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 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 99nTc-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.

The effects of computer simulated facial plastic surgery on social perception by others.

Previous studies have demonstrated the remarkable impact of facial plastic surgery on the perception of facial features. However, pre- and postoperative differences other than the surgically changed features such as facial expression, hairstyle, make-up etc., have influenced the results of previous studies. To exclude these visual cues a computer composite photograph of the changed feature mounted upon the preoperative photograph, instead of the standard postoperative photograph, was presented to observers in this study. Computer graphic technology was used to superimpose the postoperative, surgically changed facial features such as the nose, ear and chin of 16 patients on standardized preoperative photographs. The randomized preoperative photographs and the 'postoperative' composed images were presented to 67 subjects, using a person-perception questionnaire. Multivariate analysis demonstrated a more favourable postoperative judgement in only two patients (12.5%). The exclusive effect of facial plastic surgery on the social perception of patients by others when excluding visual cues, such as facial expression, hairstyle, make-up etc, is limited. It is tentatively assumed that the role played by facial plastic surgery is one of initiating a positive cycle by changing the patient's self-perception rather than one of direct social impact from the changed features.

High dose rhenium-186-labeling of monoclonal antibodies for clinical application: pitfalls and solutions.

BACKGROUND: Rhenium-186 (186Re) has ideal properties for adjuvant radioimmunotherapy (RIT). However, the lack of suitable methods for high dose 186Re labeling of monoclonal antibodies (MAbs) has hampered the use of 186Re in clinical RIT. After development of a chemically identical multistep procedure for the production of 186Re-MAG3-MAb and 99mTc/99Tc-MAG3-MAb conjugates for use as a matched pair, the authors now report on further progress to make this labeling method broadly applicable for high dose 186Re labeling. METHODS: The number of metal-MAG3 groups that can be coupled to a MAb without alteration of the biodistribution was investigated by radioimmunoscintigraphy (RIS) in patients with head and neck squamous cell carcinoma (HNSCC). For labeling with 500 mCi [186Re]ReO4-, an efficient chemoprotection was introduced to suppress the damaging effects of radiation during conjugation and conjugate purification. Furthermore, the authors developed strategies that make the procedure easy and safe to perform at any medical center. RESULTS: MAbs showed a minor variation in biodistribution in HNSCC patients when the number of metal-chelate groups per MAb varied between < 1 and 4.3. High dose 186Re-MAb conjugates (150-250 mCi) with a Re-MAG3:MAb ratio of 3.4 were obtained with a radiochemical purity of > 95% and minimal aggregate formation (< or = 6%). Furthermore, a semiautomated labeling device and a convenient 100 mCi labeling kit in the form of a dried 186Re-MAG3-TFP ester were developed. RIT studies in HNSCC-bearing nude mice showed that high dose 186Re-labeled MAb U36 is more effective than iodine-131-labeled MAb U36. CONCLUSIONS: High dose 186Re-MAb conjugates were prepared that exhibit an optimal stability, immunoreactivity, and pharmacokinetic behavior. The availability of a kit procedure for coupling 186Re to MAbs might open the possibility of a broad application of 186Re in RIT.