Development of [211At]astatine-Based Anti-CD123 Radioimmunotherapy for Acute Leukemias and Other CD123+ Malignancies
This week we profile a recent publication in Leukemia from Dr. George Laszlo (pictured, left) and the laboratory of Dr. Roland Walter (right) at Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
Our translational research is focused on acute myeloid leukemia (AML). We are particularly interested in improving antibody-based therapies, both by optimizing the efficacy/safety profile of existing therapeutics and through the preclinical and early clinical development of novel antigen-directed immunotherapies. As examples of latter efforts, our lab has contributed to candidate drug identification and preclinical development of 5 agents that have subsequently advanced to clinical testing (SGN-CD33A, SGN-CD123A, AMG 330, AMV-564, and APVO436). A major area of focus of our research lies in the delineation of the mechanisms of action and resistance that are relevant for antibody-based AML therapeutics and the rational development of combination therapies that can overcome drug resistance. Many of the studies conducted over the last years have aimed at optimizing CD33-targeted and, more recently, CD123-targeted therapies.
What is the significance of the findings in this publication?
This publication is the result of latter efforts for which we have developed our own anti-CD123 antibodies and have then explored alpha emitter-based radioimmunotherapy as a first way of utilizing these antibodies as basis for novel therapeutics. As is described in the introduction of the article, CD123 is of great interest as a therapeutic target for AML and acute lymphoblastic leukemia given its broad expression on leukemic blasts and its overexpression on leukemic stem cells. A CD123-targeted immunotoxin (tagraxofusp) is FDA approved for BPDCN, a malignancy characterized by high CD123 expression. Beyond tagraxofusp, there are several treatment modalities that are currently tested in the clinic that are based on CD123 antibodies, including antibody-drug conjugates, bispecific antibodies, and CAR T cells. Our study is the first that has used a highly potent alpha emitter, astatine-211, as a payload for CD123 antibodies.
What are the next steps for this research?
In ongoing research, we are working on the humanization of our candidate murine anti-human CD123 antibody. This might provide a suitable candidate antibody for use in a clinical therapeutic. Ultimately, our hope is to continue our research with the goal of clinical application in mind. The Fred Hutchinson Cancer Center and the University of Washington combined have the technical capabilities to bring such a therapeutic into early phase clinical testing.
If you’d like us to mention your funding sources, please list them.
The research described in this article was supported by the Leukemia & Lymphoma Society (Translational Research Program, grant 6489-16), the American Society of Hematology (Bridge Grant), the St. Baldrick Foundation (Emily Beazley Kures for Kids Research Grant), and the National Institutes of Health/National Cancer Institute (NIH/NCI; P30-CA015704).