Immunogenicity and Immune Complex Disease in Preclinical Safety Studies

被引:15
作者
Vahle, John L. [1 ]
机构
[1] Lilly Res Labs, Indianapolis, IN USA
关键词
immunogenicity; toxicity; immune complex disease; nonhuman primate; biotherapeutics; HYPERSENSITIVITY REACTIONS; CYNOMOLGUS MONKEYS; ANTIBODIES;
D O I
10.1177/0192623318797070
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
This article summarizes a continuing education presentation on immunogenicity that was part of a continuing education course entitled, "Clinical Pathology of Biotherapeutics." Immunogenicity of a biotherapeutic can have diverse impacts including altered systemic exposure and pharmacologic responses and, in a fraction of the cases, safety concerns including cross-reactive neutralization of endogenous proteins or sequela related to immune complex disease (ICD). In most cases, immune complexes are readily cleared from circulation; however, based on physiochemical properties, insoluble complexes form, activate complement, and deposit in tissues. Using published information and personal experience, a set of repeat-dose monkey toxicity studies with manifestations suggestive of ICD was reviewed to summarize the spectrum of clinical and pathology findings. The most common live-phase observation linked to ICD was an acute postdosing reaction following multiple dose administrations characterized by generalized collapse and attributed to acute complement activation. Less common live-phase observations were related to syndromes such as a consumptive coagulopathy or a protein losing nephropathy. The most common histologic change attributed to ICD was multi-organ vascular/perivascular inflammation followed by glomerulonephritis. The presentation concluded with a description of the challenges in assessing the relevance of immunogenicity-related reaction in monkey to human clinical use.
引用
收藏
页码:1013 / 1019
页数:7
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