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5 Immunogenicity of AAV Gene Therapy Products
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and genomes. Nonclinical species have ranged from non‐human primates (NHP),
rodents, pigs, and dogs to evaluate pharmacology and toxicity of gene therapies [34]. Animal disease models representing gene defects have also been
employed to evaluate pharmacology and efficacy of the gene therapy vectors.
The animal studies do have limited use as they are not predictive of adverse
events (AEs) or immunogenicity in humans due to species‐specific differences in
immune responses[35]. However, the immune response against viral vector components, especially innate immune response, can support interpretation of study
observations like impact on safety and efficacy. The aspects of the study design
like route and mode of administration, and manufacturing process used to generate IND‐enabling studies are also relatable to a certain extent.
5.2.5 Animal Models forAssessing Innate Immunity
The innate immune response can be activated by different components of the
adeno‐associated virus mediated gene therapy (AAV‐GT) product as described
earlier. Animal models like murine models with gene defects for metabolic disease, e.g. hemophilia, can be employed to assess impact of innate phase responses
on safety and efficacy of AAV‐GT. Such mice models can also evaluate the impact
of engineered capsids that could reduce the innate and subsequent adaptive
immune response [12]. Other PRR‐based innate activation mechanisms due to
critical quality attributes like presence of empty and partially packaged capsids in
the final AAV‐GT vector product can also be evaluated using the mouse and NHP
models due to homology of the innate mechanisms across species[36]. Some toxicities observed in nonclinical species like loss of dorsal root ganglia following
intrathecal delivery of high doses of rAAV‐GTs in monkeys, piglets, and mice
could be indicative of complement mediate innate phase immune response that
propagates to adaptive phase response[37, 38].
5.2.6 Animal Models forAssessing Adaptive Immunity
Both mice and monkeys were utilized as the nonclinical species for assessing
adaptive immune response to AAV‐GT components. The pre-existing sero‐
reactivity observed in these animals and its impact on transduction of gene of
interest and its expression in the target tissue could be translatable to humans and
helped drive the enrollment criterion for GT trials in clinic[39]. The pre-existing
immunity can also induce complement activation through immune complex formation. The treatment‐induced humoral response and associated adverse events
could not be predicted through studies conducted in NHP species. The cell‐
mediated responses in NHP did not reduce transgene expression unlike the clinical experience where there was an elimination of vector transduced cells. The
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Teffector and CTL responses associated with NHPs are functionally and phenotypically distinct from the human T cells. Nevertheless, there is value in conducting immune response evaluations in preclinical animal species as it provides
insight into the mechanisms behind the adverse events that may be later useful to
explain similar consequences in clinic[40, 41]. Even though disease models may
be preferred, healthy and immune‐competent species are also equally important
to be able to understand the impact of immune‐mediated adverse events to explain
immune‐toxicities and be aware of similar observations in clinic.
The preclinical administration of rAAV‐GT vectors and the subsequent outcome could be relevant for an immune‐privileged site like eye. Multiple studies
have demonstrated the value of observations from intravitreal or subretinal
administrations that could be kept in consideration while planning a mitigation
strategy for clinical trials. Most of the animal studies have not provided any direct
evidence for impact of treatment‐emergent antibodies on safety or efficacy of GT
vectors. However, some studies with monkeys and mice did indicate that preexisting neutralizing antibodies could impact transgene expression[39, 42]. This
observation led to preenrollment criterion to exclude patients with pre‐existing
antibodies at certain titers.
5.2.7 Impact ofImmunogenicity onAnimal Selection and
Interpretation ofStudy Results
The NHPs have been considered the most relevant toxicology species to understand disposition (viral vector gene expression) across tissues apart from target
where the gene is intended to transduce. Even though ocular delivery should not
elicit an immune response due to it being immune privileged, a strong innate and
adaptive immune response was observed against the AAV both locally and systemically [43, 44]. The NHP study confirmed the development of an adaptive
phase cellular immune response following subretinal injection. The mitigation
strategy implemented in clinic was adapted from the NHP study, including
immune monitoring and delay in administration between two doses.
5.3 Clinical Manifestation Associated
withImmunogenicity
The pre-existing host immunity or treatment‐emergent immune responses can
induce both humoral and cellular responses to viral capsid and transgene proteins
derived from AAV vectors, potentially compromising treatment efficacy and
patient safety.
