Safety and Biodistribution of 99mTechnetium-labeled Anti-CD44v6 Monoclonal Antibody BIWA 1 in Head and Neck Cancer Patients
The CD44 protein family consists of isoforms, encoded by standard exons and up to nine alternatively spliced variant exons (v2–v10), which are expressed in a tissue-specific way. Expression of v6-containing variants (CD44v6) has been related to aggressive behavior of various tumor types and was show...
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Published in | Clinical cancer research Vol. 6; no. 8; pp. 3046 - 3055 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
01.08.2000
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Subjects | |
Online Access | Get full text |
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Summary: | The CD44 protein family consists of isoforms, encoded by standard exons
and up to nine alternatively spliced variant exons (v2–v10), which are
expressed in a tissue-specific way. Expression of v6-containing
variants (CD44v6) has been related to aggressive behavior of various
tumor types and was shown to be particularly high in squamous cell
carcinoma (SCC). Therefore, CD44v6 might be a suitable target for
radioimmunoscintigraphy (RIS) and therapy. The present study evaluates
the novel high-affinity murine anti-CD44v6 monoclonal antibody (MAb)
BIWA 1 for its safety and targeting potential in patients with SCC of
the head and neck (HNSCC). Twelve HNSCC patients, who had planned to
undergo resection of the primary tumor and neck dissection, were
included. Preoperatively, 2, 12, or 52 mg of 99m Tc-labeled
MAb BIWA 1 was administered. RIS results obtained 21 h after
injection were compared with palpation, computed tomography, and
magnetic resonance imaging, with histopathology as the gold standard.
Moreover, biodistribution of BIWA 1 was evaluated by radioactivity
measurement in blood and bone marrow and in biopsies from the surgical
specimen obtained 40 h after injection. The distribution of BIWA 1
in tumor biopsies was analyzed by immunohistochemistry. BIWA 1
integrity in the blood was assessed by high-performance liquid
chromatography and related to soluble CD44v6 levels in serum samples.
No drug-related adverse events were observed. Human antimouse antibody
responses were observed in 11 patients. The diagnostic efficacy of RIS
appeared to be comparable for the three BIWA 1 dose levels and for the
four diagnostic methods. Besides activity uptake in tumor tissue,
minimal accumulation of activity was observed in mouth, lungs, spleen,
kidney, bone marrow, and scrotal area. Analysis of tissue biopsies
revealed high uptake in tumors, with a mean value of 14.2 ± 8.4%
of the injected dose/kg tumor tissue and a mean tumor:blood ratio of
2.0 ± 1.4 at 40 h after injection. Differences among the
three dose groups were not statistically significant, although a trend
toward lower uptake in the highest dose group was noted. Distribution
of BIWA 1 throughout the tumor was heterogeneous for all dose groups,
which might be related to the high affinity of the MAb. The mean
biological half-life in blood (34.5 ± 6.1 h) was not dose
dependent. Extensive complex formation of BIWA 1 was observed in the
2-mg group, most probably with soluble CD44v6 present in the blood, and
complex formation relatively diminished upon increase of the MAb dose.
BIWA 1 is a promising MAb for targeting HNSCC because it can be safely
administered to HNSCC patients, while it shows high and selective tumor
uptake. However, BIWA 1 is immunogenic, and therefore a chimerized or
humanized derivative of BIWA 1 with intermediate affinity will be used
in future clinical trials. |
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ISSN: | 1078-0432 1557-3265 |