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Current Radiopharmaceuticals, 2012, 5, 221-227
221
Bismuth-213 and Actinium-225 – Generator Performance and Evolving
Therapeutic Applications of Two Generator-Derived Alpha-Emitting
Radioisotopes
Alfred Morgenstern*, Frank Bruchertseifer and Christos Apostolidis
European Commission, Joint Research Centre, Institute for Transuranium Elements, PO Box 2340, 76125 Karlsruhe,
Germany
Abstract: The alpha emitters 225Ac and 213Bi are promising therapeutic radionuclides for application in targeted alpha
therapy of cancer and infectious diseases. Both alpha emitters are available with high specific activity from established
radionuclide generators. Their favourable chemical and physical properties have led to the conduction of a large number
of preclinical studies and several clinical trials, demonstrating the feasibility, safety and therapeutic efficacy of targeted
alpha therapy with 225Ac and 213Bi. This review describes methods for the production of 225Ac and 213Bi and gives an
overview of 225Ac/213Bi radionuclide generator systems. Selected preclinical studies are highlighted and the current clinical experience with 225Ac and 213Bi is summarized.
Keywords: Targeted alpha therapy, Alpha emitter, Actinium-225, Bismuth-213, Preclinical, Clinical studies.
INTRODUCTION
Alpha emitting radionuclides can kill targeted cells effectively and selectively through emission of highly energetic,
short-range alpha particles. Due to the short range (<100
m) and high linear energy transfer (LET 100 keV/m) of
alpha particles in human tissue, targeted alpha therapy (TAT)
can deliver a highly cytotoxic dose to targeted cells while
minimizing damage to surrounding healthy tissue. Cell death
induced by alpha radiation is predominantly due to DNA
double strand breaks occurring along the densely ionising
particle trajectory and is largely independent of cell cycle
phase and cell oxygenation status [1-4]. As alpha radiation is
able to overcome resistance to chemotherapeutic drugs, betaand gamma radiation [5], targeted alpha therapy can offer an
alternative therapy option for patients refractory to standard
therapies. Among the few alpha emitters suitable for application in cancer therapy, the generator derived radionuclide
pair 225Ac and 213Bi has emerged as particularly promising.
The relatively long lived mother nuclide 225Ac (T1/2 = 10
days) can be applied as therapeutic nuclide or as source for
production of its short-lived daughter nuclide 213Bi (T1/2 = 46
minutes). Both nuclides are available as no-carrier-added /
high specific activity radionuclide, independently from local
reactor or cyclotron production capabilities. While 225Ac is
produced at centralised manufacturing sites, short-lived 213Bi
is available in clinical settings from 225Ac / 213Bi radionuclide generator systems and is conveniently produced in
house immediately before application. The favourable
chemical properties of the trivalent metal ions Ac(III) and
Bi(III) allow the stable linking to biomolecules using the
established
chelate
molecules
DOTA
(1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DTPA
*Address correspondence to this author at the European Commission, Joint
Research Centre, Institute for Transuranium Elements, PO Box 2340, 76125
Karlsruhe, Germany; Tel: +49(0) 7247 95199618; Fax: +49(0) 7247
951248; E-mail: [email protected]
1874-47/12 $58.00+.00
(diethylene triamine pentaacetic acid). These advantageous
characteristics of 225Ac and 213Bi have led to the generation
of a wide body of preclinical data [6] that could be translated
into several pioneering clinical trials. To date clinical experience with 213Bi has been established in clinical trials of leukemia [7,8], lymphoma [9], malignant melanoma [10-12],
glioma [13,14] and neuroendocrine tumors [15], while clinical data on therapy with 225Ac are currently limited to a
phase I study on leukemia [16].
DECAY CHARACTERISTICS OF 225Ac AND 213Bi
225
Ac is a pure alpha emitter with a half-life of 10 days. It
decays via a cascade of six relatively short-lived radionuclide daughters to long-lived 209Bi (T1/2 = 1.9x1019 y) (Fig.