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5.3.1 Pre-existing Immunity Against AAV Vector May Compromise
Therapeutic Efficacy and Patient Safety
Patients who are exposed to wide‐type AAV serotypes early in childhood or during
later natural infection usually develop humoral immunity directed against AAV
capsid proteins[45, 46]. The pre-existing anti‐AAV capsid antibodies can result in
the reduction of treatment efficacy and may be associated with patient safety.
Pre-existing neutralizing antibody can block the binding of the AAV vector to
target receptor or prevent vector internalization into target cells. This would
directly inhibit viral transduction and reduce transgene expression, limiting the
therapeutic efficacy. In addition, pre-existing anti‐capsid antibody (both non‐
neutralizing and neutralizing) can also affect efficacy by increasing the clearance
of administered AAV vector via opsonization or complement activation [42].
Theseprocesses can also trigger safety issues, e.g. inflammation. In addition, complement effector can also cause other complications such as thrombocytopenia,
atypical hemolytic uremic syndrome (aHUS, a type of thrombotic microangiopathy), and immune complex deposition, especially in patients treated with systemic
AAV gene therapy[47].
Natural exposure to AAV can also produce pre-existing cell‐mediated immunity, although this may be less prevalent than pre-existing humoral immunity[47].
It has been reported that cellular responses could eliminate AAV particles or
transduced cells, thus affecting the persistence of AAV vector delivered through
systemic[48, 49] or intramuscular administration[50]. This can not only reduce
treatment efficacy but may also trigger tissue damage, causing potential safety
concern. For intramuscular administration, muscle cell damage would lead to the
release of biomarkers, e.g. creatine phosphokinase. When AAV vector is administered to liver, hepatic cell damage could result in an elevated level of transaminases in the circulation[37, 51].
5.3.2 Treatment Induced Anti-AAV Capsid Antibodies May Prevent
Re-dosing
It has been observed that pre-existing anti‐AAV capsid antibodies may increase in
titer after administration of AAV vectors. Most seronegative patients can also
undergo seroconversion and develop treatment‐induced antibodies after administration of AAV vector[52]. Higher dose could further boost the anti‐AAV antibody
titer[53]. High titers of circulating neutralizing antibodies (Nabs) to AAV2have
been reported to persist up to 9 years following AAV vector administration[53].
These treatment‐induced antibodies may prevent readministration of patients
using the same or even other AAV vector serotypes.
The post‐dosing boosted immunity to AAV capsid protein may be associated
with certain serious adverse events (SAEs). The severity of AEs could increase
with dose following intravenous administration. Immune complex formation,
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antibody‐dependent cellular cytotoxicity (ADCC), antibody‐dependent cellular
phagocytosis (ADCP), and opsonization could be accountable for the observed
cytotoxicity or inflammation[54]. For example, administration of high doses of
AAV9 in children with Duchenne Muscular Dystrophy (DMD) has resulted in
acute kidney injury, complement activation, reduced platelets and red blood cells
(RBCs), and thrombocytopenia[55].
5.3.3 Antibody Specific toTransgene Protein Could Lead
toToxicity or Unwanted Immunity
Patients may not produce the same endogenous protein as encoded by the AAV
vector. For example, cross‐reactive immunologic material (CRIM) negative patients
carrying a null mutation with infantile Pompe’s disease develop an immune
response to the enzyme replacement therapy[56]. A similar outcome can occur
with gene replacement therapies treating gene defects with a null mutation. In
some instances, there could be a pre-existing immunity to the transgene protein if
patients were previously treated with a replacement therapy. Under this circumstance, both humoral and cellular response can be elicited against the transgene
protein, blocking its activity, and compromising therapeutic efficacy.
Another instance where the transgene protein is homologous to an endogenous
counterpart, there is a risk of neutralizing antibodies that can cross‐react with
endogenous protein and inhibit its physiological function, potentially resulting in
more severe clinical consequence, e.g. immunodeficiency syndrome.
If the transgene product is expressed on the cell surface, anti‐transgene protein
antibodies could directly bind and mediate effector functions, e.g. ADCC, ADCP
or CDC (complement‐dependent cytotoxicity), leading to cell lysis and tissue
destruction. The transgene protein can be presented in the context of Class I MHC
on the target cells and leads to activation of cytotoxic CD8+T‐cell response driving immunotoxicity and loss of transduced cells and tissue damage.
The transgene product can also be secreted and taken up by antigen‐presenting
cells in the tissue and presented in the context of Class II MHC which leads to
activation of Teffector CD4+ T‐cell response.
