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Antibody breaks leukemia's hold

In mouse models and patient cells, anti-CD98 antibody disrupts interactions between leukemia cells and surrounding blood vessels, inhibiting cancer's spread.


The American Cancer Society estimates that there will be about 19,950 new cases of Acute myeloid leukemia (AML) and about 10,430 deaths from the disease in the United States in 2016, mostly in adults. Approximately 500 children are also diagnosed with AML in the U.S. each year, and it's the most common second cancer among children treated for other cancers, according to St. Jude Children's Research Hospital.

AML is aggressive and known for it's drug resistance and relapse. In an effort to uncover new treatments, researchers at University of California San Diego School of Medicine and Moores Cancer Center discovered that a cell surface molecule known as CD98 promotes AML.

The study, published October 27 by Cancer Cell, also shows that inhibiting CD98 with the therapeutic antibody IGN523 blocks AML growth in patient-derived cells and mouse models.


"To improve therapeutic strategies for this disease, we need to look not just at cancer cells, but also at their interactions with surrounding cells, tissues, molecules and blood vessels.

"In this study, we identified CD98 as a critical molecule driving AML. We show that blocking CD98 can effectively reduce leukemia burden and improve survival by preventing cancer cells from receiving support from a surrounding environment."


Tannishtha Reya PhD, Professor of Pharmacology, University of California San Diego, School of Medicine, and Moores Cancer Center, USA. Also, a co-senior author of the paper.


Reya led the study together with Mark Ginsberg MD, professor of medicine at UC San Diego School of Medicine and Moores Cancer Center. Co-author Edward van der Horst, PhD, senior director at Igenica Biotherapeutics Inc., provided the anti-CD98 antibody IGN523.


AML is a cancer in which bone marrow makes abnormal red or white blood cells, or platelets.


Reya's team and others have previously shown that leukemia cells interact with their surroundings in the body via molecules on their cell surfaces, and that these interactions help cancer cells divide, replicate and metastasize.

CD98 is a molecule found on the surface of cells, controlling how cells stick to one another. CD98 is known to play a role in the proliferation and activation of certain immune cells. CD98 levels are also known to be elevated in some solid tumors, and linked to a poor prognosis.


To determine CD98's role in AML, Reya's team engineered mouse models lacking the molecule. They found the loss of CD98 blocked AML growth and improved survival.

CD98 loss largely spared normal blood cells.

Researchers feel this indicates a potential therapeutic window. Further experiments revealed leukemia cells lacking CD98 had fewer stable interactions with the lining of blood vessels. These interactions are needed to fuel AML growth.


Next, researchers wanted to see what would happen if they blocked CD98 in AML with an inhibitor. In 2015, Igenica Biotherapeutics Inc. tested IGN523 in a phase 1 clinical trial at Moores Cancer Center and elsewhere. IGN523 is a humanized antibody that specifically binds and inhibits CD98. The trial's goal was to determine a safe dose for IGN523 administration in AML patients. In this study, Reya and team tested IGN523 in their own AML mouse models and human cell lines.

They found that IGN523 blocks CD98's AML-promoting activity in both mouse models of AML and human cells in the laboratory. They also transplanted human patient-derived AML cells into mice and treated the recipients soon after with either IGN523, the anti-CD98 antibody, or with a control antibody.


Anti-CD98-treatment effectively eliminated AML cells. By contrast, AML in control mice
expanded more than 100-fold.


"This study suggests that human AML can't get established without CD98, and that blocking the molecule with anti-CD98 antibodies could be beneficial for the treatment of AML in both adults and children," Reya said.

Moving forward, Reya and team are working to further define whether CD98 could be targeted to treat pediatric AML.


"Many of the models we used in this work were based on mutations found in childhood AML. While many childhood cancers have become very treatable, childhood AML continues to have a high rate of relapse and death.

"We plan to work with pediatric oncologists to test if anti-CD98 agents can be effective against pediatric AML, and whether it can improve responses to current treatments. I think this is particularly important to pursue since the anti-CD98 antibody has already been through phase I trials, and could be more easily positioned to test in drug-resistant pediatric AML."


Tannishtha Reya PhD


Abstract Highlights
•Development and analysis of conditional CD98−/− model in the hematopoietic system
•CD98 loss impairs propagation of established AML in mouse models of disease
•Antibody-mediated CD98 blockade impairs primary human AML growth
•CD98-mediated adhesion to vasculature promotes leukemia stem cell maintenance

Summary
Acute myelogenous leukemia (AML) is an aggressive disease associated with drug resistance and relapse. To improve therapeutic strategies, it is critical to better understand the mechanisms that underlie AML progression. Here we show that the integrin binding glycoprotein CD98 plays a central role in AML. CD98 promotes AML propagation and lethality by driving engagement of leukemia cells with their microenvironment and maintaining leukemic stem cells. Further, delivery of a humanized anti-CD98 antibody blocks growth of patient-derived AML, highlighting the importance of this pathway in human disease. These findings indicate that microenvironmental interactions are key regulators of AML and that disrupting these signals with targeted inhibitors such as CD98 antibodies may be a valuable therapeutic approach for adults and children with this disease.

Study co-authors also include: Jeevisha Bajaj, Takaaki Konuma, Nikki K. Lytle, Hyog Young Kwon, Jailal N. Ablack, Joseph M. Cantor, Elizabeth H. Broome, Edward D. Ball, UC San Diego; David Rizzieri, Duke University; Charles Chuah, Singapore General Hospital; and Vivian G. Oehler, Fred Hutchinson Cancer Research Center.
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Oct 31, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Leukemia cells (green) interact with blood vessels (blue) via the molecule CD98.

Image Credit:
University of California San Diego Health


 


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