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procedures. For example, in a cell‐based TI assay, 3.36 E+09 vg of an AAV reporter
gene construct may be incubated with 42
μL of a plasma test sample. Assuming a
linear dynamic range, a test sample that shows 50% transduction at MRD will
have neutralized 50% of the AAV reporter gene construct, which is equal to
× 3.36 E+09 vg=1.68 E+09 vg (Table6.1).
0.5
In comparison, an average human adult has an estimated total plasma volume
of about 3000
derived as (1.68 E+09
mL, and thus the theoretical total neutralizing capacity of plasma is
vg/0.042 mL) × 3000 mL=1.20 E+14 vg, assuming linearity
and complete mixing. Plasma samples with higher TI titers that can be diluted
beyond the MRD to achieve 50% transduction in the assay will have higher neutralizing capacity, which can be theoretically extrapolated by multiplying the previously calculated quantities of neutralized reporter gene construct with the term
“TI titer/MRD.” An example of these calculations is shown in Table6.1.
If plotted as a double‐logarithmic graph, there will be a linear relationship
between TI titer (x) and the theoretical total neutralizing capacity of plasma (y),
the latter of which is expressed as the quantity of AAV vector neutralized by
mL plasma. In the example, this relationship is represented by the equation
3000
y=6 E+13
× x (Figure6.4).
Using the theoretical total neutralizing capacity of plasma for various TI titers,
dose neutralization curves can be derived for different GTx dose levels. For example, at the 6 E+12
total vector dose of 4.2 E+14
vg/kg dose level, an adult with 70 kg body weight will receive a
vg. From the graph and table above, for a test sample
Table6.1 Theoretical neutralizing capacity of plasma volumes and .
TI
Titer
0 0 0
2 (MRD) 1.68 E+09 1.20 E+14
4 3.36 E+09 2.40 E+14
8 6.72 E+09 4.80 E+14
16 1.34 E+10 9.60 E+14
32 2.69 E+10 1.92 E+15
64 5.38 E+10 3.84 E+15
128 1.08 E+11 7.68 E+15
256 2.15 E+11 1.54 E+16
512 4.30 E+11 3.07 E+16
Theoretical neutralizing capacity (vg)
42 μL plasma
(invitro)
3000 mL plasma
(invivo)
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3000 mL plasma
1.E+17
y = 6E+13x
1.E+16
1.E+15
1.E+14
AAV vector neutralized
1.E+13
110100 1000
TI titer
Figure6.4 Theoretical relationship between TI titer and total AAV dose neutralized.
with a TI titer equal to the MRD of 2, the theoretical total neutralizing capacity of
plasma was 1.20 E+14
vg, which corresponds to 29% of the total vector dose
received by this patient (Table6.2). In other words, at least 71% of the total vector
dose are expected to remain active. This calculation can be repeated for the theoretical total neutralizing capacity of plasma for higher TI titers at the same dose
level and expanded to higher dose levels, resulting in dose neutralization curves
that estimate at which TI titer complete dose neutralization (0% active clinical
dose) would theoretically occur (Figure6.5).
While theoretical dose neutralization curves are unlikely to accurately predict
TI titer limits associated with individual treatment success, they can provide
benchmarks for empirical interrogation of GTx efficacy in the presence of preexisting AAV immunity [4, 60]. The current clinical praxis of weight‐based AAV‐
GTx dosing may also not be fully compatible with using average assumptions for
body weight and total plasma volume. The real‐world challenges of determining
patient eligibility, and tentatively adjusting vector dose level based on preexisting
TI titers, may require more sophisticated modeling than the one discussed above,
while also carefully considering infusion‐associated reactions and safety in dose
escalation studies conducted to overcome preexisting TI titers. Nonetheless, theoretical dose neutralization curves can confirm that a cell‐based TI assay has sufficient analytical sensitivity to detect AAV inhibitors that are predicted to neutralize
a substantial portion of the clinical dose.
AAV antibodies may have clinical impact apart from dose neutralization, such as
accelerated capsid clearance, modified capsid tropism, or complement activation;
corresponding orthogonal methods should therefore be implemented as needed.
