Biomedical Engineering Reference
In-Depth Information
100
bacterial enzyme, six patients received cyclosporine that
allowed up to three cycles of ADEPT to be given over
3 weeks.
Antibody-enzyme conjugate
10
Antibody-enzyme conjugate + SB43g al
23.3.1.4 Results of the First in Man ADEPT Study
Eight patients received the highest total doses of the prodrug
(
1
3.0 g/m
2
) and four of these achieved partial remission
>
0.1
(
50% reduction in volume of all visible tumors). The fifth
patient had a mixed response in which all but one metastasis
shrank by more than 50%. Seven patients survived 6 months
or more including 3 who died 18, 25, and 36 months. These
were remarkable results in patients with advanced and
resistant cancer. However, it was surprising to find that
most patients had grade 3 or 4 reversible myelotoxicity
[33]. Subsequent analysis of blood samples from these
patients showed the presence of prodrug and drug in plasma,
even though there was no detectable circulating enzyme
[34]. The half-life of the generated drug was found to be
about 30min. It was speculated that the drug generated at
cancer sites had leaked back into circulation and because of
its long half-life, caused myelosuppression.
>
0.01
0.001
0 24 48
Time after antibody-enzyme conjugate injection (h)
72
96
FIGURE 23.2
Enzyme inactivation/clearance by SB43gal.
23.3.1.3 First in Man ADEPT Study Following suc-
cessful ADEPT studies in various xenograft models, it
was important to test the system in man to assess its
feasibility. This obviously required a scale-up production
of antibody-enzyme conjugate [30] and all other compo-
nents. The anti-CEA antibody, A5B7 had already been used
in humans in the context of radioimmunolocalization of
CEA-positive tumors. The enzyme, CPG2 had also been
used to treat methotrexate toxicity in patients. The CMDA
prodrug had not been used in man before. Therefore, a dose-
escalation study of the prodrug alone was carried out to
assess its safety and to determine the maximum tolerated
dose that could be used in the three-phase ADEPT system.
The dose range of 0.2-2.4 g/m
2
was studied. The CMDAwas
well tolerated in patients with a minimal evidence of toxic-
ity. This was probably because the CMDAwas only soluble
in dimethyl sulfoxide (DMSO).
In the main part of the ADEPT study, 18 patients aged
28-75 years were studied [31,32]. All had advanced carci-
noma of colon, rectum, or appendix with multisite metastatic
disease that expressed CEA on histological examination,
had undergone initial surgery and chemotherapy but now
had progressive drug-resistant disease. Expected survival
times were
23.3.1.5 Conclusions from the First in Man ADEPT
Study Conclusions from the first in man ADEPT study
are as follows:
The A5CP conjugate and SB43gal were well tolerated.
SB43gal was effective in eliminating the enzyme from
blood.
The amount of SB43gal given needed to be propor-
tionate to the A5CP dose for the first few hours after
administration but could then be substantially reduced
such that a low dose infusion would inactivate any
enzyme leaking back from tumor sites.
Cyclosporine delayed immune response to the enzyme
but added to toxicity [35].
The prodrug, CMDA, was nontoxic but was soluble
only in DMSO, which was a substantial disadvantage.
The generated drug had a long half-life, which was a
probable cause of myelotoxicity.
It was concluded that a prodrug/drug system in which
the drug had a very short half-life (
2 months.
As this was the first ever clinical study of ADEPT,
multiple variables in terms of the components dose and
interval had to be explored. The dose of antibody-enzyme
conjugate [A5B7-F(ab
0
)
2
-CPG2 commonly referred to as
A5CP] ranged between 20,000 and 30,000 units/m
2
. The
dose range for SB43gal was 90-240mg/m
2
. The total dose
of the CMDA prodrug given ranged between 1.4 and 10 g/m
2
.
Several variations in the time interval between AEC and
SB43 and the duration of SB43 were explored. The CMDA
was initially given as a bolus but later as an infusion. A
small component of the A5CP conjugate was radiolabeled
with 131-iodine to allow SPECT imaging. In an attempt to
delay the immune response to the murine antibody and the
<
<
1min) was required.
Given the limitations of the reagents available, the results
were most encouraging.
23.3.2 The Second Clinical Study of ADEPT
The second three-phase ADEPT clinical study included
10 patients with unresectable or metastatic but CEA-positive
colorectal carcinoma [36]. The study used the same
reagents as before but with lower dose of the conjugate
(10,000 units/m
2
). The CMDAwas given as a bolus to allow
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