Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Radiology, Weill Cornell Medical College, New York, NY, 10065, USA.
Nat Commun. 2018 Apr 24;9(1):1629. doi: 10.1038/s41467-018-04107-w.
Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
人激肽释放酶 2（hK2）是一种前列腺特异性酶，其表达受雄激素受体（AR）调控。AR 是前列腺癌（PCa）的中心致癌驱动因子，也是癌症中 DNA 修复的关键调节剂。我们报告了一种创新的治疗策略，利用激素-DNA 修复回路使 PCa 能够进行分子特异性的α粒子照射。PCa 的α粒子照射是通过分子特异性靶向和内化靶向 hK2 的人源化单克隆抗体 hu11B6 来触发的，并且体内固有 DNA 修复进一步加速了这一过程，从而上调 hK2（KLK2）的表达。hu11B6 对 KLK2 具有出色的靶向特异性。单次给予放射性标记的 hu11B6 可消除疾病并显著延长动物模型的存活时间。α粒子照射引起的 DNA 损伤诱导 AR，进而诱导 KLK2，产生独特的正反馈机制，增加了 hu11B6 的结合。非人类灵长类动物的成像数据支持在人类中使用 hu11B6 的可能性。
