Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA.
Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2020-000590.
Patients with cancer receiving tumor-reactive humanized monoclonal antibody (mAb) therapy can develop a human antihuman antibody (HAHA) response against the therapeutic mAb. We evaluated for HAHA in patients with neuroblastoma treated in a phase I study of humanized anti-GD2 mAb (immunoglobulin (Ig)G1 isotype), hu14.18K322A (NCT00743496). The pretreatment sera (collected prior to mAb treatment) from 9 of 38 patients contained antitherapeutic antibodies, even though they had no prior mAb exposure. We sought to characterize these pre-existing antitherapeutic antibodies (PATA).
The PATA+ pretreatment samples were characterized via ELISA; clinical associations with PATA status were evaluated.
Pretreatment sera from eight of nine PATA+ patients also bound rituximab and demonstrated preferential ELISA reactivity against the Fc portions of hu14.18K322A and rituximab as compared with the Fab portions of these mAbs. These PATA+ sera also recognized dinutuximab (human IgG1 isotype) and mouse IgG2a isotype mAbs, but not a mouse IgG1 isotype or the fully human panitumumab (IgG2 isotype) mAb. Of the 38 treated patients, only 4 patients (all in the PATA+ cohort) demonstrated no disease progression for 2.5 years without receiving further therapy (p=0.002).
This study demonstrates an association between clinical outcome and the presence of PATA against determinant(s) on the Fc component of the therapeutic mAb, suggesting that the PATA may be playing a role in augmenting mAb-based antitumor effects. Further analyses for the presence of PATA in a larger cohort of patients with relapsed neuroblastoma, analyses of their clinical correlates, identification of their immunological targets, and potential antitumor mechanisms are warranted.
接受肿瘤反应性人源化单克隆抗体（mAb）治疗的癌症患者可能会对治疗性 mAb 产生人抗人抗体（HAHA）反应。我们评估了在接受人源化抗 GD2 mAb（免疫球蛋白（Ig）G1 同种型）hu14.18K322A 治疗的神经母细胞瘤患者（NCT00743496）中 HAHA 的情况。38 例患者中的 9 例在接受 mAb 治疗前的预处理血清（在接受 mAb 治疗前采集）中含有针对治疗性抗体的抗体，尽管他们以前没有接触过 mAb。我们试图对这些预先存在的抗治疗性抗体（PATA）进行特征描述。
通过 ELISA 对 PATA+预处理样本进行特征描述；评估与 PATA 状态的临床相关性。
9 例 PATA+患者中的 8 例预处理血清也与利妥昔单抗结合，并与这些 mAb 的 Fab 部分相比，对 hu14.18K322A 和利妥昔单抗的 ELISA 反应性具有优先性。这些 PATA+血清还识别迪努妥昔单抗（人 IgG1 同种型）和鼠 IgG2a 同种型 mAb，但不识别鼠 IgG1 同种型或完全人源帕尼单抗（IgG2 同种型）mAb。在 38 例接受治疗的患者中，只有 4 例（均在 PATA+队列中）在没有接受进一步治疗的情况下，2.5 年无疾病进展（p=0.002）。
这项研究表明，临床结果与针对治疗性 mAb Fc 成分的决定因素的 PATA 之间存在关联，表明 PATA 可能在增强 mAb 抗肿瘤作用方面发挥作用。在更大的复发性神经母细胞瘤患者队列中进一步分析 PATA 的存在情况，分析其临床相关性，鉴定其免疫靶标以及潜在的抗肿瘤机制是必要的。
