Todd Shearer, Melissa Comstock, Rex L Williams, Mark C Johnson, Ewa Cendrowicz, Cathrine Leonowens, Margaret Smith, Todd M Baughman, Caroline J Breitbach, Shinta Cheng, Damian J Green
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引用次数: 0
摘要
B细胞成熟抗原（BCMA）是治疗多发性骨髓瘤（MM）的几种在研和已获批准药物的靶点。浆细胞（PC）和 MM 细胞上表达的 BCMA 会被γ 分泌酶裂解，从而降低膜结合 BCMA（mbBCMA）受体的密度。γ泌乳素酶抑制剂（GSI）已被证明可增加mbBCMA密度，并可提高BCMA靶向疗法的疗效。我们在 MM 细胞系中评估了 GSI nirogacestat 的药效学特征，并在健康志愿者中进行了 1 期研究。在 MM 细胞系中，测量了短时暴露于 nirogacestat 之前和之后的 mbBCMA 密度和可溶性 BCMA（sBCMA）浓度，并在冲洗后的连续时间点进行了测量。在 1 期研究中，23 名参与者单次口服了 50、150 或 300 毫克的尼罗加司他，或每 12 小时重复服用 100 毫克，持续时间长达 48 小时；在基线和用药后测量了 PCs 上的 mbBCMA 密度（来自全血和骨髓）和尼罗加司他的血浆浓度。单剂量给药后，血清中的尼罗加司他浓度迅速升高（Tmax ~1小时），线性吸收和清除的两室模型最能描述尼罗加司他的药代动力学。在 MM 细胞和健康志愿者的 PC 中，尼罗加司他会导致 mbBCMA 密度快速而显著地增加，在接触后 4-8 小时内增加多达 20 倍。同时还观察到 sBCMA 的下降。目前正在评估尼罗加司他与几种 BCMA 靶向治疗药物在 MM 患者中的联合应用。阐明 BCMA 对硝酸甘油司他的反应动力学是指导 MM 剂量和治疗策略的关键。
Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma.
Significance: GSIs can enhance multiple myeloma therapies targeting BCMA by increasing mbBCMA on plasma cells. In response to the GSI nirogacestat, mbBCMA rapidly and robustly increased in vitro and in vivo. Elucidating nirogacestat's effects on BCMA kinetics will guide potential multiple myeloma dosing strategies.
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