(1)). The predominant decay path of 225Ac yields net 4 alpha
particles with a large cumulative energy of 28 MeV and 2
beta disintegrations of 1.6 and 0.6 MeV maximum energy
[17]. Gamma emissions useful for in vivo imaging are generated in the 225Ac decay path from disintegration of 221Fr (218
keV, 11.6% emission probability) and 213Bi (440 keV, 26.1%
emission probability). Its relatively long half-life of 10 days
and the multiple alpha particles generated in the rapid decay
chain render 225Ac a particularly cytotoxic radionuclide.
Its short-lived daughter nuclide 213Bi is a mixed alpha /
beta emitter with a half-life of 46 min. It mainly decays via
beta- emission to the ultra short-lived, pure alpha emitter
213
Po (T1/2 = 4.2 s, E = 8.4 MeV) with a branching ratio of
97.8% (Fig. (1)). The remaining 2.2 % of 213Bi decays lead
to 209Tl via alpha particle emission (E = 5.5 MeV, 0.16%,
E = 5.9 MeV, 2.01 %). Both 213Po and 209Tl finally decay
via 209Pb (T1/2 = 3.25 h, beta-) into long-lived 209Bi. The 8.4
MeV alpha particle emitted by 213Po has a path length of 76
m in human tissue. It is contributing more than 98% of the
alpha particle energy emitted per disintegration of 213Bi and
can therefore be considered as mainly responsible for its
cytotoxic effects. With 92.7 % the majority of the total parti© 2012 Bentham Science Publishers
222 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
Morgenstern et al.
233U
: 1.6.105 y
229Th
: 7340 y
225Ra
: 14.9 d
225Ac
: 10 d
5.8 MeV
221Fr
: 4.9 m
6.3 MeV
217At
: 46 min, 98%
1.4 MeV
: 32 ms
7.1 MeV
213Bi
213Po
: 4.2 s
8.4 MeV
209Pb
: 2%, 46 min
5.9 MeV
: 2.2 m
1.8 MeV
209Tl
: 3.3 h
0.6 MeV
209Bi
: 1.9x1019 y
Fig. (1). Decay chain of 233Uranium (Decay data are taken from [17]).
cle energy emitted per disintegration of 213Bi originates from
alpha decay, while only 7.3 % of decay energy is contributed
by beta particle emission, including the decay of 209Pb [1].
As mentioned above, the decay of 213Bi is accompanied by
the emission of a 440 keV photon (emission probability of
26.1%) that allows to monitor 213Bi-biodistribution and to
conduct pharmacokinetic and dosimetric studies using
gamma cameras equipped with commercially available high
energy collimators.
PRODUCTION OF 225Ac
Preclinical and clinical studies of targeted alpha therapy
with 225Ac or 213Bi conducted to date have been using 225Ac /
213
Bi produced via radiochemical extraction from 229Th (T1/2
= 7340 y) sources available from the decay of 233U.
229
Th/225Ac generator sources of clinically relevant activities
are currently available at the Institute for Transuranium Elements (ITU) in Karlsruhe, Germany [18,19], Oak Ridge National Laboratory (ORNL), USA [20] and at the Institute of
Physics and Power Engineering (IPPE) in Obninsk [21].
These 229Th/225Ac sources have been obtained by separation
from aged, fissile 233U originally produced by neutron irradiation of natural 232Th. The 225Ac product obtained from
229
Th is carrier-free with a specific activity of 2.1x1015 Bq/g
(5.8x104 Ci/g). The methods for production of 225Ac from
229
Th/225Ac generator sources used at ITU and ORNL have
been described in detail in [18-20], however, we are not
aware of literature data describing the production process
used at IPPE.
