Join BioTether Sciences for an engaging webinar discussing strategies and techniques

 to study the pharmacokinetics, bio-distribution, pharmacodynamics, immunogenicity, and the potency

of cell, gene, and protein therapeutics.

https://attendee.gotowebinar.com/recording/7058460459861473536

COVID is a global health crisis, the virus infecting hundreds of millions and killing hundreds of thousands worldwide. The vaccines developed in rapid order may save millions of lives and are a wonder of modern science. But in rare instances the vaccines may cause safety issues due to undesirable responses to polyethylene glycol (PEG) and AdenoAssociated Virus (AAV). These immune responses to the vaccine nanoparticles or viral vectors could have implications beyond treating COVID and may prevent safe and efficacious delivery of life saving biotherapeutics and gene therapies. Are we immunizing hundreds of millions of people against PEGylated drugs and AAV gene therapies? 

Both the Moderna and Pfizer COVID vaccines contain PEG in their formulations to create stable nanoparticles containing viral mRNA. PEG is a common additive in food, cosmetics and pharmaceuticals. PEG, when conjugated to protein therapeutics enhances pharmaceutical kinetics, pharmacodynamics and can reduce immunogenicity. However, people can and do create anti-PEG antibodies. According to a publication cited below, there is a 22 – 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds. These results raise obvious concerns regarding the efficacy of PEG-conjugated drugs for a subset of patients. (https://www.tandfonline.com/doi/full/10.1517/17425247.2012.720969). Anti-PEG antibodies can cause skin rashes and more severe allergic responses, including anaphylaxis. Anti-PEG antibodies may cause rapid clearance, poor uptake and decreased efficacy of PEGylated biotherapeutics. There are over a dozen PEGylated biotherapeutics on the market for many diseases (see below and cited above). Will a significant number of people getting the COVID vaccine develop anti-PEG antibodies? Will COVID vaccination status need to be considered when prescribing PEGylated drugs?

What about the impact of COVID vaccination on gene therapy drugs? Two adenoviral vector COVID-19 vaccines are now being used to protect people from COVID. The first, Ad5-nCoV from CanSino, uses a human adenovirus 5 (AAV5) vector; the second, AZD1222, licensed by AstraZeneca from University of Oxford, uses a chimpanzee adenovirus vector. At least seven adenovirus vector vaccines are in development for COVID-19. The AAV5 serotype, is used for gene therapy, and has double-digit pre-existing antibody prevalences that presents challenges to effective treatment.  AAVs are used for the few approved gene therapies and many more in development. Gene therapy may be the future of medicine and save millions with rare genetic diseases. But now AAVs are being leveraged to strongly activate both B and T cells against COVID-19 (https://www.biocentury.com/article/305392/aav-covid-19-vaccine-aims-for-the-sweet-spot-between-antibody-and-t-cell-immunity). Will gene therapy developers need to find ways to avoid these antibodies and T-cells once hundreds of millions of people have been immunized against COVID? Pre-existing antibodies to certain AAV serotypes are common and sometimes neutralizing antibodies develop. These neutralizing antibodies can be tested in functional bioassays. Clever ways to engineer AAVs or reduce the immune response to the gene therapy are being explored. This may be increasingly important once millions of people are immunized with AAV-SARS-CoV-2.

The wonders of gene therapy using technologies to deliver or modify genes to treat inherited diseases, cancer, and other disorders is just becoming a reality. So far only a few such therapies have been approved. For example, Spark Therapeutics, Luxturna (voretigene neparvovec-rzyl) for an inherited form of blindness, and Zolgensma for spinal muscular atrophy are the only approved gene therapies in the USA for inherited genetic diseases. Many more of these life changing therapies are navigating clinical trials and some will be approved in the coming months and years. But many challenges confront gene therapy. The viral vectors used to deliver the gene therapy elicit an immune response or are met with an experienced immune system ready to stop the viral vectors before they can deliver the payload.

Gene therapies rely on adeno-associated virus (AAV), adeno virus, lentivirus, Herpes Virus, or another modified viral vector. In the case of AAV, approximately 70% of adults have antibodies and memory T cells that can bind and clear the vector. The viral capsid proteins are displayed by antigen presenting cells and rally an adaptive immune response.

Manufacturing high quality viral vectors requires specialized services. The gene therapy vectors should be assessed by immuno-assay, viral titer, infectious titer, host cell protein contaminants and stability. High quality gene therapies need to be well characterized and free of host proteins, degradation products, impurities or other manufacturing related liabilities that increase the risk of an immune response.  BioTether Sciences team has experience working with viral vectors and assessing immunogenicity risk.

Antibodies to AAV and other viral vectors can be detected by pre-screening clinical trial subjects and monitoring them during therapy Pre-existing antibodies or newly formed antibodies can be measured using an ELISA. Screening patients for viral antibodies may be helpful to design an effective clinical trial and improve safety. Tracking immunogenicity of gene therapy vectors during clinical trials and correlating the antibody response to efficacy and safety is important for a successful, FDA compliant, and safe clinical trial.