接受血浆置换的卡哌珠单抗治疗的免疫介导的血栓性血小板减少性紫癜患者的复杂免疫原性评估

IF 3.4 3区医学 Q2 HEMATOLOGY

Research and Practice in Thrombosis and Haemostasis Pub Date : 2024-11-01 DOI:10.1016/j.rpth.2024.102620

Brendy Van Butsel , Maria Laura Sargentini-Maier , Ana Paula Marques , Yana Vandenbossche , Gabriela Marcheva , Sriya Gunawardena , Samuel Pine

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引用次数: 0

摘要

国际血栓形成和止血学会免疫介导的血栓性血小板减少性紫癜（iTTP）治疗指南推荐同步治疗血浆置换（TPE）、免疫抑制治疗（IST）和卡帕单抗。TPE通过供体血浆将预先存在的抗体（pre-Abs）转移到患者体内和/或稀释治疗产生的（TE） ADAs，从而使抗药抗体（ADA）的测量复杂化。目的评估接受卡普拉珠单抗治疗的iTTP患者中ADAs的存在。方法分析iTTP患者在4项临床试验（TITAN、HERCULES、Post-HERCULES和一项日本患者试验）中接受每日1次卡帕珠单抗加TPE/免疫抑制治疗的免疫原性数据。ADA和改良的ADA检测将pre-Abs与TE - ADA区分开来。功能性中和抗体（NAb）测定和中和表位表征测定（NECA）评估具有中和电位的ADAs的存在。评估ADAs对疗效、药代动力学/药效学和安全性的影响。结果在4项研究的228例患者中，预抗体的患病率从17.1% （TITAN）到56.7% （HERCULES）不等，而TE ADA的患病率从3.1% （HERCULES）到14.3%（日本研究）不等。使用功能性NAb检测，TE NAb阳性率从0%（日本研究）到12% （HERCULES后），使用NECA检测，TE NAb阳性率从2.7% （HERCULES后）到14.3%（日本研究）。这些抗体的存在不影响治疗的有效性和安全性。结论：在临床试验中，需要一种复杂的免疫原性检测策略来确定使用卡普拉珠单抗治疗的iTTP患者的ab /TE前ADA状态。除了观察到广泛的预抗体外，很少有患者检测到TE ADAs或nab，这两者都不影响疗效/安全性。

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Complex immunogenicity assessment in caplacizumab-treated patients with immune-mediated thrombotic thrombocytopenic purpura who have received plasma exchange

Background

International Society on Thrombosis and Haemostasis guidelines for immune-mediated thrombotic thrombocytopenic purpura (iTTP) treatment recommend concurrent therapeutic plasma exchange (TPE), immunosuppressive therapy (IST), and caplacizumab. TPE can complicate antidrug antibody (ADA) measurements by transferring pre-existing antibodies (pre-Abs) into patients via donor plasma and/or diluting treatment-emergent (TE) ADAs.

Objectives

To assess the presence of ADAs in patients with iTTP who received caplacizumab.

Methods

Immunogenicity data from patients with iTTP receiving caplacizumab once daily plus TPE/immunosuppressive therapy in 4 clinical trials (TITAN, HERCULES, Post-HERCULES, and a trial conducted in Japanese patients) in the clinical development program were analyzed. ADA and modified ADA assays differentiated pre-Abs from TE ADAs. A functional neutralizing antibody (NAb) assay and a neutralizing epitope characterization assay (NECA) assessed the presence of ADAs with neutralizing potential. The impact of ADAs on efficacy, pharmacokinetics/pharmacodynamics, and safety was evaluated.

Results

Among 228 patients in 4 studies, prevalence of pre-Abs ranged from 17.1% (TITAN) to 56.7% (HERCULES), while TE ADA prevalence ranged from 3.1% (HERCULES) to 14.3% (Japanese study). The TE NAb-positive rate ranged from 0% (Japanese study) to 12% (Post-HERCULES) using the functional NAb assay and from 2.7% (Post- HERCULES) to 14.3% (Japanese study) using the NECA. The presence of these antibodies did not impact treatment efficacy or safety.

Conclusion

A complex immunogenicity assay strategy was required to define the pre-Ab/TE ADA status of patients with iTTP treated with caplacizumab in a clinical trial setting. In addition to the wide range of pre-Abs observed, few patients had detectable TE ADAs or NAbs, neither of which affected efficacy/safety.

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