The process developed at ITU for the separation of 225Ac
from 229Th is a two-step process combining ion exchange
and extraction chromatography [18,19]. At regular time intervals, typically every 8 weeks, 225Ra and 225Ac are separated from 229Th / 232Th using anion exchange in nitric acid
media. In the second step of the separation process, 225Ac is
separated from 225Ra and residual traces of 229Th / 232Th by
extraction chromatography using a combination of UTEVA
and TEHDGA resin. The 225Ra fraction is stored for subse-
quent extractions of 225Ac in 2-3 week intervals. The resulting 225Ac product is supplied by ITU with a radiochemical
purity of > 99.98% (< 2 x 10-5 of 225Ra and < 9 x 10-5 of 233U
/ 229Th relative to the activity of 225Ac) and is available as
dried actinium nitrate, actinium chloride, or loaded on a
225
Ac / 213Bi radionuclide generator. The total annual production of 225Ac at ITU is approximately 13 GBq (350 mCi)
with a maximum activity available in a single batch of 1.3
GBq (35 mCi). ORNL is using a four-step process combining anion and cation exchange chromatography [20]. 225Ra
and 225Ac are separated from thorium (228Th / 229Th / 232Th)
by repeated anion exchange in 8 M HNO3, followed by separation of 225Ac from 225Ra via two sequential cation exchange steps. The radiochemical purity of the 225Ac product
supplied by ORNL is > 99.99% with a 225Ra content of < 3 x
10-3 % and a 229Th content of < 2 x 10-3 %. Over an 8-week
campaign, ORNL is producing 3.7 GBq (100 mCi) 225Ac
in 5-6 batches ( 80 % of the theoretical yield), with the
largest batch typically consisting of 1.85 GBq (50 mCi).
IPPE is reporting production capacities of 2.2 GBq (60
mCi) per month [21], the radiochemical purity of the 225Ac
product is > 99.9% (< 0.02 % 225Ra, < 0.02% 224Ra, <
0.007% 229Th), the sum of non-radioactive cations is stated
as < 10 g/ml.
Overall the current worldwide production of 225Ac from
Th/225Ac generators amounts to approximately 63 GBq
(1.7 Ci) per year. This level of production is sufficient to
conduct preclinical studies and a limited number of clinical
trials. However, for a widespread clinical application of
225
Ac and 213Bi their availability needs to be increased significantly. In this respect, a number of alternative production
routes have been investigated, including the irradiation of
226
Ra targets using neutrons, protons, deuterons or gammarays [22-26] and the irradiation of 232Th targets with high
energy protons [27-29]. Among these routes, the production
of 225Ac by proton irradiation of 226Ra targets in a cyclotron
through the reaction 226Ra(p,2n)225Ac seems most promising
for cost-effective, large scale production [23]. The production can be performed in medium-sized cyclotrons at proton
energies below 30 MeV with thick target yields of 18
229
Bismuth-213 and Actinium-225 – Generator Performance
100
Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
223
225Ac
Activity (%) .
80
60
213Bi
40
20
0
0
1
2
3
4
5
Time (h)
Fig. (2). Ingrowth of 213Bi Activity (squares) from Decay of 225Ac (circles) Following Generator Elution. Two hours after Elution of the Generator 83% of the Maximum Activity of 213Bi have grown back in, while after three hours 93% are available.
Polypropylene
Fittings
Perfluoroalkoxy
Tubing
AG-MP 50 Resin
Inlet
Outlet
Silicone Tubing
Frit
Quartz Wool
Frit
Fig. (3). Schematics of the ITU Standard 225Ac/213Bi Radionuclide Generator.
MBq/Ah at 25 MeV. In other words, a single irradiation of
a thick target of 226Ra for 20 h at a moderate proton current
of 50 A would result in the production of 18 GBq (486
mCi) 225Ac, corresponding to approximately one third of its
current annual world-wide production from 229Th/225Ac generators. The 225Ac product obtained from proton irradiation
of 226Ra is essentially carrier-free and suitable for synthesis
of high specific targeting agents. Although the handling of
cyclotron targets containing 226Ra is technically demanding,
the production of 225Ac via cyclotron irradiation of 226Ra can
be expected to provide the amounts of 225Ac required for
widespread application in the mid-term future.
PRODUCTION OF 213Bi FROM
NUCLIDE GENERATORS
225
Ac /
213
Bi RADIO-
Short-lived 213Bi can be obtained from radionuclide generators loaded with its longer lived mother nuclide 225Ac.
