Biomedical Engineering Reference
In-Depth Information
Translocation out of the endosome to the cytosol appears to
be carried out by the B chain and conjugates without it are
nontoxic [27,70].
TransMID
TM
targets tumor cells via the Tf receptor
(TfR). TfR is a transmembrane glycoprotein that mediates
cellular uptake of iron. TfR are overexpressed on rapidly
dividing cells, such as hematopoietic and neoplastic cells,
including GBM cells [73]. This fact is thought to reflect an
increased requirement for iron in rapidly dividing cells [74].
TfR in normal brain are sparse and their expression is largely
restricted to the luminal surface of brain capillaries [75]. It is
this relative difference in the density of TfR that TransMID
uses to generate differential toxicity to highly TfR express-
ing neoplastic cells, while sparing low expressing normal
brain cells [76]. Low-density background expression of the
respective target receptor in normal tissue remains a major
concern, however, with TransMID (and with all other tar-
geted toxin-based therapies).
TransMID has been thoroughly evaluated in cell culture.
Hall et al. [77] showed that human Tf conjugated to either
the Abrus plant toxin, abrin, or the P. aeruginosa exotoxin A
had comparable cytotoxic potency in glioma and melanoma
cell lines. All toxins had an ID
50
in the low picomolar range.
Martell et al. [78] compared the efficacy and cytotoxic
properties of TransMID to 454A12-rRA, a conjugate of a
monoclonal antibody to the human TfR receptor (454A12)
with the recombinant Ricinus plant toxin, ricin A chain
(rRA). Cell lines were sensitive to toxin doses of 10
10
M
and less. Highly malignant tumor cells such as GBM or
medulloblastoma had lower IC
50
values (10
12
M), indicat-
ing high sensitivity of such tumors to the targeted toxin.
Expression of TfR on the cell lines and resection specimens
correlated with sensitivity to the toxin in cell culture [78].
Chignola et al. [79] treated monolayer and multicellular
spheroid cultures of human breast cancer, human GBM, and
rat gliosarcoma with a toxin composed of TfR and ricin A
chain (TfR-RTA) and with TransMID
TM
, which yielded
similar patterns of toxicity. The results indicated that the
efficacy of targeted toxins against three-dimensional (3D)
tumors might be heavily influenced by the number of target
molecules expressed by the tumor cells, as well as by the
affinity of toxin-cell interaction.
In vivo efficacy of locally administered TransMID against
human glioma in nude mice was demonstrated by Laske
et al. [80]. These authors studied TransMID compared to
454A12-rRA and administered toxins intratumorally in a
subcutaneous model. Repeated intratumoral injections of
10
m
g TransMID or 10
m
g 454A12-rRA were compared to
equimolar doses of the untargeted native toxin CRM-107,
454A12 antibody, rRA, and phosphate-buffered saline. By
day 14, TransMID administration resulted in almost com-
plete tumor regression (
toxin components (CRM-107, 454A12, or rRA) caused sig-
nificant, but less potent tumor growth inhibition than the
conjugated toxins [80]. In a more recent study, Engebraaten
et al. [81] compared the efficacy of TransMID with that of PE
conjugated with the 425.3 antibodies directed against
EGFR. Mice with subcutaneous gliomas or rats with
intracranial gliomas received different doses (1-10
m
g)
of TransMID or 425.3-PE injected intratumorally in estab-
lished tumors. Both toxins showed significant antitumor
effects in subcutaneous tumors, but only 425.3-PE was effec-
tive in intracranial gliomas in rats. Intracerebral TransMID
was toxic in doses above 10 ng, while intracerebral 425.3-PE
was tolerated up to a dose of 4
m
g per animal. The authors
concluded that both toxins have promising efficacy in brain
tumor models, but that 425.3-PE is better tolerated and has a
more specific activity at higher doses.
Laske et al. [82] treated 18 patients with recurrent
malignant glioma with intratumoral high flow interstitial
microinfusion of TransMID in a dose-escalating single arm
Phase I clinical trial. The drug was infused at a maximum
flow rate of 4-10
m
L/min with toxin concentration of
0.1
m
g/mL. On the basis of preclinical data, the rate of
infusion was limited to a maximum of 10
m
L/min per
catheter to avoid leakage via the catheter track. Drug
concentration at a given infusion volume was escalated
by half log increments in every 3-4 patients, unless severe
toxicity was detected in one of the first 2-3 patients. Nine of
the 15 evaluable patients responded to treatment by at least
50% reduction in tumor volume on MRI, including two
complete responses. Reduction in tumor volume occurred no
earlier than 1 month after completion of the first toxin
infusion. In four patients, response was not maximal until
6-14 months after the first treatment. Tumor response
appeared to be concentration and dose dependent. Only
two of the eight patients in the first two treatment groups
(0.1-0.32
m
g/mL) had partial responses. In contrast, two of
four patients
1.0
m
g/mL had complete
responses and the other two patients had partial responses.
Those patients treated with a total dose of 60
m
g or higher all
had partial responses; however, toxicity was noted 1-4
weeks after treatment. At intermediate toxin concentrations,
responses correlated more with total dose than with concen-
tration of drug. Although pretreatment tumor volume
seemed to be related to the likelihood of response, it did
not reach statistical significance. Median survival after
treatment in the responder group was 74 weeks, with three
of the responders still alive at 102-142 weeks after the first
treatment. Nonresponders survived a median of 36 weeks.
Intratumoral infusions of TransMID with total volumes of
5-180mL were well tolerated. There were no treatment-
related deaths or life-threatening or irreversible toxicity.
Transient worsening of a pre-existing neurological deficit
during infusion occurred 3 times in 44 treatments. No
symptomatic systemic toxicity occurred [82].
treated with
>
95%), without evidence of recur-
rence by day 30. Treatment with 454A12-rRA caused a less
significant decrease (30%) in tumor volume. Unconjugated
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