RT Journal Article SR Electronic T1 Differential Effects of Predosing on Tumor and Tissue Uptake of an 111In-Labeled Anti-TENB2 Antibody–Drug Conjugate JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1454 OP 1461 DO 10.2967/jnumed.112.103168 VO 53 IS 9 A1 Boswell, C. Andrew A1 Mundo, Eduardo E. A1 Zhang, Crystal A1 Stainton, Shannon L. A1 Yu, Shang-Fan A1 Lacap, Jennifer A. A1 Mao, Weiguang A1 Kozak, Katherine R. A1 Fourie, Aimee A1 Polakis, Paul A1 Khawli, Leslie A. A1 Lin, Kedan YR 2012 UL http://jnm.snmjournals.org/content/53/9/1454.abstract AB TENB2, also known as tomoregulin or transmembrane protein with epidermal growth factor–like and 2 follistatin-like domains, is a transmembrane proteoglycan overexpressed in human prostate tumors. This protein is a promising target for antimitotic monomethyl auristatin E (MMAE)–based antibody–drug conjugate (ADC) therapy. Nonlinear pharmacokinetics in normal mice suggested that antigen expression in normal tissues may contribute to targeted mediated disposition. We evaluated a predosing strategy with unconjugated antibody to block ADC uptake in target-expressing tissues in a mouse model while striving to preserve tumor uptake and efficacy. Methods: Unconjugated, unlabeled antibody was preadministered to mice bearing the TENB2-expressing human prostate explant model, LuCaP 77, followed by a single administration of 111In-labeled anti-TENB2-MMAE for biodistribution and SPECT/CT studies. A tumor-growth-inhibition study was conducted to determine the pharmacodynamic consequences of predosing. Results: Preadministration of anti-TENB2 at 1 mg/kg significantly increased blood exposure of the radiolabeled ADC and reduced intestinal, hepatic, and splenic uptake while not affecting tumor accretion. Similar tumor-to-heart ratios were measured by SPECT/CT at 24 h with and without the predose. Consistent with this, the preadministration of 0.75 mg/kg did not interfere with efficacy in a tumor-growth study dosed at 0.75 mg or 2.5 mg of ADC per kilogram. Conclusion: Overall, the potential to mask peripheral, nontumor antigen uptake while preserving tumor uptake and efficacy could ameliorate toxicity and may significantly affect future dosing strategies for ADCs.