5.3.4 Risk ofImmunogenicity Associated withDifferent
Administration Routes
The route of administration would dictate the immunogenicity risk and its clinical consequence. While systemic administration could induce systemic immune
reaction, local administration may result in a lower exposure or activation of Treg
cells. Therefore, local, e.g. intravitreal, subretinal, intrathecal, intramuscular,
administration may result in a lower risk of immunogenicity than systemic, e.g.
intravenous, administration[33, 57, 58].
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Delivery of AAV vector to different target tissues may trigger various level of
immune response due to differences in the nature and the density of antigen‐
presenting cells, the cytokine environment, and the existence of tissue/blood barriers.
5.3.4.1 Gene Delivery tothe Eye or Central Nervous System
Local administration to an immune‐privileged site, such as the eye or central
nervous system (CNS) may have a lower risk to induce an immune response. For
example, AAV gene therapy for the treatment of retinal diseases usually delivers
viral vectors to the subretinal space or vitreous cavity. In addition to the blood–
retina barrier, induction of antigen‐specific Tregs, the presence of immunosuppressive TGFβ2 cytokine, and a tendency toward Th2 responses (induction of
antibodies with no recruitment of complement) would contribute to the ocular
immune privilege. The significantly reduced immune response in eyes would protect the inner eye from immunogenic inflammation after administration of first or
even repeated dose of AAV vector to the eye [44, 53]. However, inflammation
could be detected after elevated level of ADA response was developed to viral capsid following high dose of AAV vector administration[59, 60].
5.3.4.2 Gene Delivery toLiver
AAV gene therapy has also targeted liver for the treatment of a range of genetic and
metabolic diseases due to its central function in metabolism, heavy vascularization, and unique immune environment. It has been reported that induction of
+
antigen‐specific CD4+CD25+FoxP3+ Tregs and CD8
Tregs together with apoptosis of reactive T cells would account for the liver‐mediated immune tolerance and
help establish long‐term expression of transgene protein after administration of
AAV vector[61, 62]. For example, when all subjects previously undergoing protein
replacement therapy were enrolled for the AAV hemophilia B clinical trials, none
of the subjects, including CRIM‐negative patients, developed immune response to
transgene product and the long‐term transgene expression was observed [15].
Despite the induced immune tolerance in liver, the cellular response to AAV capsid
protein has been reported that led to specific destruction of transduced hepatocytes, transaminase elevation and loss of transgene expression[49, 63].
5.3.4.3 Gene Delivery toMuscle
Muscle is another valuable target tissue for AAV gene therapy to treat diseases
related to this organ or to serve as an alternative organ other than liver to produce
therapeutic protein in the long term [64]. When compared to liver, muscle presents a unique immune environment that would determine the outcome of AAV
gene therapy. Some neuromuscular diseases, e.g. Duchenne muscular dystrophy,
are associated with muscle inflammation[65]. This may result in upregulated
MHC class I expression and elevated cytotoxic T‐cell response to AAV transduced
tissue cells, leading to loss of transgene expression[31]. In addition, it has been
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demonstrated that intramuscular delivery usually results in concentrated
transgene expression at the site of injection and thereby could mount more prominent immune response when compared to intravascular delivery[58], potentially
reducing the transgene protein production. Nonetheless, sustained transgene
expression was documented for subjects administered intramuscularly with AAV1
vector encoding α1‐antitrpsin when CD4+CD25+FoxP3+ Tregs were present
around the injected site, attenuating the immune response to viral and transgene
protein derived from the administered vector[66, 67].
5.3.5 Product- and Process-related Impurity Related Immunogenicity
The product‐related impurity includes empty capsid and viral particles with partial
genome. The oxidized, deamidated, and aggregated forms of viral particles are also
part of the product generated from the cell culture[68]. While empty capsids may be
used as a mitigation strategy to quench pre-existing antibodies, empty capsids or capsid protein undergoing biotransformation can also elicit anti‐AAV immune response.
The anti‐capsid humoral response may result in elimination of viral particle through
immune complex formation between pre‐existing antibodies and capsids. Such
immune complexes can also activate complement and impact safety. Cellular response
against capsid could additionally be involved in the clearance of AAV‐transduced target cells[69]. Both would lead to loss of transgene expression, reduced efficacy, and
cytotoxicity. In addition, the AAV genome could potentially recombine with genomic
DNA from target cells leading to genotoxicity. The CpG motifs associated with AAV
genome may contribute to host immune activation as well as safety risk[11, 68].
