Capsid-specific removal of circulating antibodies to adeno-associated virus vectors

Abstract

Neutralizing antibodies directed against adeno-associated virus (AAV) are commonly found in humans. In seropositive subjects, vector administration is not feasible as antibodies neutralize AAV vectors even at low titers. Consequently, a relatively large proportion of humans is excluded from enrollment in clinical trials and, similarly, vector redosing is not feasible because of development of high-titer antibodies following AAV vector administration. Plasmapheresis has been proposed as strategy to remove anti-AAV antibodies from the bloodstream. Although safe and relatively effective, the technology has some limitations mainly related to the nonspecific removal of all circulating IgG. Here we developed an AAV-specific plasmapheresis column which was shown to efficiently and selectively deplete anti-AAV antibodies without depleting the total immunoglobulin pool from plasma. We showed the nearly complete removal of anti-AAV antibodies from high titer purified human IgG pools and plasma samples, decreasing titers to levels that allow AAV vector administration in mice. These results provide proof-of-concept of a method for the AAV-specific depletion of neutralizing antibodies in the setting of in vivo gene transfer.

Viral vector platforms within the gene therapy landscape

“… 171 The goal of discovering new capsids seeks to partially address the presence of NAbs against serotypes commonly found in populations. For circumstances where tailoring the vector platform to the patient is not possible, plasmapheresis is a plausible means of removing anti-AAV antibodies from the bloodstream 229 or pre-treatment with IgG-cleaving endopeptidases such as imlifidase (IdeS) can nonspecifically reduce IgG antibodies from the sera of patients. 230 IdeZ, a homolog of IdeS, isolated from Streptococcus zooepidemicus , demonstrated efficacious removal of capsid NAbs in non-human primate (NHP) studies.…”

Long-term correction of ornithine transcarbamylase deficiency in Spf-Ash mice with a translationally optimized AAV vector

“…Different strategies are being studied, such as interfering with the immune response at the time of viral administration 46 , 47 , 48 or depleting the serum of the patient from Nab generated during the first AAV administration. 49 , 50 , 51 Recently, co-administration of AAV8 vectors with ImmTOR nanoparticles containing rapamycin have been shown to mitigate the formation of anti-AAV antibodies and enable vector re-dosing in mice and non-human primates. 48 However, these promising approaches still require validation in the clinic.…”

Therapeutic Strategies Targeting DUX4 in FSHD

“…For example, pre-existing immunities to AAV are often found in humans, excluding a large proportion of patients from enrolment [79] and AAV gene transfer triggers an immune response to the AAV capsid, thus preventing the re-administration of the vector. Many laboratories are working on these limitations and proposed solutions include the AAV-specific depletion of neutralizing antibodies using a plasmapheresis column [80], the administration of IgG-cleaving endopeptidases to decrease anti-AAV antibody titers [81], the chemical modification of the AO to improve its pharmacokinetic and pharmacodynamic properties, and the conjugation to antibody or peptide to ameliorate muscle uptake.…”