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R. Pranomphon etal.
fusions of receptors with Fc domains, and more complex glycans on mAbs emerge,
new challenges may arise. For example, while mAbs are generally not sialylated,
new studies indicate that increased sialyation increases half-life, impacts stability,
and may reduce dosing frequency [138, 139]. These new demands may require
alternative hosts including human cell lines or highly engineered lower eukaryotes
such as yeast or modications to CHO using targeted gene and process manipulation to maximize their post-translational potential.
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Chapter 7
Even aWorm Will Turn: Immunity
Following AAV Vector Administration
KrutiPatel, ArpanaKhatri, andSuryanarayanSomanathan
Abstract While several approaches have been considered for invivo delivery of
therapeutic genes, vectors based on a small defective parvovirus, adeno-associated
virus (AAV), have proven to be safer in achieving durable therapeutic transgene
expression. Nevertheless, the use of vectors based on a virus that infects humans
carries the risk of pre-existing host immunity from previous exposure to the virus.
Even in the absence of prior infection, administration of large doses of a viral vector
can activate host immune responses that can reduce, or prevent, therapeutic gene
expression. Hence, careful monitoring of host immune responses before and after
vector administration is required when delivering AAV-based gene therapies. Here
we review anti-AAV immune responses and the approaches currently being explored
to mitigate host immunity and achieve successful therapeutic gene expression.
Keywords Gene therapy · Adeno-associated virus · Innate immunity · Adaptive
immunity · Antibodies · Cytotoxic T cells
7.1 Introduction
Extreme remedies are most appropriate for extreme diseases
Hippocrates, Greek Physician, c.460–357 BCE
Genetic medicines are expected to be the next generation of transformational therapies. In contrast to treatments with small molecules and monoclonal antibodies that
address disease symptoms, genetic medicines treat the root cause of the disease.
These novel therapies were rst touted to be the panacea for xing or altering
disease- causing genes and alleviating patient suffering. Integration of knowledge
from the elds of human genetics, molecular and cell biology, virology, and immunology in the 1970s led to early proposals to develop genetic medicines [1]. Nucleic
K. Patel · A. Khatri · S. Somanathan (*)
Rare Disease Research Unit, Pzer, Inc., Cambridge, MA, USA
169© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
K. Gadamasetti, S. A. Kolodziej (eds.), Bioprocessing, Bioengineering
and Process Chemistry in the Biopharmaceutical Industry,
https://doi.org/10.1007/978-3-031-62007-2_7