5.4 Clinical Mitigation Strategy
The impact of immunogenicity on AAV gene therapy could be mitigated using
different strategies to curtail or overcome the immune responses to AAV capsid
and transgene protein.
To mitigate the impact of pre-existing antibodies, one important approach is to
exclude seropositive patients and enroll patients with undetectable or marginal preexisting immunity to AAV vector, especially for clinical studies with systemic
administration. Therefore, it is important to screen pre-existing anti‐AAV antibodies for patient stratification. Either total binding anti‐drug antibody ADA assay
(TAb) or transduction inhibition assay can be used to measure anti‐AAV capsid
antibody titer to determine the level of pre-existing immunity and eligibility of
patients for clinical trial enrollment. TAb assays are typically immunoassays that
are sensitive with adequate robustness. The cell‐based transduction inhibition
assays can detect not only NAb but also non‐antibody factors in the matrix samples
that can block the transduction. However, the invitro cell‐based transduction inhibition assay may not predict transduction inhibitors invivo and could be susceptible
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to assay variation. Either assay can be used to exclude patients with antibody titer
above a predefined threshold cut‐off. The sponsors should consider developing a
companion diagnostic test (CDx) for market approval to help determine patient
eligibility.
It is also feasible to reduce the pre-existing immunity by engineering AAV vector. Site‐directed or random mutagenesis technology can be implemented to
deplete the immunogenic motif in the capsid protein or select recombinant
mutants with a lower sero‐reactivity to pre-existing antibodies in patient circulation without reducing the vector transduction to target cells. Alternatively, AAV
vector derived from nonhuman species, e.g. rhesus macaques[70, 71], may have
lower seroprevalence and can be used as gene delivery vector. For example,
AAVrh74 is a recombinant gene therapy vector from rhesus macaques. It has been
reported that 83% of patients with DMD were seronegative for anti‐AAVrh74
antibodies[72].
Since an elevated dose of AAV vector may be associated with a higher risk of
immunogenicity and potentially elevated incidence of SAEs, a decreased dose can
be considered, if possible, during clinical trial planning. Alternatively, a genetically engineered AAV vector could carry mutations that enable a higher transduction efficiency at a lower dose[73].
Other possible solutions to reduce the impact of pre-existing immunity involve
removal of anti‐capsid antibodies by plasmapheresis or degradation. It has been
reported that removal of immunoglobulins in blood from seropositive NHPs via
plasmapheresis resulted in a transduction efficiency like that in seronegative animals[74]. To circumvent the limitation of current plasmapheresis procedure that
nonspecifically removes all circulating antibodies, many clinical studies consider
using AAV‐specific plasmapheresis to reduce the pre-existing immunity against
AAV gene therapy [75]. Transient degradation of circulating antibodies using
Imflidase/IdeS, a bacterial cysteine protease, may provide an alternative approach
for efficient AAV transduction of seropositive patients and even readministration
of an AAV vector[76, 77].
Immunomodulation is another effective strategy to circumvent the immune
response to AAV gene therapy. Transient immunosuppression with immunomodulatory drugs, e.g. rituximab combined with methylprednisolone, prior to AAV
vector administration has resulted in reduced immune response to capsid and
transgene proteins[16, 78]. Rapamycin is a general immunosuppressant. When
combined with prednisolone and coadministered with AAV vector, it can inhibit
activation of B and T cells, leading to reduced anti‐AAV antibody production[78].
Corticosteroids and other immunomodulatory medications are also available to
inhibit innate/adaptive immune cells or T/B‐cell production to suppress the
immune response to AAV gene therapy[1].
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Strategies to mitigate immune response to AAV vector should also involve product optimization and removal of product impurity. Immune reactivity to AAV vector can be reduced by blocking reverse‐strand transcription and depletion of CpG
motifs. In addition, short non‐coding DNA oligonucleotides can be incorporated
into the vector genome to inhibit TLR9 activation[16, 78] and lower the risk of
CD8+ T‐cell response to the transgene product[12, 79]. The risk of immunogenicity could be further mitigated by minimizing the product‐related and process‐
related impurities through optimization of upstream (cell culture) and downstream
(purification) manufacturing processes.
Selection of appropriate administration route can help to modulate immune
response to AAV gene therapy. It has been known that delivery of AAV vector to
liver can introduce the immunotolerance to AAV vector and transgene protein
[61, 62]. Likewise, local administration of AAV vector to immune‐privileged sites,
e.g. eyes or central nervous system, can reduce the risk of immunogenicity and
support long‐term transgene expression as well[80, 81].
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