Due to the 10 day half life of 225Ac the useful life time of
225
Ac/213Bi generators is several weeks. The generator derived 213Bi product is of high specific activity, containing
variable, but low amounts of long-lived 209Bi (Fig. (1)). According to its 46 min half-life, a 213Bi activity corresponding
to 93% of the activity of 225Ac loaded on the generator can
be eluted every 3 hours, while after 2 hours 83% are available (Fig. (2)). In clinical settings generators are typically
eluted every 2-3 hours, depending on the activity required
per patient dose. Several types of 225Ac/213Bi radionuclide
generators have been proposed, based on the use of cation
and anion exchange or extraction chromatography [22, 3038]. 225Ac / 213Bi generators based on AG MP-50 cation ex-
change resin [32,33,38] are by far most widely used, have
been applied for all patient studies with 213Bi to date and will
be described in more detail below.
The stable oxidation state for both actinium and bismuth
under conditions relevant for generator operation is +3. In
dilute acid both trivalent cations are efficiently sorbed to AG
MP-50 cation exchange resin. As hard Lewis acid the Bi3+
cation has a strong affinity for oxygen and nitrogen donors
and a strong affinity to form complexes with sulfur and
halogens, in particular iodide. The strong affinity of Bi(III)
for complexation with iodide is used for selective elution of
213
Bi from the cation exchange resin as anionic BiI4-/BiI52species [39]. A solution of 0.1 M HCl / 0.1 M NaI has been
determined as most favorable as eluent, providing a high
yield of 213Bi elution, low breakthrough of the parent nuclide
and a medium suitable for subsequent labeling reactions
[30,32]. The schematics of a typical 225Ac/213Bi radionuclide
generator based on cation exchange are shown in Fig. (3).
The standard generator produced at ITU shown here contains
0.3 ml of AG MP-50 resin in perflouroalkoxy tubing with
polyproylene fittings and is equipped with silicone tubing.
The distribution of 225Ac activity on AG MP-50 generator
columns is determining the radiation dose absorbed by the
organic cation exchange resin and has important consequences for the generator lifetime. Loading of firstgeneration generator systems with high levels of 225Ac in
dilute hydrochloric acid directly onto pre-packed AGMP-50
columns resulted in the activity being deposited in a very
small layer at the very top of the resin, leading to large local
radiation doses delivered to the organic resin. This loading
224 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
method resulted in catastrophic failure of generators within
1-2 days of operation, due to radiolytic degradation and sintering of the resin and cracking of the plastic body of the
column. The radiation dose (J/kg) to the resin can be decreased by spreading the activity over a larger mass of resin.
McDevitt et al. at MSKCC have described a method to
achieve a homogeneous distribution of activity over large
parts of the resin by pre-loading a slurry of cation exchange
resin outside the generator column. After sorption of 225Ac
from dilute acid, the slurry is filled into a partially assembled
generator column, containing a small aliquot of unloaded
resin serving as catch plug at the outlet of the generator [32].
By spreading the activity over a larger resin mass this
method significantly reduces the dose to the resin and has
been shown to assure constant performance of the generators
loaded with 740-1036 MBq for several weeks. Ma et al. [38]
have further developed this generator principle and constructed tandem generators consisting of two serial columns
loaded with 225Ac connected to a third, smaller, unloaded
column acting as catch plug to trap parent breakthrough.
This design allowed reliable operation of the generator with
activities up to 2.6 GBq 225Ac and parent breakthrough of
less than 5 ppm (activity). However, an obvious drawback of
the generator loading method described by McDevitt and Ma
is the need for manual and lengthy handling of large amounts
of actinium activity when filling the pre-loaded slurry into
the generator columns. This operation results in a significant
radiation dose received by the operator and is associated with
the risk of spilling, contamination and loss of activity. A
much simplified method for generator loading that allows
semi-automated, remote operation and greatly reduces dose
to the operator has been developed at ITU [18]. 225Ac loading of prepacked AG-MP 50 generator columns from 4 M
HNO3 solution has been found to result in distribution of the
activity over the first two thirds of the resin and can be performed using a peristaltic pump without manual intervention.
