JNJ-63898081 的安全性和初步临床活性的 1 期研究，一种 PSMA 和 CD3 双特异性抗体，用于转移性去势抵抗性前列腺癌。
Phase 1 Study of Safety and Preliminary Clinical Activity of JNJ-63898081, a PSMA and CD3 Bispecific Antibody, for Metastatic Castration-Resistant Prostate Cancer.
机构信息
Columbia University Medical Center, New York, NY.
University of Washington; Fred Hutchinson Cancer Center, Seattle, WA.
出版信息
Clin Genitourin Cancer. 2023 Jun;21(3):366-375. doi: 10.1016/j.clgc.2023.02.010. Epub 2023 Feb 28.
INTRODUCTION
Cancer immunotherapies have limited efficacy in prostate cancer due to the immunosuppressive prostate microenvironment. Prostate specific membrane antigen (PSMA) expression is prevalent in prostate cancer, preserved during malignant transformation, and increases in response to anti-androgen therapies, making it a commonly targeted tumor associated antigen for prostate cancer. JNJ-63898081 (JNJ-081) is a bispecific antibody targeting PSMA-expressing tumor cells and CD3-expressing T cells, aiming to overcome immunosuppression and promoting antitumor activity.
PATIENTS AND METHODS
We conducted a phase 1 dose escalation study of JNJ-081 in patients with metastatic castration-resistance prostate cancer (mCRPC). Eligible patients included those receiving ≥1 prior line treatment with either novel androgen receptor targeted therapy or taxane for mCRPC. Safety, pharmacokinetics, and pharmacodynamics of JNJ-081, and preliminary antitumor response to treatment were evaluated. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route.
RESULTS
Thirty-nine patients in 10 dosing cohorts received JNJ-081 ranging from 0.3 µg/kg to 3.0 µg/kg IV and 3.0 µg/kg to 60 µg/kg SC (with step-up priming used at higher SC doses). All 39 patients experienced ≥1 treatment-emergent AE, and no treatment-related deaths were reported. Dose-limiting toxicities were observed in 4 patients. Cytokine release syndrome (CRS) was observed at higher doses with JNJ-081 IV or SC; however, CRS and infusion-related reaction (IRR) were reduced with SC dosing and step-up priming at higher doses. Treatment doses >30 µg/kg SC led to transient PSA decreases. No radiographic responses were observed. Anti-drug antibody responses were observed in 19 patients receiving JNJ-081 IV or SC.
CONCLUSION
JNJ-081 dosing led to transient declines in PSA in patients with mCRPC. CRS and IRR could be partially mitigated by SC dosing, step-up priming, and a combination of both strategies. T cell redirection for prostate cancer is feasible and PSMA is a potential therapeutic target for T cell redirection in prostate cancer.
简介
由于前列腺的免疫抑制微环境，癌症免疫疗法在前列腺癌中的疗效有限。前列腺特异性膜抗原（PSMA）在前列腺癌中广泛表达，在恶性转化过程中得以保留，并在抗雄激素治疗中增加，使其成为前列腺癌中常用的靶向肿瘤相关抗原。JNJ-63898081（JNJ-081）是一种针对表达 PSMA 的肿瘤细胞和表达 CD3 的 T 细胞的双特异性抗体，旨在克服免疫抑制并促进抗肿瘤活性。
患者和方法
我们对转移性去势抵抗性前列腺癌（mCRPC）患者进行了 JNJ-081 的 1 期剂量递增研究。符合条件的患者包括那些接受过≥1 种新型雄激素受体靶向治疗或紫杉烷类药物治疗 mCRPC 的患者。评估了 JNJ-081 的安全性、药代动力学和药效学，以及初步的抗肿瘤治疗反应。JNJ-081 最初通过静脉（IV）给药，然后通过皮下（SC）途径给药。
结果
10 个剂量组的 39 名患者接受了 JNJ-081 的治疗，剂量范围为 0.3μg/kg 至 3.0μg/kg IV 和 3.0μg/kg 至 60μg/kg SC（高剂量时采用逐步递增的预注）。所有 39 名患者均出现≥1 次治疗后出现的不良事件，无治疗相关死亡报告。4 名患者出现剂量限制毒性。JNJ-081 IV 或 SC 较高剂量时观察到细胞因子释放综合征（CRS）；然而，SC 给药和高剂量逐步递增预注可减轻 CRS 和输注相关反应（IRR）。SC 剂量>30μg/kg 导致 PSA 短暂下降。未观察到放射学反应。19 名接受 JNJ-081 IV 或 SC 治疗的患者出现了抗药物抗体反应。
结论
在 mCRPC 患者中，JNJ-081 给药导致 PSA 短暂下降。通过 SC 给药、逐步递增预注和两种策略的联合应用，可部分减轻 CRS 和 IRR。针对前列腺癌的 T 细胞重定向是可行的，PSMA 是前列腺癌中 T 细胞重定向的潜在治疗靶点。
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