Memorias II Congreso Latinoamericano de Ingeniería Biomédica, Habana 2001, Mayo 23 al 25, 2001, La Habana, Cuba
RADIATION ABSORBED DOSES AND SAFETY OF THE
HUMANIZED MONOCLONAL ANTIBODY H-R3 LABELED
Leonel A. Torres, Marco A. Coca, Maria E. Solano, Alejandro Perera, Juan F. Batista, Abel Hernandez, Tania
Crombet, Marilyn Perez, Mayra Ramos, Elvia L Sanchez, Susana Romero, Vicente Aguilar, Normando Iznaga
Calle 34 #4501 esq. 45. Reparto Kohly, Playa, Havana, Cuba
AP 11300 Telf.: (537) 23 0087 Fax: (537) 24 3298
(MAbs) could be useful for immunoscintigraphic diagnosis
. Labeled humanized monoclonal antibodies
(Mab) for the diagnosis and treatment of tumors using
In order to decrease the immunogenicity and HAMA
Nuclear Medicine procedures have contributed to decrease
response to the murine MAbs, and increase the half-live of
the immunogenicity and HAMA response of murine
the molecule in the patient, it was developed a reshaped
MAbs, increasing the effectiveness and usefulness of
humanized monoclonal antibody H-R3. This study include
radioimmunoscintigraphic procedures. The objective of
the preliminary results of the internal radiation dosimetry,
this study was to evaluate the internal radiation dosimetry
biodistribution and safety of the 99mTc-labelled H-R3 used
and safety of the 99mTc-labeled H-R3 Mab, in humans.
for radioimmunodiagnosis of tumors of epithelial origin.
Material and methods
: Ten patients with suspicions ofepithelial tumors were included on this study. They
2. MATERIAL AND METHODS
received 1110 MBq of 99mTc H-R3, intravenously.
Multiple blood, urine samples and sequential whole-body
Antibody Labelling and Quality Control.
images were collected at different times. The internal
Freeze-dried kits with 3 mg of humanised MAb H-R3
radiation dosimetry was estimated using the Medical
(Centre of Molecular Immunology, Havana, Cuba) were
Internal Radiation Dosimetry (MIRD) Committee
reconstituted with 1295 MBq of pertechnetate from a
methodology. Biodistribution was computed from the
99Mo/99mTc generator (CIS-BioInternational, France).
scintigraphic images and regression analysis of the time-
Labelled product was subjected to ascending paper
activity curves was employed to compute the residence
chromatography. Radiochemical purity higher 90% was
times of the source organs. Hematological toxicity and
considered satisfactory for patient’s administration.
adverse effects were evaluated using the WHOclassification. Results:
Liver received the higher absorbed
dose (4,90E-02mGy/MBq), followed by the kidneys
Ten adult patients (6 females and 4 males) were enrolled
(1,60E-02mGy/MBq) and gallbladder wall (1,53E-
on this study. They received 3 mg of MAb labeled with
02mGy/MBq). The effective dose and the effective
1110 MBq of 99mTc. All patients were suspected of
equivalent dose were 0,0143 mSv/MBq and 0,0190
having either primary or recurrent cancer of epithelial
mSv/MBq, respectively. The main source organs of this
origin and had undergone CT scanning, x-ray and other
radiopharmaceutical were liver, spleen, kidneys and heart.
determinations. Histopathological findings were considered
No significant changes were observed in the hematological
as a confirmation criterion (gold standard). All studied
parameters and only two patients showed mild and
patients gave their written informed consent previously to
moderate adverse effects, solved during the studies and not
Biodistribution studies and internal radiation dosimetry
Palabras clave: absorbed doses, monoclonal antibody,
Anterior and posterior whole body images were acquired at5 min, 1 h, 3 h, 5 h and 24 h after administration of
radiopharmaceutical, using a gamma camera(SOPHYCAMMERA DS7, France). The gamma camerahead was fitted with a diverging parallel-hole collimator to
Almost 90% of malignancies are epithelial derived tumors.
increase the lateral viewing aspect. A 20% window
Cancer of epithelial origin constitutes one of the first
centered on the 140 keV emission peak of the 99mTc was
causes of death world-wide . Tumors of epithelial
employed. On the gantry movements were used a speed of
origin, like cancer of lung, digestive tract, breast and
20 cm/min. All whole-body images were stored in the
others, have an overexpression of the epidermal growth
computer in 2048x512 byte mode matrix.
factor receptor (EGF-R) . This fact is often related to
All images were processed in a SOPHY-20P system using
malignancy and poor prognosis of the disease . Clinical
the software BioDose v1.0, developed at the Centre for
trials have shown that anti-EGF-R monoclonal antibodies
Clinical Research. Geometric mean images were computed
950-7132-57-5 (c) 2001, Sociedad Cubana de Bioingeniería, artículo 00437
from the anterior and posterior whole-body scans. They
were reviewed to determine the subjective biodistribution
99mTc-H-R3 Human biodistribution. Data corrected by
of 99mTc-H-R3 and to select which organs and tissues were
clearly visible in the total image series. Such organs were
Regions of interest (ROI) were drawn over heart, liver,spleen, small intestine, kidneys, upper large intestine (ULI),
lower large intestine (LLI) and urinary bladder. Total
counts were computed for each one, at the different time
intervals. For each source organ count values were
converted to activity, corrected for decay and expressed as
percentage of the total administered activity. Whole-body
activity was initially 100 % following a exponential
clearance by biological removal and physical decay of
The MIRD Committee method was used to assess the
internal radiation dosimetry. Time-activity curves for each
source organ and the remainder of the body tissues were
obtained and fitted to exponential disappearance curves.