ITU standard 225Ac/213Bi radionuclide generators loaded in
this manner afford 76±3 % elution yield of 213Bi in 0.6 ml of
0.1 M NaI / 0.1 M HCl (two column bed volumes) with low
parent breakthrough of < 0.2 ppm [33]. To date the standard
ITU generator has been used for preparation of patient doses
in clinical studies of neuroendocrine tumors, glioma, malignant melanoma and lymphoma with > 90 patients.
Quality Control of 213Bi Preparations
213
Bi produced from 225Ac/213Bi radionuclide generators
can be used for labeling of monoclonal antibodies or peptides following established labeling protocols [14, 32]. Owing to the short half live of 213Bi, quality control of 213Bi
preparations is preferably performed within few minutes to
avoid significant decay losses. The radiochemical purity of
213
Bi labeled antibodies is typically assessed by ITLC within
less than 5 minutes, while 213Bi labeled peptides can be rapidly analyzed by ITLC and/or Radio-HPLC. However, direct
quantification of 225Ac parent breakthrough from the generator and the content of 225Ac in the final preparation is not
feasible within an acceptable time frame. Due to the low
ratio of 225Ac over 213Bi activity of less < 10-6 and the low
emission probability of gamma rays associated with 225Ac
decay of < 2%, analysis of 225Ac activity is typically performed via gamma spectrometry after quantitative decay of
Morgenstern et al.
eluted 213Bi, typically after 24 hours. An acceptable level of
Ac activity in 213Bi preparations used for clinical application is therefore typically assured in an indirect manner, deduced from previous testing of generators of identical type.
225
Ac/213Bi generators based on AG MP-50 resin that have
been used in humans studies to date allow the synthesis of
213
Bi labelled antibodies and peptides with a content of 225Ac
of less than 1 ppm (activity of 225Ac over activity of 213Bi at
time of injection). To date 225Ac/213Bi radionuclide generators are not available in sterile form, sterility of the 213Bi
preparation is typically assured via aseptic handling, microbial monitoring and sterile filtration of the final formulation.
225
SELECTED PRECLINICAL STUDIES WITH
AND 213Bi
225
Ac
In the last decades a wide body of preclinical studies on
targeted alpha therapy using 225Ac and 213Bi has been generated and has been summarized in e.g. [6, 40, 41]. A variety
of targeting strategies has been investigated, using full antibodies, antibody fragments, low molecular weight peptides
or liposomes as vehicles. The considerable difference in half
life between 225Ac and 213Bi has important implications on
the choice of successful targeting strategies. When using
short half lived 213Bi, rapid targeting is essential and can be
achieved e.g with locoregional application [42], pretargeting
[43] or with fast-diffusible peptides as carrier molecules
[44]. In contrast, the 10 day half life of 225Ac also allows
targeting with full antibodies that may require up to several
days for maximum tumor uptake. To give a detailed overview of all preclinical studies with 225Ac and 213Bi is beyond
the scope of this review, therefore we have attempted to
summarize a selection of more recent reports.
In a series of studies Hong et al. have investigated targeted alpha therapy of breast cancer metastases in a neu-N
transgenic mouse model that closely resembles the pattern of
metastatic spread in breast cancer patients [45-48]. Treatment with a 213Bi-labeled anti–HER-2/neu monoclonal antibody at the maximum tolerated dose of 4.44 MBq was found
to be effective in treating early-stage HER-2/neu–expressing
micrometastases, however, due to the relatively slow tumor
uptake of the labeled antibody, radiation doses delivered to
metastases with 213Bi were limited [46]. When labeled with
longer-lived 225Ac, the anti–HER-2/neu antibody radioconjugate delivered a nearly 5 fold higher dose to metastases
and was consequently therapeutically more effective [47]. In
a related study Lingappa et al. attempted to increase the
number of 213Bi-atoms delivered to the target sites by engineering liposomal vesicles that carry a greater number of
213
Bi atoms than radiolabeled anti–HER-2/neu antibodies. It
could be demonstrated that these high–specific activity 213Biconjugated immunoliposome constructs were stable in vitro
and in vivo, significantly increasing the median survival over
untreated mice and merit further development [48].
