Regeneron scientists have successfully demonstrated a potential breakthrough in addressing one of gene therapy's most significant limitations – the inability to redose patients with adeno-associated virus (AAV) vectors due to immune responses. At the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting in New Orleans, the company presented promising data showing successful AAV redosing in non-human primates using novel antibody-based approaches.
Two Strategic Approaches to Overcome Immune Barriers
Nicholas Giovannone, PhD, a senior principal scientist at Regeneron, presented research focused on two distinct immunomodulation strategies designed to prevent the formation of neutralizing antibodies against AAV vectors.
The first approach employs antibody-mediated blockade of CD40, a key receptor involved in antibody response development. By temporarily inhibiting this pathway before AAV administration, researchers aim to prevent the initial antibody response from forming.
The second strategy utilizes a CD20xCD3 bispecific antibody to deplete B-cells that would otherwise develop into antibody-secreting cells. This approach represents an advancement over conventional B-cell depletion methods like rituximab, which has shown limited success in clinical settings.
"Rather than taking a broad immunosuppression approach, we went back to first immunological principles and said, 'Okay, what is one of the key players in generation of antibody response?'" Giovannone explained. "One of those key players is CD40."
Superior B-Cell Depletion in Critical Tissues
A key finding from Regeneron's research reveals why current B-cell depletion approaches may be failing in clinical applications. The team discovered that rituximab, commonly used in AAV therapy protocols, ineffectively depletes B-cells in lymph nodes and the spleen – critical areas for preventing antibody responses.
"Rituximab is not so great at depleting B-cells in the critical areas you need to deplete them to prevent an antibody response: namely, the lymph nodes and spleen," Giovannone noted. "We tested an approach using this bispecific antibody that we found is a much better depleter in those tissues."
Successful Redosing Demonstrated in Non-Human Primates
Both approaches – CD40 blockade and enhanced B-cell depletion – proved effective at preventing antibody responses to AAV vectors in non-human primates. Most significantly, the researchers successfully administered a second AAV vector dose to the treated animals, achieving substantially higher transduction levels compared to control subjects that received no immunomodulation.
This represents a critical first step toward potentially enabling multiple doses of gene therapy in human patients – a capability that could dramatically expand treatment options and efficacy for numerous genetic conditions.
Transient Immunomodulation: A Key Advantage
An important aspect of Regeneron's approach is that the immunomodulation is temporary rather than permanent. This transient suppression is designed to block immune reactions only during the critical period when AAV vectors are present in the body.
"These approaches are meant to be transient," Giovannone emphasized. "The idea is to temporarily block the AAV antibody response so that during that time the AAV is around, you're preventing an immune reaction, and then you can redose in the future."
Implications for the Future of Gene Therapy
The inability to redose AAV-based gene therapies has been a significant limitation in the field. Many patients develop neutralizing antibodies after initial treatment, preventing future administrations of the same or similar vectors. This is particularly problematic for treatments that may require dose adjustments or when initial treatment efficacy wanes over time.
If successfully translated to human applications, Regeneron's approaches could fundamentally change the treatment paradigm for AAV gene therapies. Patients could potentially receive multiple doses throughout their lifetime, allowing for dose optimization, sequential treatment of different conditions, or renewal of therapeutic effects.
The company's genetic medicine division continues to advance this research, with these non-human primate studies representing an important milestone in addressing one of gene therapy's most persistent challenges.
