Cleaving AAV Antibodies to Improve Gene Therapy Accessibility

While adeno-associated virus vector (AAV) gene therapies have transformed the treatment landscapes for many rare diseases, there are still many challenges that need to be overcome with the mode of gene therapy, including access to people with preexisting antibodies to AAV and the ability to redose. Researchers and institutions are starting to investigate possible strategies to overcome these challenges.

One company, Hansa Biopharma, is investigating the use of its antibody-cleaving enzyme imlifidase to remove AAV antibodies in patients prior to dosing or possibly even redosing gene therapy. Imlifidase currently has conditional authorization conditional authorization in the European Union and United Kingdom for the desensitization treatment of highly sensitized adult kidney transplant patients with a positive crossmatch against an available deceased donor.

CGTLive spoke with Lena Winstedt, PhD, global franchise lead, gene therapy, Hansa Biopharma, to learn more about imlifidase’s potential to improve accessibility to gene therapy. She touched on previous studies and uses for imlifidase as well as presentations on the enzyme from the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California.

CGTLive: What are some outstanding challenges with AAV gene therapies?

Lena Winstedt, PhD, global franchise lead, gene therapy, Hansa Biopharma: There are a lot of gene therapies using AAV as a vector to transduce the desired gene into the cells. There are a couple of approved ones, but many in the pipeline and many in clinical phases right now. Wild type AAVs cause many of the common infections, like throat and stomach infections, in particular in smaller children, so the majority of the population have been exposed to those before. We develop antibodies against those viral vectors, and depending on the type of vector, there's a prevalence of about 15 to 70% of the population who has developed antibodies to the vectors. And if you use one of the vectors in a patient with antibodies, those antibodies would prevent that vector from entering into the cell and releasing the gene product.

This is a major problem for gene therapy patients. I would say at least 30% of all patients using the most common vectors have antibodies towards the vector. This prevents them from getting treatments, both approved products, but also those in clinical trials. So this is a major problem for the gene therapy area. That's the first obstacle, then we have the problem of redosing. There's probably a need to redose those patients at some point, maybe after 5 or 10 years. And if you've had gene therapy treatment before, you will get antibodies, and those antibody levels are very high. You will need to do something about the antibodies before you can redose.

How could imlifidase work to address the challenges with AAV antibodies?

Winstedt: Imlifidase is a bacterial enzyme, it's from a streptococci that specifically cleaves IgG antibodies, and it does so extremely effectively. Within a few hours, you have inactivated almost the entire pool of IgG antibodies. So, this is a very quick and efficient way to remove the antibodies. And this concept has been tested in several indications so far, and imlifidase has conditional approval for removal of antibodies prior to kidney transplantation by the EMA. And it's developed and tested in other indications as well such as autoimmune diseases like Guillain Barre Syndrome and anti GBM disease. And it has also been used to remove antibodies in organ transplant rejection. We know that it can remove antibodies quickly and efficiently, and we also know that it has a very nice safety profile. So, it can, of course, also be used to remove antibodies against AAVs, and we’ve seen that ability in animal models so far.

Transcript has been edited for clarity. Click here to read more coverage of ASGCT 2023.