Pretargeting with antibody-streptavidin constructs and
Bi-labeled DOTA-biotin has been investigated by Park et
al. [43]. In a model of athymic mice bearing Ramos lymphoma xenografts pretargeting resulted in rapid and specific
targeting of tumor sites, displayed a favorable biodistribution
profile with excellent therapeutic efficacy and clearly merits
further investigation.
213
Bismuth-213 and Actinium-225 – Generator Performance
Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
225
Table 1. Overview of Clinical Studies with 225Ac and 213Bi Conducted to Date
Cancer Type
Leukemia
Lymphoma
Melanoma
Radioconjugate
Phase
No. of Patients
Reference
213
Phase I
18
[7]
213
Bi-HuM195mAb
Phase I/II
31
[8]
225
Ac-HuM195mAb
Phase I
15
[16]
213
Bi-rituximab
Phase I
12
[9]
213
Bi-9.2.27mAb
Phase I (intralesional)
16
[10]
213
Bi-9.2.27mAb
Phase I (systemic)
38
[11,12]
Bi-Substance P
Pilot
Phase I
2
5
[13,14]
Pilot
12
[15]
Bi-HuM195mAb
Glioma
213
Neuroendocrine Tumors
213
Bi-DOTATOC
Rapid targeting of tumor sites can often also be achieved
by use of low molecular weight peptides as carrier molecules. Potential advantages of small radiopeptides over
monoclonal antibodies include their fast diffusion, lack of
immunogenicity, and fast blood clearance. The somatostatin
analogue [DOTA0,Tyr3]octreotide (DOTATOC) labeled with
low linear energy transfer (LET) -emitters, such as 177Lu or
90
Y is increasingly used for peptide receptor radionuclide
therapy (PRRT) of neuroendocrine tumors and has yielded
impressive results on tumor response, overall survival, and
quality of life in a large number of patients [49]. Norenberg
et al. have evaluated DOTATOC labeled with 213Bi in an
animal model of rat pancreatic carcinoma [50] and have
compared its therapeutic effectiveness with 177LuDOTATOC in vitro [51]. In the animal study 213BiDOTATOC showed dose-related antitumor effects with
minimal treatment related organ toxicity, no acute or chronic
hematologic toxicities were observed. In vitro 213BiDOTATOC was found to be more effective in decreasing
clonogenic survival at the same absorbed dose than 177LuDOTATOC in human pancreatic adenocarcinoma cells due
to its comparatively higher RBE. Based on these promising
findings peptide receptor alpha therapy with 213BiDOTATOC is now in clinical testing [15].
In a recent study of peptide receptor radiotherapy Wild et
al. [44] compared 213Bi- vs. 177Lu-radiopeptide therapy of
prostate carcinoma in vivo. Two novel 213Bi-labeled peptides,
DOTA-PEG4-bombesin (DOTA-PESIN) and DO3ACH2CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH2
(AMBA) were evaluated in a human androgen-independent
prostate carcinoma xenograft model (PC-3 tumor) in comparison with 177Lu-DOTA-PESIN. At the maximum tolerated
dose, 213Bi-DOTA-PESIN and 213Bi-AMBA prolonged median survival significantly longer than 177Lu-DOTA-PESIN.
The authors conclude that -therapy with 213Bi-DOTAPESIN or 213Bi-AMBA is more effective than -therapy and
represents a possible new approach for treating recurrent
prostate cancer.
Drecoll et al. [52] investigated a 213Bi-labeled dimer of
the peptide F3 (213Bi-DTPA-[F3]2) in an animal model of
intraperitoneally growing xenograft tumors of peritoneal
carcinomatosis. F3 is a 32 amino acid peptide that is internalized into the nucleus of tumor cells upon binding to nu-
cleolin on the cell surface. 213Bi-DTPA-[F3]2 significantly
increased survival time of the animals when injected 4-14
days or 16-26 days after tumor cell inoculation in a fractionated regime without signs of toxicity. A follow up study
comparing the therapeutic efficacy of 213Bi-DTPA-F3 and
225
Ac-labeled DOTA-F3 in the same tumor model has demonstrated similar therapeutic efficacy of the 225Ac labelled
peptide at 1000 fold lower activities with comparable mild
renal toxicity [53].
