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Publications of the Week

The CD33 Splice Isoform Lacking Exon 2 as Therapeutic Target in Human Acute Myeloid Leukemia

By March 6, 2020No Comments

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This week we profile a recent publication in Leukemia from Dr. Colin
Godwin
(pictured) in the laboratory of Dr. Roland Walter at Fred Hutch.

Can you provide a brief overview of your lab’s current research focus?

Our lab is focused on improving antibody-based therapies for acute myeloid leukemia (AML), an aggressive blood cancer, both by optimizing the efficacy and safety profile of existing therapeutics as well as through the preclinical and early clinical development of novel antigen-directed immunotherapies. A major area of interest 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 our studies conducted have aimed to optimize use of therapies targeting CD33, a cell surface protein that is expressed on at least a subset of the leukemia cells in almost all AML patients and may be displayed on underlying AML stem/progenitor cells in some.

What is the significance of the findings in this publication?

Data from several randomized studies have shown that the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO; Mylotarg) reduces relapse risks and improves survival when added to intensive chemotherapy in some patients with AML. This led to the recent approval of GO in Europe and the U.S. and validated CD33 as the first (and, so far, only) targeted for antibody-based therapies for AML. Because GO is ineffective in many patients with CD33+ AML, there is great interest in developing improved CD33-targeted drugs, particularly for patients for whom GO does not provide benefit. To accomplish this, one line of research is focusing on targeting a splice variant of CD33 that lacks exon 2 (CD33∆E2). This splice variant is of interest because 1) it lacks the extracellular domain that is recognized by GO, 2) it is expressed at the mRNA level in leukemia cells in all AML patients, and 3) related to a single nucleotide polymorphism in the CD33, it is expressed to a greater degree in patients who may not respond well to GO. However, the lack of antibodies recognizing the extracellular domain that is preserved in CD33∆E2 has made it impossible so far to study whether the CD33∆E2 splice variant is indeed expressed, at the protein level, on AML cells. In our publication, we describe the generation and characterization of two such antibodies. We also describe the findings we obtained with these two antibodies that, in a nutshell, suggest that CD33∆E2 is neither expressed on human AML cell lines nor on primary blast cells from a smaller cohort of AML patients. While our studies cannot exclude that CD33∆E2 might be expressed on the cell surface of myeloblasts in a smaller subset of AML patients, or might be expressed at earlier differentiation stages in AML, our data do not provide evidence for the value of CD33∆E2 as a therapeutic target in AML.

What are the next steps for this research?

Research in our group and others is ongoing to improve the success with CD33-targeted therapies. Current efforts not only include work toward making such drugs more effective and potent, but also be devising strategies to protect normal blood cells that physiologically express CD33 from the toxicities of such drugs. Together, the hope is that these strategies will improve the therapeutic window, and ultimately the outcome, when using CD33-targeting drugs in the clinic.

This work was funded by:

Research reported in our publication was supported by the Leukemia & Lymphoma Society (Translational Research Program, grant 6489-16) and the National Institutes of Health/National Cancer Institute (NIH/NCI) (R21-CA234203, P30-CA015704, and P50-CA100632 [MD Anderson Cancer Center Leukemia SPORE]). Additionally, the lead author was supported by a fellowship training grant from the NIH/National Heart, Lung, and Blood Institute (NHLBI; T32-HL007093), an institutional K12 grant from the NIH/NCI (K12-CA076930) an American Society of Clinical Oncology/Conquer Cancer Foundation Young Investigator Award and an Alex’s Lemonade Stand Young Investigator Grant.

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