Corvus Pharmaceuticals Inc, Burlingame, California, USA
Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2022 Dec;10(12). doi: 10.1136/jitc-2022-005802.
CD73 is widely expressed on immune cells playing a critical role in immunomodulatory functions including cell adhesion and migration, as a costimulatory molecule for T cells and in production of adenosine. The function of CD73 expressed on B cells has not been fully characterized. Mupadolimab is an anti-human CD73 antibody that activates B cells. We evaluated the characteristics of this antibody and its effects on immune cells in vitro and in vivo.
Mupadolimab binding to CD73, inhibition of CD73 enzymatic activity, and effects on lymphocyte activation were evaluated in vitro by measuring changes in immunophenotype by flow cytometry. Cryogenic-transmission electron microscopy was used to determine epitope binding. Effects on human B cells in vivo were evaluated in immunodeficient NSG-SGM3 mice immunized with SARS-CoV-2 and influenza viral antigens. Safety and immune effects were evaluated in the completed dose escalation portion of a phase 1 trial conducted in patients with cancer.
Mupadolimab binds to a unique epitope on CD73 B cells resulting in their activation and differentiation through B cell receptor signaling pathways. Mupadolimab induces expression of CD69, CD83, CD86 and MHC class II on B cells along with morphological transformation into plasmablasts and expression of CD27, CD38 and CD138. These effects are independent of adenosine. Mupadolimab binds to the N-terminal of CD73 in the closed position and competitively inhibits substrate binding. Mupadolimab enhanced antigen specific antibody response to SARS-CoV-2 spike protein and influenza hemagglutinin in humanized mouse models. Mupadolimab was evaluated as a monotherapy in a phase 1 trial (NCT03454451) in 34 patients with advanced cancer and demonstrated binding to CD73 circulating cells and transient reduction in the number of B cells, with return of CD73 B cells with memory phenotype. No dose-limiting toxicities or changes in serum immunoglobulins were seen.
Mupadolimab activates B cells and stimulates the production of antigen specific antibodies. The effects in patients with cancer suggest that activated, CD69 B cells redistribute to lymphoid tissues. Minor tumor regression was observed in several patients. These results support further investigation of mupadolimab as an immunotherapy for cancer and its potential use as a vaccine adjuvant.
NCT03454451.
CD73 在免疫细胞上广泛表达，在免疫调节功能中发挥关键作用，包括细胞黏附和迁移、作为 T 细胞的共刺激分子以及腺苷的产生。B 细胞上 CD73 的功能尚未完全表征。Mupadolimab 是一种抗人 CD73 的抗体，可激活 B 细胞。我们评估了这种抗体的特性及其对体外和体内免疫细胞的影响。
通过流式细胞术测量免疫表型变化来评估 Mupadolimab 与 CD73 的结合、抑制 CD73 酶活性以及对淋巴细胞激活的影响。利用低温透射电子显微镜确定表位结合。在接种 SARS-CoV-2 和流感病毒抗原的免疫缺陷性 NSG-SGM3 小鼠体内评估对人 B 细胞的影响。在癌症患者中进行的 1 期试验的已完成剂量递增部分评估安全性和免疫效应。
Mupadolimab 结合 B 细胞上 CD73 的独特表位，通过 B 细胞受体信号通路导致其激活和分化。Mupadolimab 诱导 B 细胞表达 CD69、CD83、CD86 和 MHC Ⅱ类，同时形态转化为浆母细胞，并表达 CD27、CD38 和 CD138。这些作用不依赖于腺苷。Mupadolimab 结合 CD73 的 N 端在封闭位置并竞争性抑制底物结合。Mupadolimab 增强了人源化小鼠模型中针对 SARS-CoV-2 刺突蛋白和流感血凝素的抗原特异性抗体反应。Mupadolimab 在一项 1 期试验（NCT03454451）中作为单药在 34 名晚期癌症患者中进行了评估，结果表明它与循环 CD73 细胞结合，并短暂减少 B 细胞数量，具有记忆表型的 CD73 B 细胞恢复。未观察到剂量限制性毒性或血清免疫球蛋白变化。
Mupadolimab 激活 B 细胞并刺激抗原特异性抗体的产生。在癌症患者中的作用表明，激活的 CD69 B 细胞重新分布到淋巴组织中。在一些患者中观察到肿瘤有轻微消退。这些结果支持进一步研究 Mupadolimab 作为癌症的免疫疗法及其作为疫苗佐剂的潜在用途。
NCT03454451。
