Department of Medicine A, Hematology, Oncology, Hemostaseology and Pneumology, University Hospital Münster, Münster, Germany.
Blood Adv. 2024 Apr 23;8(8):1934-1945. doi: 10.1182/bloodadvances.2023011647.
Antibody-based immunotherapies have revolutionized leukemia and lymphoma treatment, with animal studies being crucial in evaluating effectiveness and side effects. By targeting the evolutionary conserved Slamf7 immune receptor, which is naturally expressed by the murine multiple myeloma cell line MPC-11, we have developed a syngeneic mouse model for direct comparison of 3 immunotherapies: monoclonal antibodies (mAb), bispecific T-cell engagers (BiTE), and chimeric antigen receptor (CAR) T cells (CART), all targeting Slamf7. Slamf7-BiTE is a bispecific single-chain antibody consisting of α-Slamf7 and α-CD3 Fv fragments joined through a Gly-Ser linker, and Slamf7-CART comprises the α-Slamf7 Fv fragment fused to the msCD8α transmembrane and msCD28, 4-1BB, and CD3ζ intracellular signaling domains. Slamf7-BiTE and Slamf7-CART effectively killed MPC-11 cells in vitro, independently of Slamf7-mediated inhibitory signaling by self-ligation. After chimerizing the constant region of the rat-anti-mouse Slamf7 antibody to mouse Fc-immunoglobulin G2a for enhanced effector functions, Slamf7-mAb triggered antigen-specific antibody-dependent cellular cytotoxicity by binding to Fcγ receptor IV. In vivo, all 3 immunotherapies showed antitumor effects against Slamf7-expressing targets. Unlike Slamf7-mAb, Slamf7-BiTE led to considerable side effects in test animals, including weight loss and general malaise, which were also observed to a lesser extent after Slamf7-CART infusion. In allogeneic transplant, Slamf7-BiTE and Slamf7-CART maintained activity compared with the nontransplant setting, whereas Slamf7-mAb displayed enhanced antimyeloma activity. In summary, our model faithfully replicates treatment efficacy and side effects detected after human immunotherapy. It aids in developing and improving immunotherapies and may help devise novel approaches to mitigate undesired effects in steady state and allogeneic stem cell transplantation.
基于抗体的免疫疗法彻底改变了白血病和淋巴瘤的治疗方式，动物研究在评估疗效和副作用方面至关重要。通过靶向进化上保守的 Slamf7 免疫受体，该受体天然表达于鼠多发性骨髓瘤细胞系 MPC-11 中，我们开发了一种同基因小鼠模型，用于直接比较 3 种免疫疗法：单克隆抗体 (mAb)、双特异性 T 细胞衔接器 (BiTE) 和嵌合抗原受体 (CAR) T 细胞 (CART)，均靶向 Slamf7。Slamf7-BiTE 是一种双特异性单链抗体，由 α-Slamf7 和 α-CD3 Fv 片段通过 Gly-Ser 接头连接而成，而 Slamf7-CART 由 α-Slamf7 Fv 片段融合到 msCD8α 跨膜和 msCD28、4-1BB 和 CD3ζ 细胞内信号结构域组成。Slamf7-BiTE 和 Slamf7-CART 可有效杀伤 MPC-11 细胞，独立于 Slamf7 介导的自连接抑制信号。将大鼠抗鼠 Slamf7 抗体的恒定区重建成小鼠 Fc-免疫球蛋白 G2a 后，增强了效应功能，Slamf7-mAb 通过与 Fcγ 受体 IV 结合触发抗原特异性抗体依赖性细胞毒性。在体内，所有 3 种免疫疗法对表达 Slamf7 的靶标均显示出抗肿瘤作用。与 Slamf7-mAb 不同，Slamf7-BiTE 在试验动物中引起相当大的副作用，包括体重减轻和全身不适，在 Slamf7-CART 输注后也观察到程度较轻的副作用。在同种异体移植中，Slamf7-BiTE 和 Slamf7-CART 与非移植环境相比保持活性，而 Slamf7-mAb 显示出增强的抗骨髓瘤活性。总之，我们的模型忠实地复制了人类免疫治疗后检测到的治疗效果和副作用。它有助于开发和改进免疫疗法，并可能有助于设计新方法来减轻稳定状态和同种异体干细胞移植中的不良影响。