Cumulative activities and residence times for each source
The assessed absorbed dose of 8 target organs (mGy/MBq
organ were estimated integrating the time-activity curves.
The absorbed doses to whole body and organs were
or rad/mCi) after the injection of 99mTc- MAb ior H-R3
estimated using the residence times and the modified ”S”
are presented in Table No II. The absorbed dose for the
values reported on MIRD Pamphlets [6,7]. Based on the
whole body and the effective dose are also reported. The
results of the absorbed dose estimated to various target
highest absorbed dose was received by the liver with a
value of approximately 4,90E-02 mGy/MBq and thekidneys 1,60E-02mGy/MBq). The effective dose and the
Clinical laboratory analysis and safety studies.
equivalent effective dose were 0,0143 mSv/MBq and
Complete blood cell counts with differential and platelet
0,0190 mSv/MBq respectively. The main contributor
counts, chemistry panel evaluation, liver function test and
organs to the absorbed dose per organ were the hepatic
urinary analysis were performed 1-7 days before and 24 h
after antibody administration. Patients did not have any
food for 12 hours before blood collection. Fifteen millilitres
Normal organ dosimetry for the labelled MAb
of blood were withdrawn from a patient’s vein 1 week
before and 24 h after 99mTc-H-R3 administration. Five
millilitres of blood were carefully added to a brand
collection tube with 50 µL of 15% EDTA (K
(Vacutainer, Becton Dickinson, USA) for haematology.
One drop of blood was extended in a microscope slide
(Shanghai Company, China) for differential leukocyte
counting. Five millilitres of blood were added to a
centrifuge tube and were incubated at room temperature for
1 h. After that, sample was centrifuged at 3000 rpm for 10
min and two 1mL-specimens of serum were added in
Eppendorf tubes for analytical chemistry tests. On the
other hand one hundred millilitre urine sample of the first
morning urination was collected in a sterile container to
All patients were monitored up-to 24 h after injection
in order to detect any adverse reaction.
Biodistribution and Internal Radiation Dosimetry
Only two patients (20%) showed adverse reactions.
The computed biodistribution of the 99mTc-MAb H-R3 is
Reactions were clasified as follows: Patient No.7, acuterhinitis at 30 minutes after injection. It was maintained for
6 hours, responding partially to the treatment with
intramuscle Benadryl. According to the WHO criteria itwas considered as moderated reaction. On this patient thehematological analysis showed normal results. PatientNo.9, Chills that no required medication and disappearedat a few minutes. It was considered as mild reaction (grade1). The complementary blood examinations had alterationsin two parameters: glucose=21 milimols/L andalcalinephosphatase=312 u/L. These blood samples wereobtained a day after the injection of the product. We cannotestablish the causes of such abnormalities because no otherpatient injected had such abnormal parameters. On theother hand, no significant changes of the vital signs weredetected in any of the studied cases after the injection ofthe radiopharmaceutical and anyone patient showedadverse events at the administration site.
Clinical laboratory parameters before and 24 h after
intravenous injection of the 99mTc-h R3 were assessed andno significant changes were observed. Additionally did notexist any abnormality repeated in more than one patient.
There were not hematologic and biochemical abnormalitieswith clinical significance that could be produced by theMAb or by radiation exposure.
The obtained results of Biodistribution and Dosimetry of99mTc-labeled Monoclonal Antibody H-R3 have shownthat liver is the target organ of this product and presentedan uptake peak at 1hr post-injection with a high retention.
This organ also received the higher absorbed dose. Theseresults should be taking into account for a future use of thiscompound for therapeutical purposes and for its current usein diagnostic procedures.
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DOSIS DE RADIACIÓN ABSORBIDAS Y SEGURIDAD DEL
ANTICUERPO MONOCLONAL HUMANIZADO H-R3
MARCADO CON 99MTC
Introducción. Los anticuerpos monoclonales humanizados (AcM) marcados para el diagnóstico y eltratamiento de tumores usados en la Medicina Nucleares han contribuido a disminuir la inmunogenicidad y larespuesta HAMA de los AcM murinos, aumentado la efectividad y utilidad de los procedimientos deradioinmunodiagnóstico. El objetivo de este estudio fue evaluar las dosis de de radiación interna y laseguridad del AcM H-R3 marcado con 99mTc, en humanos. Materiales y métodos: Diez pacientes consospechas de tumores epiteliales fueron incluidos en este estudio. Ellos recibieron 1110 MBq de 99mTc-H-R3, por vía intravenosa. Múltiples muestras de sangre y orina e imágenes secuenciales de cuerpo enterofueron colectadas en diferentes tiempos. Las dosis de radiación interna fueron estimadas usando lametodología del Comité de Dosimetría Interna de la Sociedad Americana de Medicina Nuclear (MIRD). Labiodistribución se calculó a partir de las imágenes gammagráficas. Se empleó análisis de regresión de lascurvas de actividad-tiempo para calcular los tiempos de residencia de los órganos fuente. Se evaluaron latoxicidad hematológica y los efectos adversos usando la clasificación de la OMS. Resultados: El hígadorecibió la dosis absorbida más alta (4,90E-02mGy/MBq), seguido por los riñones (1,60E-02mGy/MBq) y lapared de la vesícula (1,53E-02mGy/MBq). La dosis efectiva y la dosis efectiva equivalente fueron 0,0143mSv/MBq y 0,0190 mSv/MBq, respectivamente. Los principales órganos fuentes de este estudio fueronhígado, bazo, riñones y corazón. No se observo ningún cambio significativo en los parámetros hematológicosy sólo dos pacientes mostraron efectos adversos ligeros y moderados, no relacionados con las exposiciones ala radiación y resueltos durante los estudios.
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