The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer
The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer
复制标题
靶向PSMA的半衰期延长BiTE疗法AMG 160在转移性去势抵抗性前列腺癌临床前模型中具有强效抗肿瘤活性
DOI：
10.1158/1078-0432.ccr-20-3725
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发表时间：
2021-05-15
影响因子：
11.5
通讯作者：
Bailis, Julie M.
中科院分区：
文献类型：
--
作者：
Deegen, Petra;Thomas, Oliver;Bailis, Julie M.
目的：转移性去势抵抗性前列腺癌（mCRPC）仍然是一种高度未满足医疗需求的疾病，因为大多数患者在现有治疗下无法实现持久缓解。前列腺特异性膜抗原（PSMA）是mCRPC的重要靶点。实验设计：我们开发了AMG 160，一种半衰期延长的双特异性T细胞免疫肿瘤学疗法，其结合前列腺癌细胞上的PSMA和T细胞上的分化簇3用于治疗mCRPC。在体外和mCRPC异种移植模型中评价AMG 160。在非人灵长类动物（NHP）中评估了AMG 160耐受性。AMG 160作为单一疗法以及与PSMA显像剂、新型激素疗法和免疫检查点阻断剂组合的活性进行了评估。结果：AMG 160在体外诱导强效、特异性杀伤表达PSMA的前列腺癌细胞系，半数最大裂解为6-42 pmol/L。在体内，以0.2 mg/kg每周给药一次的AMG 160与全身给药的T细胞结合，并促进已建立的22 Rv-1 mCRPC异种移植肿瘤消退。AMG 160与显像剂镓68标记的PSMA-11相容，当与enzalutamide或抗程序性死亡-1抗体联合使用时，显示出增强的细胞毒性活性。AMG 160具有延长的半衰期，并具有可接受的安全性在NHPs.Conclusions：AMG 160的临床前表征突出了其在体外和体内的有效抗肿瘤活性，以及其与已知的诊断或治疗药物一起用于mCRPC的潜力。这些数据支持正在进行的AMG 160在mCRPC患者中的临床评价。
Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy.Experimental Design: We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated.Results: AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6-42 pmol/L. In vivo, AMG160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68-labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs.Conclusions: The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.