利妥昔单抗（Rituximab，简称R）是一种抗CD20单克隆抗体（mAb），也是世界上首个获批用于肿瘤患者的抗体药物。将其与CHOP化疗方案联合应用可以显著改善全球最常见的血液系统恶性肿瘤-各类B细胞淋巴瘤的预后。然而，在将近30年前将R与经典的CHOP化疗方案联合应用以来，一线治疗并未取得进展，有35%的疾病会复发。有证据表明R与化疗药物具有协同作用，但R与CHOP之间或者新一代抗CD20 mAbs与CHOP之间的药理相互作用仍然大部分未被探索。 我们使用体外模型评估了R与CHOP在多种淋巴瘤细胞系之间的药理相互作用。我们将这些药理相互作用与第二代抗CD20 mAb ofatumumab和CHOP进行了比较。最后，我们使用RNA测序技术表征了这两种抗体引发的转录谱，并确定了调节其不同效应的潜在分子途径。 我们发现在药理相互作用中存在着非常广泛的异质性，这与当前的临床分类预测的情况不符。然后我们发现R和ofatumumab分别与CHOP的细胞毒作用和抑制细胞增殖的能力在B细胞淋巴瘤细胞系的独立不同亚群中具有协同作用，从而拓展了除R-CHOP之外更多细胞系中的理想免疫化疗作用。最后，我们发现这两种mAbs分别调节了JNK和p38 MAPK家族富集的基因，该家族调控着细胞凋亡和增殖。 我们的发现完全出乎意料，因为长期以来认为这些mAbs在生物学和临床上是等效的，但实际上可能在患者个体方面表现更好。这一发现可能具有直接的临床意义，因为这两种免疫化疗联合方案已经获得FDA批准，且在I、II和III期临床试验中毒性没有差异。因此，这一发现可以为使用符合临床标准的免疫化疗联合方案，为B细胞淋巴瘤患者提供额外的治疗效益提供新的精准医学策略的参考。 版权所有 © 2023 Lee, Pierpont, August and Richards.

Rituximab (R), an anti-CD20 monoclonal antibody (mAb) and the world's first approved antibody for oncology patients, was combined with the CHOP chemotherapy regimen and markedly improved the prognosis of all B- cell-derived lymphomas, the most common hematological malignancy worldwide. However, there is a 35% disease recurrence with no advancement in the first-line treatment since R was combined with the archetypal CHOP chemotherapy regimen nearly 30 years ago. There is evidence that R synergizes with chemotherapy, but the pharmacological interactions between R and CHOP or between newer anti-CD20 mAbs and CHOP remain largely unexplored.We used in vitro models to score pharmacological interactions between R and CHOP across various lymphoma cell lines. We compared these pharmacological interactions to ofatumumab, a second-generation anti-CD20 mAb, and CHOP. Lastly, we used RNA-sequencing to characterize the transcriptional profiles induced by these two antibodies and potential molecular pathways that mediate their different effects.We discovered vast heterogeneity in the pharmacological interactions between R and CHOP in a way not predicted by the current clinical classification. We then discovered that R and ofatumumab differentially synergize with the cytotoxic and cytostatic capabilities of CHOP in separate distinct subsets of B-cell lymphoma cell lines, thereby expanding favorable immunochemotherapy interactions across a greater range of cell lines beyond those induced by R-CHOP. Lastly, we discovered these two mAbs differentially modulate genes enriched in the JNK and p38 MAPK family, which regulates apoptosis and proliferation.Our findings were completely unexpected because these mAbs were long considered to be biological and clinical equivalents but, in practice, may perform better than the other in a patient-specific manner. This finding may have immediate clinical significance because both immunochemotherapy combinations are already FDA-approved with no difference in toxicity across phase I, II, and III clinical trials. Therefore, this finding could inform a new precision medicine strategy to provide additional therapeutic benefit to patients with B-cell lymphoma using immunochemotherapy combinations that already meet the clinical standard of care.Copyright © 2023 Lee, Pierpont, August and Richards.