Advancing Delivery of AAV Vector-Based Gene Therapies Using Bispecific Antibodies (ASGCT 2024)

There are several challenges that the viral vector field has been facing over the past few decades, noted Sven Moller-Tank, PhD, director of Viral Delivery Technologies, Regeneron Genetic Medicines, Regeneron, in an interview with BioPharm International® at the American Society of Gene and Cell Therapy’s (ASGCT’s) 27th Annual Meeting, which is occurring May 7–11, 2024 in Baltimore, Md.

The first challenge is pre-existing immunity because people have naturally been exposed to adeno-associated virus (AAV) and have developed immune responses. This makes it a challenge to run clinical trials, when patients have pre-existing immunity, Moller-Tank stated. The second challenge has been delivery; as a whole, it has been extremely difficult to get enough virus to the peripheral tissues, as opposed to the liver, where it can cause issues with your immune response, and thirdly, there has always been an issue with cargo capacity, he explained. “AAVs can only package about 4.7 kb, and [many] therapeutic genes really don't fit into that capacity,” he said.

A fourth challenge dealing with viral vectors would be sustained expression, Moller-Tank added. “The idea with AAV gene therapies generally is that it's a one-and-done therapeutic. However, there [are many] unknowns about how long it's going to express. We're now seeing [in] clinical trials [that] it can indeed last a long time, but it's really unknown for maybe more junior populations, children, where they're going to grow over time, and, after receiving a therapeutic, they may lose expression,” he observed.

Moller-Tank emphasized that the field has seen much success in terms of viral delivery, at least in mice, “Often, however, that has unfortunately not translated very well to non-human primates and to humans. Over the past decade, the industry has really focused on doing screenings and developing relevant animal models. That's gone a long way to improving the translate-ability,” he said. However, this work has not really addressed the issue of off-target delivery, which has an impact on the immune response and the safety of AAVs.

Regeneron has been working on using bispecific antibodies to retarget AAV specificity. “The concept is you have one arm against your target receptor—and we identify specific receptors that are expressed in the tissues of interest, so we can control the specificity of the delivery—and then you have another arm against the AAV. The idea, essentially, is that [the] antibody is bridging the AAV capsid to the target cell of interest,” Moller-Tank explained.

“We show, maybe for the first time and most convincingly, that bispecifics are a viable approach to deliver AAVs in vivo. I think, historically, the field has been using bispecifics in vitro, but [getting]that jump to doing in vivo delivery has been a challenge,” Moller-Tank remarked.