Abstract
11006 Background: SAR566658 is an antibody-drug immunoconjugate consisting of a humanized monoclonal antibody (huDS6) against the tumor-associated MUC1-sialoglycotope, CA6, conjugated to a cytotoxic maytansinoid (DM4). SAR566658 is currently undergoing phase I clinical trials in patients with CA6-positive solid tumors. A companion diagnostic based on huDS6 may facilitate patient stratification and early evaluation of therapeutic efficacy. The present study describes the development and preclinical evaluation of three novel Copper-64 (t½= 12.7h) labeled antibody fragments (two Fabs and a diabody) derived from the huDS6 antibody. One fragment was chosen based on imaging figures of merit for further specificity evaluations. Methods: The affinity of all fragments and their DOTA conjugates to CA6 was validated using flow cytometry. The DOTA conjugates were labeled with Copper-64 and evaluated in human serum stability studies, in vivo small animal PET imaging and 24-hour biodistribution studies in nude mice bearing either CA6 positive (WISH) or CA6 negative (A2780) subcutaneous tumors. The specificity of the lead tracer was evaluated in vivo via blocking studies and isotype controls. Results: All fragments and their DOTA conjugates had high affinity (Kd = 4-20 nM) for WISH cells. 64Cu-DOTA-B-Fab gave superior results in radio-synthesis (RCY - 60%, SA - 55 GBq/µmole, >99% purity), serum stability (94±5%, n=3) and biodistribution profile. Its two isotype controls gave statistically significant (P<0.05) uptake values in WISH but not A2780 tumors (see table). Blocking with B-Fab or huDS6 prior to tracer administration afforded a 23% (p<0.05, n=8) and 26% (p<0.05, n=7) decrease in WISH tumor uptake, respectively. Conclusions: These preclinical studies suggest that 64Cu-DOTA-B-Fab may be a suitable companion diagnostic for SAR566658 in cancer patients and requires further investigation.[Table: see text]
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