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New Apoptosis-Targeting Drug Gets B Cells, Spares Platelets


By Anette Breindl
Science Editor

Researchers have developed an experimental drug, ABT-199, that interferes with anti-apoptotic proteins. Unlike its precursor navitoclax, though, ABT-199 does not interfere with platelet function.

The rationale for the therapeutic targeting of apoptosis, or programmed cell death, to treat cancer, is not hard to understand. It is, Andrew Souers told BioWorld Today, "a fundamental process in the life span of all cells." And it is a process that is frequently derailed in cancer cells.

But in practice, apoptosis has been a tough nut to crack.

There are several proteins that influence apoptosis, some by encouraging it and others by inhibiting it. Importantly, at least as far as drugging those proteins is concerned, they "do not bind substrates," as kinases, for example, do, Souers explained. Instead, they interact with each other. Inhibiting such protein-protein interactions, in turn, "requires larger drug molecules that are often quite hydrophobic. These molecular attributes are associated with poor solubility, low oral absorption and other challenges that make drug development quite difficult," he said.

Souers is associate director of cancer research at AbbVie Inc., a spinoff – if that is the proper term for a company with 21 ,000 employees and product sales in more than 170 countries – of Abbott. (See BioWorld Today, Jan. 3, 2013.)

AbbVie and Abbott scientists, Souers said, "have been engaged with this field for quite some time." Those efforts have led to the development of one drug, navitoclax, which targets two apoptosis pro-survival proteins, BCL-2 and BCL-XL.

Blood cells – and blood cancers – depend on BCL-2 more than BCL-XL for their survival, while many solid tumors appear to rely more on BCL-XL.

BCL-XL is important in at least one type of blood cells, however: platelets. And that's a problem for navitoclax, which inhibits both proteins.

"Navitoclax showed early signs of efficacy in patients with BCL-2-dependent hematological tumors," particularly chronic lymphocytic leukemia, or CLL. But treatments with that drug in the clinic setting lead to concentration-dependent reductions in platelets, which are critical for blood clotting. That effect, in turn, limited the amount of drug that could be given and hence the efficacy.

Further benchwork showed that navitoclax's effects on platelets were due to its inhibition of BCL-XL. And so, AbbVie scientists tweaked the drug to make it more specific for BCL-2.

In the Jan. 6, 2013, issue of Nature Medicine, Souers and his colleagues reported on the compound to come out of those engineering efforts – ABT-199.

The authors showed that ABT-199 bound to BCL-2 1,000 times more strongly than to BCL-XL. In animal models, the drug was able to kill different types of xenografted hematological tumors, and for tumor types that do not respond to BCL-2 inhibition by itself, the drug "enhanced the efficacy of clinically relevant chemotherapy and immunotherapy."

At the same time, the drug had only minimal effects on platelets in both cell culture and animal models, suggesting that it will enable clinicians to avoid the toxic effects on platelets that are often dose-limiting for navitoclax.

In the paper, Souers and his team described three patients with refractory CLL who were treated with ABT-199. Two of those patients had a more than 95 percent reduction in lymphocytes after a single dose of ABT-199, and in patients, too, the effects on platelets were much milder than comparable doses of navitoclax.

Souers said AbbVie also is "studying the effects of ABT-199 administration on patients with various hematological cancers beyond CLL – namely, non-Hodgkin's lymphoma and multiple myeloma. Efforts beyond hematological malignancies remain a near-future goal."

But the work also represents a scientific advance. For one, Souers said, his team's efforts have resulted in a molecule that is still fairly similar to navitoclax, but "with dramatically heightened potency and excellent selectivity against a highly homologous protein" to the one first targeted by navitoclax.

Already, that has "allowed for a clinical proof of concept for selective BCL-2 inhibition. This is a milestone for the apoptosis field, which numerous scientists around the world have spent greater than 20 years developing."

And Souers and his team plan to continue to use ABT-199 for scientific exploration.

"Highly selective small molecules are invaluable tools for studying and unlocking disease biology," he said. "We know that BCL-2 plays a major role in the life span of lymphocytes, for example, but we and others have also found roles for BCL-2 in the survival of certain solid tumors, the progression of immunological diseases and the rewiring of certain tumor biology to resist standard-of-care therapy, just to name a few. By using highly selective inhibitors of BCL-2 family proteins, we plan to dissect the role of multiple BCL-2 proteins in a number of disease states."