肿瘤细胞治疗研究
英文原题：IGM-7354, an Immunocytokine with IL15 Fused to an Anti-PD-L1 IgM, Induces NK and CD8+ T cell-Mediated Cytotoxicity of PD-L1-Positive Tumor Cells.
本研究表明，开发一种安全有效的基于IgM的免疫细胞因子用于治疗癌症是可行的，利用IgM抗体的多价性以高亲和力和亲合力结合PD-L1，并刺激NK和CD8+ T细胞效应器。
IgM 抗体是预先形成的五聚体或六聚体分子，可通过工程化改造生成高亲和力和高亲合力的全人源抗体治疗药物。在本研究中，我们报道了一种免疫细胞因子 IGM-7354，其被设计为可结合多个 PD-L1 受体，同时在 J 链上反式呈递单个 IL15/IL15Rα 复合物至表达 IL15Rβγ 的细胞毒性 NK 细胞和 CD8+ T 细胞。我们在临床前模型中评估了 IGM-7354 的药理学和抗肿瘤特性。IGM-7354 通过 IL15/IL15Rα 复合物，在体外使用健康人外周血单个核细胞以及体内人源化小鼠中，均诱导了 NK 细胞和 CD8+ T 细胞的强效增殖。在与耗竭人 T 细胞的混合淋巴细胞反应试验中，与 IL15/IL15Rα 复合物或单用抗 PD-L1 相比，IGM-7354 恢复了 IFNγ 的分泌，提示在体外可挽救耗竭 T 细胞。在人源化 PD-L1+ MDA-MB-231 乳腺癌小鼠模型中观察到稳健的单药活性。在 RPMI-8226 多发性骨髓瘤模型中，将 IGM-7354 加入抗 CD38 达雷妥尤单抗，或在 Raji 淋巴瘤模型中加入抗 CD19 CAR-T 细胞疗法，抗肿瘤反应均得到增强。最后，在食蟹猴中，多个组织隔室中观察到 NK 和 CD8+ T 细胞增殖增加的药效学活性。综上所述，本研究证明了开发一种安全有效的基于 IgM 的免疫细胞因子用于治疗癌症的可行性，利用 IgM 抗体的多价性以高亲和力和高亲合力结合 PD-L1，并刺激 NK 和 CD8+ T 细胞效应细胞。
IgM antibodies are preformed pentameric or hexameric molecules that can be engineered to generate high-affinity and high-avidity fully human antibody therapeutics. In this study, we report an immunocytokine, IGM-7354, which was designed to bind multiple PD-L1 receptors while trans-presenting a single IL15/IL15Rα complex on the joining chain to IL15Rβγ-expressing cytotoxic NK and CD8+ T cells. We evaluated the pharmacologic and antitumor properties of IGM-7354 in preclinical models. IGM-7354 induced potent proliferation of NK and CD8+ T cells, both in vitro using healthy human peripheral blood mononuclear cells and in vivo in humanized mice, through the IL15/IL15Rα complex. In a mixed-lymphocyte reaction assay with exhausted human T cells, IGM-7354 restored the secretion of IFNγ compared with the IL15/IL15Rα complex or anti-PD-L1 alone, suggesting a rescue of exhausted T cells in vitro. Robust single-agent activity was observed in the humanized PD-L1+ MDA-MB-231 breast cancer mouse model. Antitumor responses were enhanced by adding IGM-7354 to the anti-CD38 daratumumab in RPMI-8226 multiple myeloma or anti-CD19 chimeric antigen receptor T-cell therapies in Raji lymphoma models. Finally, in cynomolgus monkeys, pharmacodynamic activity of increased NK and CD8+ T-cell proliferation was observed in multiple tissue compartments. Taken together, this study demonstrates the feasibility of developing a safe and effective IgM-based immunocytokine for the treatment of cancer, exploiting the multivalency of an IgM antibody to bind PD-L1 with high affinity and avidity and stimulate NK and CD8+ T-cell effectors.
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