Minimizing salivary gland and renal toxicity arising from PSMA-targeted alpha therapy

摘要 转移性去势耐药前列腺癌(MCRPC)是一种致命的不治之症，可导致约33,500人死亡。 2020年美国的患者数量。为了应对对安全有效的新疗法的迫切需求， 利用前列腺特异性膜抗原(PSMA)在mCRPC病变中的高表达，几个 基于小分子的靶向放射性核素疗法(TRT)已经被开发出来。其中，有针对性的 尤其是含有[225Ac]-PSMA-617的阿尔法治疗剂(TAT)在 难治性患者的治疗--甚至在部分患者中实现完全和持久的反应。 然而，由于非靶标毒性，许多有反应的患者已经停止治疗。唾液腺 毒性(不可逆转的口干症)和潜在的肾毒性对患者的资格、最大剂量 和最大剂量，严格限制[225Ac]-PSMA-617的使用。因此，有一个紧急情况 和未得到满足的需求，开发战略，可以减少这些治疗的不良副作用，而不是 影响治疗效果。反过来，我们提出了一种减少唾液腺和肾脏的简单方法 毒性：通过添加PSMA-11降低[225Ac]-PSMA-617的有效比活度(ESA)。在我们的 初步研究，用PSMA-11降低[68Ga]-PSMA-11和[177Lu]-PSMA-617的ESA导致 在不影响肿瘤摄取的情况下，显著减少唾液腺和肾脏的摄取 前列腺癌。我们已经组建了一支高度合格和协作的研究团队-包括 放射化学家、医学物理学家、核医学内科医生、泌尿生殖系统肿瘤学家、兽医 病理学家和毒理学家-明确证明我们的方法在减少 临床相关的[225Ac]-PSMA-617或其他PSMA-TRT制剂的唾液腺和肾脏辐射剂量 小鼠和大鼠模型。作为我们建议的一部分，我们将确定可以减少唾液的ESA的范围 [225Ac]-PSMA-617的腺体和肾脏剂量为75%而不影响小鼠和 大鼠；证明唾液腺和肾功能长期(治疗后约2年)保持不变 消除肿瘤负担；展示该方法对其他PSMA-TRT试剂的适用性；进行 PSMA-11在所需剂量(5-10毫克/患者)下的GLP毒理学研究，以确定其安全性；并使 所有研究人员都可以获得数据，以促进临床试验。这些实验是作为IND- 使近期临床翻译研究成为可能。一旦确立，我们简单但创新的方法将 改进[225Ac]-PSMA-617和其他PSMA-TRT试剂的治疗方法，减少对唾液腺和 肾脏在不影响治疗效果的情况下有助于延长mCRPC患者的生命，同时 保持他们的生活质量。

ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, incurable disease that will kill ~33,500 patients in the US in 2020. Responding to the urgent need for novel treatments that are safe and efficacious, and leveraging the high expression of prostate specific membrane antigen (PSMA) in mCRPC lesions, several small-molecule-based targeted radionuclide therapies (TRTs) have been developed. Among them, targeted alpha therapy agent (TAT) with [225Ac]-PSMA-617 in particular has demonstrated striking responses in the treatment of refractory patients — even achieving complete and durable responses in a subset of patients. However, many responding patients have discontinued treatment due to non-target toxicity. Salivary gland toxicity (irreversible xerostomia) and potential renal toxicity place hard limits on patient eligibility, maximum dose and maximum number of doses, severely restricting the use of [225Ac]-PSMA-617. As such, there is an urgent and unmet need to develop strategies that can reduce the unwanted side effects of these treatments without compromising treatment efficacy. We in turn are proposing a simple method to reduce salivary gland and kidney toxicity by reducing the effective specific activity (ESA) of [225Ac]-PSMA-617 by addition of PSMA-11. In our preliminary studies, reducing the ESA of [68Ga]-PSMA-11 and [177Lu]-PSMA-617 with PSMA-11 led to significantly reduced salivary gland and kidney uptake without compromising tumor uptake in mouse models of prostate cancer. We have assembled a highly qualified and collaborative team of researchers — including radiochemists, medical physicists, nuclear medicine physicians, genitourinary oncologists, veterinary pathologists and toxicologists — to unequivocally demonstrate the efficacy of our methodology for reducing the salivary gland and renal radiation dose of [225Ac]-PSMA-617 or other PSMA-TRT agents in clinically relevant mouse and rat models. As part of our proposal, we will determine the range of ESAs that will reduce salivary gland and kidney dose of [225Ac]-PSMA-617 by > 75% without compromising tumor radiation dose in mice and rats; demonstrate that salivary gland and renal function are maintained long-term(~2 years post-treatment) while eliminating tumor burden; demonstrate the methodology’s applicability to other PSMA-TRT agents; conduct a GLP toxicology study of PSMA-11 at required doses (5–10 mgs/patient) to establish its safety; and make the data available to all researchers in order to facilitate clinical trials. The experiments are being conducted as IND- enabling studies for near-term clinical translation. Once established, our simple but innovative approach will refine treatment with [225Ac]-PSMA-617 and other PSMA-TRT agents by reducing toxicity to salivary glands and kidneys without compromising treatment efficacy and help to extend the lives of mCRPC patients while maintaining their quality of life.