尽管对侵袭性淋巴瘤的治疗取得了近期的进展，但仍有相当一部分患者在疾病中丧生。因此，迫切需要新的治疗方法。由于抗CD20抗体利妥昔单抗和CD19靶向抗体塔法西单抗具有不同的作用方式，我们研究了通过联合应用利妥昔单抗和塔法西单抗来双靶向侵袭性淋巴瘤B细胞是否能增强细胞毒作用。 通过研究直接细胞毒性、抗体依赖性细胞介导的细胞毒作用以及抗体依赖性细胞吞噬作用等不同作用方式，我们确定了单抗和联合治疗在体外和体内模型中对侵袭性B细胞淋巴瘤（包括弥漫性大B细胞淋巴瘤和伯基特淋巴瘤）的疗效。在体外模型中观察到3种对单抗治疗或联合治疗的敏感性表现：其中1/11个细胞系主要对塔法西单抗敏感，2/11对利妥昔单抗敏感，而联合治疗在至少一种作用方式下导致了8/11个细胞系细胞死亡增强。使用任一抗体或联合治疗导致了癌基因转录因子MYC的表达降低和AKT信号抑制，这与细胞系特异性对直接细胞毒性的敏感性相一致。最后，在PBMC人源化Ramos NOD/SCID小鼠模型中，联合治疗导致了协同的生存益处。 该研究表明，与单药治疗相比，塔法西单抗和利妥昔单抗的联合应用在体外和体内侵袭性B细胞淋巴瘤模型中提高了疗效。Copyright © 2023 Patra-Kneuer, Chang, Xu, Augsberger, Grau, Zapukhlyak, Ilieva, Landgraf, Mangelberger-Eberl, Yousefi, Berning, Kurz, Ott, Klener, Khandanpour, Horna, Schanzer, Steidl, Endell, Heitmüller and Lenz。

Despite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects.Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).Three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model.This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.Copyright © 2023 Patra-Kneuer, Chang, Xu, Augsberger, Grau, Zapukhlyak, Ilieva, Landgraf, Mangelberger-Eberl, Yousefi, Berning, Kurz, Ott, Klener, Khandanpour, Horna, Schanzer, Steidl, Endell, Heitmüller and Lenz.