PT  - JOURNAL ARTICLE
AU  - C. Andrew Boswell
AU  - Eduardo E. Mundo
AU  - Crystal Zhang
AU  - Shannon L. Stainton
AU  - Shang-Fan Yu
AU  - Jennifer A. Lacap
AU  - Weiguang Mao
AU  - Katherine R. Kozak
AU  - Aimee Fourie
AU  - Paul Polakis
AU  - Leslie A. Khawli
AU  - Kedan Lin
TI  - Differential Effects of Predosing on Tumor and Tissue Uptake of an <sup>111</sup>In-Labeled Anti-TENB2 Antibody–Drug Conjugate
AID  - 10.2967/jnumed.112.103168
DP  - 2012 Sep 01
TA  - Journal of Nuclear Medicine
PG  - 1454--1461
VI  - 53
IP  - 9
4099  - http://jnm.snmjournals.org/content/53/9/1454.short
4100  - http://jnm.snmjournals.org/content/53/9/1454.full
SO  - J Nucl Med2012 Sep 01; 53
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.