, the induction of off-target toxicity limits their clinical use. In addition, since AXL is expressed in approximately 50% of the AML patients, it is imperative to select patients who could draw clinical benefit from AXL-targeted therapy as well as to avoid potential toxicities.
During my PhD, I developed AXL-specific single domain antibodies (sdAbs) to non-invasively image and treat AXL-expressing cancer cells. We were able to select a lead sdAb, called sdAb20, and evaluated its in vivo diagnostic potential using cell line-based xenografts and fully immunocompetent mice. To validate our findings and aid clinical translation, we still want to evaluate sdAb20 in patient-derived xenograft (PDX) models in the current project. For therapeutic application, sdAb20 was linked to a fully functional Fc-domain (sdAb20-Fc) and its anti-tumor effects on human AML cell lines and primary patient samples was thoroughly investigated. In the upcoming year, we still aim to evaluate the anti-tumor efficacy of sdAb20-Fc, as single agent and in combination with chemotherapy and/or immune checkpoint inhibitors, using primary patient samples and preclinical models. Overall, this application relates to the finalization of my PhD thesis and hopefully provides the necessary data for clinical application of AXL-specific sdAbs as diagnostic tracer and/or therapeutic compound in AML.