CLINICAL EXPERIENCE WITH 225Ac AND 213Bi
To date targeted therapy with 225Ac and 213Bi has been
clinically investigated for the treatment of leukemia, lymphoma, malignant melanoma, glioma and neuroendocrine
tumors. An overview of the current status of clinical trials is
given in Table 1. Although the numbers of patients that have
been treated with 225Ac or 213Bi are still moderate, these studies have provided evidence that targeted therapy with both
alpha emitters is feasible and safe and can have anti-tumor
efficacy with minimal toxicity.
We have summarized 213Bi studies on leukemia, lymphoma, malignant melanoma and glioma in [6]. More recently, a pilot study of therapy of neuroendocrine tumors
using 213Bi-DOTATOC has been started in collaboration
between University Hospital Heidelberg, Germany, and ITU
[15]. To date, twelve patients with unresectable neuroendocrine primary tumor or liver metastases, refractory to a previous treatment with 90Y-/177Lu-DOTATOC, have been
treated with 213Bi-DOTATOC. The cumulative activity administered was up to 10 GBq 213Bi per patient and the activity administered during a single treatment cycle has been
escalated from 1- 7.5 GBq. The activity was injected in fractions of 0.5 -1.5 GBq into an arterial catheter placed in the
tumor feeding vessel. While no acute kidney, endocrine or
hematologic toxicity higher than grade 0/I were observed,
short term follow up demonstrated reduced tumor-perfusion
(as assessed by contrast enhanced sonography) and tumor
shrinkage (as assessed by MRI) in several patients.
Clinical experience with 225Ac therapy is currently still
limited to an ongoing phase I study on therapy of relapsed/refractory AML using the 225Ac labeled anti-CD33
antibody lintuzumab [16]. To date, 15 patients (median age,
226 Current Radiopharmaceuticals, 2012, Vol. 5, No. 3
65 yrs; range, 45-80 yrs) have been treated with total injected activities of 225Ac ranging from 851 to 14,430 kBq
with antibody doses of 0.7 to 2.6 mg. While no acute toxicities were seen, dose-limiting toxicities (myelosuppression
lasting > 35 days; death due to sepsis) were seen in one patient treated with 111 kBq/kg and in both patients receiving
148 kBq/kg. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities. With a median
follow-up of 5 months (range, 1-24 months), no evidence of
radiation nephritis was seen. Peripheral blood blasts were
eliminated in 7 of 11 evaluable patients. Bone marrow blast
reductions of > 33% were seen in 6 of 10 evaluable patients
at 4 weeks, including 2 patients with < 5% blasts. This first
in human study shows that therapy with 225Ac-lintuzumab is
feasible, tolerable at doses < 148 kBq/kg and has antileukemic activity.
Morgenstern et al.
[5]
[6]
[7]
[8]
[9]
CONCLUSIONS AND OUTLOOK
The alpha emitters 225Ac and 213Bi can be reliably produced from established radionuclide generator systems with
high specific activity and high radionuclidic purity. Their
availability in clinical settings is independent from local reactor or cyclotron facilities, their favourable chemical properties allow the synthesis of stable radioconjugates using
established chelate molecules. Consequently, a large number
of preclinical studies and several pioneering clinical trials
have been conducted, showing that targeted alpha therapy
with 225Ac and 213Bi is feasible, safe and may provide new
therapeutic options to patients refractory to standard therapies. In particular peptide receptor alpha therapy with 225Ac
and 213Bi using fast diffusible, low molecular weight peptides such as DOTATOC and Substance P as carrier molecules is promising and can be expected to play an increasing
role in future clinical application.
[10]
[11]
[12]
[13]
[14]
ACKNOWLEDGEMENTS
Declared none.
CONFLICT OF INTEREST
[15]
Declared none.
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Revised: March 28, 2012
Accepted: April 03, 2012