GPCR Therapeutics USA, Inc., Redwood City, California, United States of America.
GPCR Therapeutics Inc., Gwanak-gu, Seoul, Republic of Korea.
PLoS One. 2023 Oct 25;18(10):e0287863. doi: 10.1371/journal.pone.0287863. eCollection 2023.
Autologous Stem Cell Transplant (ASCT) is increasingly used to treat hematological malignancies. A key requisite for ASCT is mobilization of hematopoietic stem cells into peripheral blood, where they are collected by apheresis and stored for later transplantation. However, success is often hindered by poor mobilization due to factors including prior treatments. The combination of G-CSF and GPC-100, a small molecule antagonist of CXCR4, showed potential in a multiple myeloma clinical trial for sufficient and rapid collection of CD34+ stem cells, compared to the historical results from the standards of care, G-CSF alone or G-CSF with plerixafor, also a CXCR4 antagonist. In the present study, we show that GPC-100 has high affinity towards the chemokine receptor CXCR4, and it potently inhibits β-arrestin recruitment, calcium flux and cell migration mediated by its ligand CXCL12. Proximity Ligation Assay revealed that in native cell systems with endogenous receptor expression, CXCR4 co-localizes with the beta-2 adrenergic receptor (β2AR). Co-treatment with CXCL12 and the β2AR agonist epinephrine synergistically increases β-arrestin recruitment to CXCR4 and calcium flux. This increase is blocked by the co-treatment with GPC-100 and propranolol, a non-selective beta-adrenergic blocker, indicating a functional synergy. In mice, GPC-100 mobilized more white blood cells into peripheral blood compared to plerixafor. GPC-100 induced mobilization was further amplified by propranolol pretreatment and was comparable to mobilization by G-CSF. Addition of propranolol to the G-CSF and GPC-100 combination resulted in greater stem cell mobilization than the G-CSF and plerixafor combination. Together, our studies suggest that the combination of GPC-100 and propranolol is a novel strategy for stem cell mobilization and support the current clinical trial in multiple myeloma registered as NCT05561751 at www.clinicaltrials.gov.
自体干细胞移植（ASCT）越来越多地用于治疗血液系统恶性肿瘤。ASCT 的一个关键要求是动员造血干细胞进入外周血，在外周血中通过单采术收集并储存以备后用。然而，由于先前的治疗等因素，成功往往因动员不良而受阻。在一项多发性骨髓瘤临床试验中，与 G-CSF 单独使用或 G-CSF 联合plerixafor（也是一种 CXCR4 拮抗剂）的护理标准相比，CXCR4 的小分子拮抗剂 GPC-100 与 G-CSF 的组合显示出了在足够和快速收集 CD34+干细胞方面的潜力。在本研究中，我们表明 GPC-100 对趋化因子受体 CXCR4 具有高亲和力，并且它能有效地抑制其配体 CXCL12 介导的β-arrestin 募集、钙通量和细胞迁移。邻近连接分析显示，在具有内源性受体表达的天然细胞系统中，CXCR4 与β-2 肾上腺素能受体（β2AR）共定位。用 CXCL12 和β2AR 激动剂肾上腺素共同处理可协同增加 CXCR4 的β-arrestin 募集和钙通量。这种增加被 GPC-100 和普萘洛尔（一种非选择性β-肾上腺素能阻滞剂）的共同处理所阻断，表明存在功能协同作用。在小鼠中，与 plerixafor 相比，GPC-100 将更多的白细胞动员到外周血中。普萘洛尔预处理进一步放大了 GPC-100 诱导的动员，与 G-CSF 动员相当。将普萘洛尔添加到 G-CSF 和 GPC-100 联合中可导致比 G-CSF 和 plerixafor 联合的动员更多的干细胞。总之，我们的研究表明，GPC-100 和普萘洛尔的联合是一种新的干细胞动员策略，并支持目前在多发性骨髓瘤患者中进行的临床试验，该试验已在 www.clinicaltrials.gov 上注册为 NCT05561751。