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Table6.2 Theoretical relationship between TI titer and percentage dose neutralization.
Theoretical percentage of total clinical vector dose neutralized by 3000 mL plasma
TI titer 6 E+12 (vg/kg) 2 E+13 (vg/kg) 6 E+13 (vg/kg) 2 E+14 (vg/kg)
0 0% 0% 0% 0%
2 29% 9% 3% 1%
4 57% 17% 6% 2%
8 114% 34% 11% 3%
16 229% 69% 23% 7%
32 457% 137% 46% 14%
64 914% 274% 91% 27%
128 1829% 549% 183% 55%
256 3657% 1097% 366% 110%
a
The total clinical vector dose was calculated for a 70‐kg adult patient as 4.2 E+14vg (at 6
E+12 vg/kg dose level), 1.4 E+15 vg (at 2 E+13 vg/kg dose level), 4.2 E+15 vg (at 6 E+13 vg/kg),
and 1.4 E+16 vg (at 2 E+14 vg/kg).
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
Percentage of active clinical dose
0%
050 100 150
TI titer
2 E14 vg/kg
6 E13 vg/kg
2 E13 vg/kg
6 E12 vg/kg
200
250
a
Figure6.5 Theoretical dose neutralization curves were obtained by plotting the
difference between 100% and the theoretical percentage of the total clinical dose
neutralized by 3000 mL plasma from Table6.2.
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6.3.6 Value and Challenges ofStandardizing TAb and TI Assays
There are ongoing discussions on how to harmonize AAV TAb and TI assays across
sponsors. Potential benefits could be increased transparency of data used to inform
GTx patient eligibility and comparability of antibody titers and efficacy across clinical trials. Presently, AAV antibody titers from different sponsors are not comparable, due to different assay formats, technologies, cut‐points, titer schemes, and
algorithms (endpoint vs. interpolated titer; endpoint titer is the reciprocal of the
highest sample dilution empirically detectable, interpolated titer is the reciprocal
of the mathematically derived sample dilution at the assay cut‐point using curve fit
or linear regression). Moreover, TAb and TI assays generally do not use reference
standards against which antibody concentrations in test samples would be calibrated, since no single reference standard would adequately represent the unique
mixture of AAV antibodies in individual samples. This idiosyncrasy distinguishes
immunogenicity assays from pharmacokinetic or biomarker assays, for which
standardization can be achieved by using universally accepted and widely accessible primary and secondary reference standards[61].
A first step toward AAV TAb and TI assay standardization could be regulatory
guidance detailing minimally required assay performance characteristics and best
practices for bioanalytical method validation. A second step could be to establish a
panel of positive polyclonal reference samples, and/or a panel of representative
monoclonal AAV antibodies isolated from human subjects. While these reference
samples or antibodies would not serve as calibration standards, they could be tested
and titered in assays across sponsors and compared to real‐world clinical samples[62, 63]. This would allow for comparison of analytical sensitivity across sponsors and thus provide a better understanding of numerical titer measurements.
A third step toward harmonization could be to gain alignment on whether AAV
TAb or TI assays are more clinically meaningful for detecting preexisting AAV
immunity. Agreements across industry and academia on analytical assay formats
have been achieved previously, for example, for detecting coagulation factor VIII
inhibitors (Nijmegen‐Bethesda Assay,[64–69], or for detecting NAbs to interferon
beta [70]. For detecting preexisting AAV immunity, the choice of assay would
need to reflect not only its predictive value with regard to clinical GTx efficacy but
also the feasibility of commercialization as a CDx. Cell‐based TI assays are intrinsically more complex and thus more challenging to develop into a globally viable
CDx. Hence, even though TI titers can adequately describe the neutralizing potential of AAV antibodies, as opposed to TAb titers that represent a combined measure of binding strength and concentration, TAb assays could be a less expensive
and more practical solution for large‐scale real‐world CDx implementation. For
more information, see Chapter15, Chapter16, and Chapter17.
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