Differential Effects of Predosing on Tumor and Tissue Uptake of an 111In-Labeled Anti-TENB2 Antibody–Drug Conjugate
| Autor: | C. Andrew Boswell, Aimee Fourie, Eduardo E. Mundo, Paul Polakis, Leslie A. Khawli, Crystal Zhang, Shang-Fan Yu, Weiguang Mao, Katherine R. Kozak, Jennifer A. Lacap, Shannon Stainton, Kedan Lin |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Biodistribution Antibody-drug conjugate Immunoconjugates Pharmacology Multimodal Imaging Antibodies Mice chemistry.chemical_compound Antigen Cell Line Tumor Animals Humans Radiology Nuclear Medicine and imaging Dose-Response Relationship Drug biology Chemistry Indium Radioisotopes Membrane Proteins Prostatic Neoplasms Biological Transport Neoplasm Proteins Monomethyl auristatin E Isotope Labeling Positron-Emission Tomography Pharmacodynamics Toxicity biology.protein Antibody Tomography X-Ray Computed Conjugate |
| Zdroj: | Journal of Nuclear Medicine. 53:1454-1461 |
| ISSN: | 2159-662X 0161-5505 |
| DOI: | 10.2967/jnumed.112.103168 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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