Genentech Research and Early Development, South San Francisco, California 94080, USA.
J Nucl Med. 2012 Sep;53(9):1454-61. doi: 10.2967/jnumed.112.103168. Epub 2012 Aug 7.
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.
Unconjugated, unlabeled antibody was preadministered to mice bearing the TENB2-expressing human prostate explant model, LuCaP 77, followed by a single administration of (111)In-labeled anti-TENB2-MMAE for biodistribution and SPECT/CT studies. A tumor-growth-inhibition study was conducted to determine the pharmacodynamic consequences of predosing.
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.
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.
TENB2 又称 tomoregulin 或跨膜蛋白，具有表皮生长因子样和 2 个卵泡抑素样结构域，在人前列腺肿瘤中过度表达。该蛋白是抗有丝分裂单甲基澳瑞他汀 E（MMAE）为基础的抗体药物偶联物（ADC）治疗的有前途的靶点。正常小鼠的非线性药代动力学表明，正常组织中的抗原表达可能有助于靶向介导的处置。我们评估了一种预给药策略，即在表达 TENB2 的人前列腺组织模型小鼠中给予未缀合的抗体，以阻断 ADC 在靶组织中的摄取，同时努力保留肿瘤摄取和疗效。
在表达 TENB2 的人前列腺组织模型 LuCaP 77 荷瘤小鼠中预先给予未缀合的、未标记的抗体，然后单次给予（111）In 标记的抗 TENB2-MMAE 进行生物分布和 SPECT/CT 研究。进行肿瘤生长抑制研究以确定预给药的药效学后果。
1 mg/kg 的抗 TENB2 预给药可显著增加放射性 ADC 的血液暴露，并减少肠道、肝脏和脾脏摄取，而不影响肿瘤生长。SPECT/CT 测量的 24 小时肿瘤与心脏的比值在有无预给药时相似。与此一致的是，在 0.75 或 2.5 mg/kg 的 ADC 剂量下进行肿瘤生长研究时，0.75 mg/kg 的预给药不会干扰疗效。
总的来说，掩蔽外周非肿瘤抗原摄取而保留肿瘤摄取和疗效的潜力可能会改善毒性，并可能显著影响 ADC 的未来给药策略。
