Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies

Kronenberg, Sven; Husar, Elisabeth; Schubert, Christine M.; Freichel, Christian; Emrich, Thomas; Lechmann, Martin; Giusti, Anna Maria; Regenass, Franziska

doi:10.1016/j.yrtph.2017.06.004

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…The level of detail available for each study varied greatly as the information was derived from publications, workshop presentations, personal communications, and personal experience. Key publications that either review a series of cases or present detailed results from a single-case experience include (Rojko et al 2014), (Heyen et al 2014), Husar et al ( 2017), and Kronenberg et al (2017). From the information available across the studies reviewed, key study design elements, live phase-findings, laboratory findings, and anatomic pathology findings were summarized.…”

Section: Findings Attributed To Icd In Nonhuman Primate Toxicity Studiesmentioning

confidence: 99%

Immunogenicity and Immune Complex Disease in Preclinical Safety Studies

Vahle

2018

Toxicol Pathol

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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.

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Section: Findings Attributed To Icd In Nonhuman Primate Toxicity Studiesmentioning

confidence: 99%

Immunogenicity and Immune Complex Disease in Preclinical Safety Studies

Vahle

2018

Toxicol Pathol

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“…80 In the lung, this may present as thrombosis and vascular/perivascular inflammation. 81,82 Determination of ICD is not straight forward as it may present in any dose group with a tendency to show an inverse correlation with dose (ie, occur more frequently in the mid- and low dose groups) 9 and in a single animal (36% frequency of studies) or multiple animals (64% frequency of studies). 80 The clinicopathological response can vary significantly between animals even within the same dose group.…”

Section: Resultsmentioning

confidence: 99%

BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics

Hall

Tepper²,

Boyle

et al. 2021

Toxicol Pathol

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The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple (“uncomplicated”) increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.

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“…Formation of antidrug antibodies (ADAs) following administration of human protein-based drugs to animals may lead to altered drug efficacy, changes in pharmacokinetics, and hypersensitivity reactions. 1,2 Antidrug antibodies can together with the administered protein form circulating immune complexes (CIC) potentially followed by activation of the complement system and formation of complement-bound CICs (cCICs). [3][4][5] If the ADAs and administered protein reach molar equivalence, large amount of insoluble CICs and/or cCICs of larger lattice sizes can be formed, [5][6][7][8] which potentially may saturate intrinsic clearance mechanisms, leading to vascular immune complex (IC) deposition and vascular pathology.…”

Section: Introductionmentioning

confidence: 99%

Formation and Glomerular Deposition of Immune Complexes in Mice Administered Human Antibodies: Evaluation of Dose, Frequency, and Biomarkers

et al. 2020

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Administration of human protein–based drugs to animals often leads to formation of antidrug antibodies (ADAs) that may form circulating immune complexes (CICs) with the dosed protein. Circulating immune complexes can activate and bind complement (cCICs), and if large amount of CICs or cCICs is formed, the clearance mechanism potentially becomes saturated, which can lead to immune complex (IC) deposition and inflammation. To obtain a better understanding of the underlying factors, including the relationship between different dose regimes on IC formation and deposition and identification of possible biomarkers of IC deposition and IC-related pathological changes in kidneys, BALB/c and C57BL/6J mice were administered with human anti-tumor necrosis factor α (aTNFα, adalimumab) or a humanized anti-TNP (aTNP) antibody for 13 weeks. Particularly, ADA, CIC, cCIC formation, IC deposition, and glomerulonephritis were observed in C57BL/6J administered with aTNFα, whereas the immunologic response was minor in BALB/c mice administered with aTNFα and in BALB/c and C57BL/6J mice administered aTNP. Changing dose levels or increasing dosing frequency of aTNFα on top of an already-established CIC and cCIC response did not lead to substantial changes in CIC, cCIC formation, or IC deposition. Finally, no association between the presence of CICs or cCIC in plasma and glomerular IC deposition and/or glomerulonephritis was observed.

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Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies

Cited by 24 publications

References 25 publications

Immunogenicity and Immune Complex Disease in Preclinical Safety Studies

Immunogenicity and Immune Complex Disease in Preclinical Safety Studies

BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics

Formation and Glomerular Deposition of Immune Complexes in Mice Administered Human Antibodies: Evaluation of Dose, Frequency, and Biomarkers

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