Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls

Christina Giannakou; Margriet V. D. Z. Park; Irene E. M. Bosselaers; Wim H. de Jong; Jan Willem van der Laan; Henk van Loveren; Rob J. Vandebriel; Robert E. Geertsma

doi:10.1002/wnan.1633

Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls

Christina Giannakou, Margriet V. D. Z. Park^*, Irene E. M. Bosselaers, Wim H. de Jong, Jan Willem van der Laan, Henk van Loveren, Rob J. Vandebriel, Robert E. Geertsma

^*Corresponding author for this work

Research output: Contribution to journal › (Systematic) Review article › peer-review

Abstract

Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation.

This article is categorized under:

Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine

Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

Original language	English
Article number	1633
Number of pages	16
Journal	Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology
Volume	12
Issue number	5
DOIs	https://doi.org/10.1002/wnan.1633
Publication status	Published - Sept 2020

Keywords

ICH-S8
immunotoxicity
in vitro
nanomedicinal product
regulatory
COMPLEMENT ACTIVATION
SILVER NANOPARTICLES
TISSUE DISTRIBUTION
SKIN INTERACTIONS
IN-VITRO
TOXICITY
INFLAMMASOME
ACCUMULATION
DISEASE

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10.1002/wnan.1633Licence: CC BY

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Giannakou, C., Park, M. V. D. Z., Bosselaers, I. E. M., de Jong, W. H., van der Laan, J. W., van Loveren, H., Vandebriel, R. J., & Geertsma, R. E. (2020). Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls. Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology, 12(5), Article 1633. https://doi.org/10.1002/wnan.1633

@article{d3de70097a0d45ea9fef6fc7ac885a5d,

title = "Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls",

abstract = "Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 {"}Immunotoxicity Studies for Human Pharmaceuticals{"} of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation.This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials",

keywords = "ICH-S8, immunotoxicity, in vitro, nanomedicinal product, regulatory, COMPLEMENT ACTIVATION, SILVER NANOPARTICLES, TISSUE DISTRIBUTION, SKIN INTERACTIONS, IN-VITRO, TOXICITY, INFLAMMASOME, ACCUMULATION, DISEASE",

author = "Christina Giannakou and Park, {Margriet V. D. Z.} and Bosselaers, {Irene E. M.} and {de Jong}, {Wim H.} and {van der Laan}, {Jan Willem} and {van Loveren}, Henk and Vandebriel, {Rob J.} and Geertsma, {Robert E.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals, Inc.",

year = "2020",

month = sep,

doi = "10.1002/wnan.1633",

language = "English",

volume = "12",

journal = "Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology",

issn = "1939-5116",

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Nonclinical regulatory immunotoxicity testing of nanomedicinal products: Proposed strategy and possible pitfalls. / Giannakou, Christina; Park, Margriet V. D. Z.; Bosselaers, Irene E. M. et al.
In: Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology, Vol. 12, No. 5, 1633, 09.2020.

Research output: Contribution to journal › (Systematic) Review article › peer-review

TY - JOUR

T1 - Nonclinical regulatory immunotoxicity testing of nanomedicinal products

T2 - Proposed strategy and possible pitfalls

AU - Giannakou, Christina

AU - Park, Margriet V. D. Z.

AU - Bosselaers, Irene E. M.

AU - de Jong, Wim H.

AU - van der Laan, Jan Willem

AU - van Loveren, Henk

AU - Vandebriel, Rob J.

AU - Geertsma, Robert E.

PY - 2020/9

Y1 - 2020/9

N2 - Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation.This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

AB - Various nanomedicinal products (NMPs) have been reported to induce an adverse immune response, which may be related to their tendency to accumulate in or target cells of the immune system. Therefore, before their market authorization, NMPs should be thoroughly evaluated for their immunotoxic potential. Nonclinical regulatory immunotoxicity testing of nonbiological medicinal products, including NMPs, is currently performed by following the guideline S8 "Immunotoxicity Studies for Human Pharmaceuticals" of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). However, this guideline does not cover all the immunotoxicity endpoints reported for NMPs in the literature, such as complement activation related pseudo allergy, hypersensitivity and immunosuppression. In addition, ICH-S8 does not provide any nanospecific testing considerations, which is important given their tendency to interfere with many commonly used toxicity assays. We therefore propose a nonclinical regulatory immunotoxicity assessment strategy, which considers the immunotoxicity endpoints currently missing in the ICH-S8. We also list the known pitfalls related to the testing of NMPs and how to tackle them. Next to defining the relevant physicochemical and pharmacokinetic properties of the NMP and its intended use, the proposed strategy includes an in vitro assay battery addressing various relevant immunotoxicity endpoints. A weight of evidence evaluation of this information can be used to shape the type and design of further in vivo investigations. The final outcome of the immunotoxicity assessment can be included in the overall risk assessment of the NMP and provide alerts for relevant endpoints to address during clinical investigation.This article is categorized under:Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in NanomedicineToxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

KW - ICH-S8

KW - immunotoxicity

KW - in vitro

KW - nanomedicinal product

KW - regulatory

KW - COMPLEMENT ACTIVATION

KW - SILVER NANOPARTICLES

KW - TISSUE DISTRIBUTION

KW - SKIN INTERACTIONS

KW - IN-VITRO

KW - TOXICITY

KW - INFLAMMASOME

KW - ACCUMULATION

KW - DISEASE

U2 - 10.1002/wnan.1633

DO - 10.1002/wnan.1633

M3 - (Systematic) Review article

C2 - 32266791

SN - 1939-5116

VL - 12

JO - Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology

JF - Wiley Interdisciplinary Reviews-Nanomedicine and Nanobiotechnology

IS - 5

M1 - 1633

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