Synthetic mRNA that's been optimized, modified, and formulated to spur the production of bispecific antibodies in the liver can eradicate large tumors in mice. The strategy circumvents some of the manufacturing challenges associated with conventional antibody production and creates a therapeutic that's easier and more convenient to administer.

Therapeutic antibody production is an expensive and laborious process, requiring cell expression systems, stainless steel bioreactors, and careful purification. A new preclinical strategy circumvents these manufacturing hurdles by using the body's own protein assembly line to make tumor-targeted antibodies with a simple injection of synthetic RNA (Nat Med 2017 June 12 [Epub ahead of print]).

“The method looks very promising,” says Sherie Morrison, PhD, a pioneer in bispecific antibody technology at the University of California, Los Angeles, who was not involved in the research. “It would appear that the approach is one which could be used by many different laboratories.”

Such an RNA-encoded antibody therapy should be easier to administer and require less frequent dosing than a conventional biologic like blinatumomab (Blincyto; Amgen), the only bispecific antibody currently approved in the United States. However, according to study author Katalin Karikó, PhD, vice president of RNA Pharmaceuticals at BioNTech in Mainz, Germany, “the major advantage is on the development side.”

“You can just change the DNA, make the RNA from it, and compare it” to other candidate antibody constructs, she says. “That allows you to evaluate your antibody in a very short period of time.”

In addition to Moderna Therapeutics and CureVac, BioNTech is one of the leading companies spearheading the use of mRNA for cancer immunotherapy. Most of their efforts have been on mRNA-based cancer vaccines that target dendritic cells to elicit strong anticancer immune responses. In some of the company's clinical candidates, the mRNA encodes fixed combinations of shared antigens; in others, it encodes bespoke compendiums chosen to match an individual's tumor. Last year, the company inked a $310 million deal with Genentech to advance the technology further.

In their most recent work, however, Karikó and her colleagues—led by BioNTech cofounder and CEO Ugur Sahin, MD, who is also affiliated with Johannes Gutenberg University in Mainz, Germany—designed mRNAs to encode a bispecific antibody directed against CD3, a coreceptor that can activate T cells, and one of three different antigens found commonly on the surface of tumors: the cell adhesion molecule EPCAM or one of the tight-junction proteins claudin-6 or claudin-18.2.

They also optimized the mRNA sequence for improved stability and enhanced translation, and modified the RNA chemistry to avoid triggering an unwanted immune reaction. The researchers then formulated the resulting lab-made RNA molecule with liver-targeting nanoparticles to ensure sustained production of their bispecific antibodies, which they dubbed RiboMABs.

After intravenously injecting their RNA into mice, the BioNTech team saw rapid production of the bispecific RiboMABs that lasted at therapeutic levels for days. The researchers then tested two of the mRNA constructs in xenograft models with large ovarian tumors. In the one encoding claudin-6, for example, three weekly treatments completely eliminated the cancer. An analog recombinant bispecific antibody made in a human cell line was just as effective but, owing to its short half-life—a problem for patients taking blinatumomab as well—it had to be administered three times as often to achieve the same degree of tumor eradication.

“The mRNA certainly showed superiority over the purified bispecific antibody,” says Michael Heartlein, PhD, chief technical officer and head of mRNA research at Translate Bio (formerly RaNA Therapeutics) in Lexington, MA. “It looks like it's doing what it's supposed to do, which is to really drive those lymphocytes into the tumor.”

The mRNA therapy proved safe, with no signs of liver toxicity or nonspecific immune activation. According to Sahin, the company plans to test the approach in clinical trials—and although he declined to provide a timeline or lead indication, he says the aim is to develop mRNA-encoded bispecific antibodies against various cancer targets. –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.