Purpose

Biologic molecules constitute a major part of the therapeutics portfolio across the pipeline of several biotech and pharmaceutical companies. They have the advantage of being more target-specific, and recent progress in protein engineering has allowed product designs on various platforms that befit the therapeutic indication and allow differentiation from competitor molecules. They are fundamentally large proteins, with complex structural heterogeneity arising from production using recombinant gene technology in cell lines. These biotherapeutics run the risk of being recognized as foreign by the host immune system, eliciting both B and T cell responses. The impact ranges from none to benign infusion reactions to life-threatening anaphylaxis, and with evolving modalities for such molecules in the pipeline, it is critical to understand the interplay of various risk factors that modulate the immune response. During risk assessment and mitigation strategies in drug development, risk factors are broadly classified arising from patient and product-related origins, and this review will focus on the product-related risk factors.

Methods

A basic primer on immune mechanisms underlying immunogenicity to a biotherapeutic is provided to highlight those aspects that are influenced by product attributes; this is followed by a more focused discussion of relevant and recently published works pertaining to each critical product attribute and the in vitro and in vivo methodologies utilized to assess their risk.

Results

Some product-related factors have an influence on the product’s immunogenicity. This varies with the type of biotherapeutic product, the disease background, and the diversities seen in the subjects.

Conclusion

This article highlights some of the experimental limitations on risk evaluation of individual product attributes and emphasizes that immunogenicity manifesting as an undesirable clinical outcome results from the cumulative effect of several risk factors.

中文翻译：

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产品相关因素和生物疗法的免疫原性

目的

生物分子构成了多家生物技术和制药公司正在开发的治疗产品组合的主要部分。它们的优势在于具有更强的靶标特异性，并且蛋白质工程领域的最新进展已允许在各种平台上进行产品设计，以适应治疗适应症并使其与竞争者分子区分开。它们基本上是大蛋白，在细胞系中使用重组基因技术生产时会产生复杂的结构异质性。这些生物疗法有被宿主免疫系统识别为异物的风险，从而引起B细胞和T细胞反应。影响范围从无到良性输注反应到危及生命的过敏反应，并且管道中此类分子的形态不断发展，了解调节免疫应答的各种危险因素之间的相互作用至关重要。在药物开发的风险评估和缓解策略期间，对来自患者和与产品相关的起源所产生的风险因素进行了大体分类，并且本文将重点关注与产品相关的风险因素。

方法

提供了针对生物治疗药物免疫原性的免疫机制的基础引物，以突出显示受产品属性影响的那些方面；接下来，将对与每个关键产品属性以及用于评估其风险的体外和体内方法有关的最新出版的相关工作进行更集中的讨论。

结果

一些与产品相关的因素会影响产品的免疫原性。这随生物治疗产品的类型，疾病背景以及受试者所见的多样性而异。

结论

本文重点介绍了对单个产品属性进行风险评估的一些实验局限性，并强调了免疫原性表现为不良临床结果的原因是多种风险因素的累积作用。