CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Improvement of daratumumab- or elotuzumab-mediated NK cell activity by the bi-specific 4-1BB agonist, DARPin α-FAPx4-1BB: A preclinical study in multiple myeloma.
Improvement of daratumumab- or elotuzumab-mediated NK cell activity by the bi-specific 4-1BB agonist, DARPin α-FAPx4-1BB: A preclinical study in multiple myeloma.
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多发性骨髓瘤（MM）的进展与骨髓（BM）微环境中的细胞密切相关，包括成纤维细胞（FB）和免疫细胞。在骨髓生态位中，MM 细胞黏附于 FB，从而维持免疫逃逸、药物耐药及肿瘤细胞不可检测的残留状态，即微小残留病灶（MRD）。本文介绍新型双特异性设计锚蛋白重复蛋白（DARPin）α-FAP×4-1BB（MP0310），其具有 FAP 依赖的 4-1BB 激动活性。α-FAP×4-1BB DARPin 同时结合 FAP 和 4-1BB；前者在活化 FB 上过表达，后者在免疫细胞上过表达。尽管流式细胞术分析显示 MM 患者 T 细胞和 NK 细胞未被活化，且不表达 4-1BB，但采用目前治疗 MM 的单克隆抗体（mAb）达雷妥尤单抗或 elotuzumab 刺激后，体外和患者 mAb 治疗后均可显著上调 4-1BB。mAb 诱导的 4-1BB 过表达使 α-FAP×4-1BB 能够发挥桥接作用，连接 FAP 阳性 FB 和 4-1BB 阳性 NK 细胞。
因此，α-FAP×4-1BB 可增强达雷妥尤单抗处理的 NK 细胞与 FB 黏附，并通过促进 CD107a 和穿孔素释放激活这些 NK 细胞，进而通过抗体介导的细胞毒作用（ADCC）杀伤 MM 细胞。有趣的是，存在 FB 时，α-FAP×4-1BB 可显著增强达雷妥尤单抗介导的 ADCC，提示其可能克服骨髓 FB 的免疫抑制作用。
总体而言，我们推测 α-FAP×4-1BB 治疗可作为有价值的策略，增强 mAb 诱导的 NK 细胞活性，通过清除潜伏 MRD 细胞促进 MM 患者达到 MRD 阴性。
Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD).
Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) -FAPx4-1BB (MP0310) with FAP-dependent 4-1BB agonistic activity. The -FAPx4-1BB DARPin simultaneously binds to FAP and 4-1BB overexpressed by activated FBs and immune cells, respectively.
Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4-1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4-1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4-1BB overexpression allowed the engagement of -FAPx4-1BB that acted as a bridge between FAP + FBs and 4-1BB + NK cells.
Therefore, -FAPx4-1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, -FAPx4-1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs' immunosuppressive effect.
Overall, we speculate that treatment with -FAPx4-1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.
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