Safety and biodistribution of (99m)technetium-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 express ed in a tissue-specific way, Expression of v6-containing variants (CD44v6) has been related to aggressive behavior of various tumor types and was show n to be particularly high in squamous cell carcinoma (SCC). Therefore, CD44 V6 might be a suitable target for radioimmunoscintigraphy (RIS) and therapy . The present study evaluates the novel high-affinity murine anti-CD44v6 mo noclonal antibody (MAb) BIWA 1 for its safety and targeting potential in pa tients with SCC of the head and neck (HNSCC). Twelve HNSCC patients, who ha d planned to undergo resection of the primary tumor and neck dissection, we re included. Preoperatively, 2, 12, or 52 mg of Tc-99m-labeled MAb BIWA 1 w as administered. RIS results obtained 21 h after injection were compared wi th palpation, computed tomography, and magnetic resonance imaging, with his topathology as the gold standard, Moreover, biodistribution of BIWA 1 was e valuated by radioactivity measurement in blood and bone marrow and in biops ies from the surgical specimen obtained 40 h after injection, The distribut ion of BIWA 1 in tumor biopsies was analyzed by immunohistochemistry, BIWA 1 integrity in the blood was assessed by high-performance liquid chromatogr aphy and related to soluble CD44v6 levels in serum samples. No drug-related adverse events were observed. Human antimouse antibody responses were obse rved in II patients. The diagnostic efficacy of RIS appeared to be comparab le for the three BIT-VA 1 dose levels and for the four diagnostic methods. Besides activity uptake in tumor tissue, minimal accumulation of activity w as observed in mouth, lungs, spleen, kidney, bone marrow, and scrotal area. Analysis of tissue biopsies revealed high uptake in tumors, with a mean va lue 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 t hree dose groups were not statistically significant, although a trend towar d lower uptake in the highest dose group was noted. Distribution of BIWA I 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 b lood (34.5 +/- 6.1 h) was not dose dependent. Extensive complex formation o f BIWA 1 was observed in the 2-mg group, most probably with soluble CD44v6 present in the blood, and complex formation relatively diminished upon incr ease 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 s elective tumor uptake. However, BIWA I is immunogenic, and therefore a chim erized or humanized derivative of BIWA 1 with intermediate affinity will be used in future clinical trials.