Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products

Prediction and prevention

J. Szebeni, Franco Muggia, Alberto Gabizon, Yechezkel Barenholz

Research output: Contribution to journalArticle

223 Citations (Scopus)

Abstract

Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil ®) and paclitaxel (Taxol ®). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin-induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D.

Original languageEnglish
Pages (from-to)1020-1030
Number of pages11
JournalAdvanced Drug Delivery Reviews
Volume63
Issue number12
DOIs
Publication statusPublished - Sep 16 2011

Fingerprint

Complement Activation
Excipients
Liposomes
Lipids
Nanomedicine
Hypersensitivity
Carboplatin
Paclitaxel
Immune System
Therapeutics
Safety
Immediate Hypersensitivity
Antigen-Antibody Complex
Combination Drug Therapy
Pharmaceutical Preparations
Doxorubicin
Sulfates
Signal Transduction
Swine
liposomal doxorubicin

Keywords

  • Adverse drug effects
  • Allergy
  • Cancer chemotherapy
  • CARPA
  • Hypersensitivity reactions
  • Immune toxicity
  • Nanomedicines

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products : Prediction and prevention. / Szebeni, J.; Muggia, Franco; Gabizon, Alberto; Barenholz, Yechezkel.

In: Advanced Drug Delivery Reviews, Vol. 63, No. 12, 16.09.2011, p. 1020-1030.

Research output: Contribution to journalArticle

@article{4a3d0a8aeac240d091ad866f422f1f46,
title = "Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products: Prediction and prevention",
abstract = "Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil {\circledR}) and paclitaxel (Taxol {\circledR}). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin-induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D.",
keywords = "Adverse drug effects, Allergy, Cancer chemotherapy, CARPA, Hypersensitivity reactions, Immune toxicity, Nanomedicines",
author = "J. Szebeni and Franco Muggia and Alberto Gabizon and Yechezkel Barenholz",
year = "2011",
month = "9",
day = "16",
doi = "10.1016/j.addr.2011.06.017",
language = "English",
volume = "63",
pages = "1020--1030",
journal = "Advanced Drug Delivery Reviews",
issn = "0169-409X",
publisher = "Elsevier",
number = "12",

}

TY - JOUR

T1 - Activation of complement by therapeutic liposomes and other lipid excipient-based therapeutic products

T2 - Prediction and prevention

AU - Szebeni, J.

AU - Muggia, Franco

AU - Gabizon, Alberto

AU - Barenholz, Yechezkel

PY - 2011/9/16

Y1 - 2011/9/16

N2 - Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil ®) and paclitaxel (Taxol ®). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin-induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D.

AB - Some therapeutic liposomes and lipid excipient-based anticancer drugs are recognized by the immune system as foreign, leading to a variety of adverse immune phenomena. One of them is complement (C) activation, the cause, or major contributing factor to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a novel subcategory of acute (type I) hypersensitivity reactions (HSR), which is mostly mild, transient, and preventable by appropriate precautions. However, in an occasional patient, it can be severe or even lethal. Because a main manifestation of C activation is cardiopulmonary distress, CARPA may be a safety issue primarily in cardiac patients. Along with an overview of the various types of liposome-immune system interactions, this review updates the experimental and clinical information on CARPA to different therapeutic liposomes and lipid excipient-based (micellar) anticancer drugs, including PEGylated liposomal doxorubicin sulfate (PLD, Doxil ®) and paclitaxel (Taxol ®). The substantial individual variation of in vitro and in vivo findings reflects an extremely complex immune phenomenon involving multiple, redundant pathways of C activation, signal transduction in allergy-mediating cells and vasoactive mediator actions at the effector cell level. The latest advances in this field include the proposal of doxorubicin-induced shape changes and aggregation of liposomes in Doxil as possible contributing factors to CARPA caused by PLD, and the finding that Doxil-induced immune suppression prevents HSR to co-administered carboplatin, a significant benefit of Doxil in combination chemotherapy with carboplatin. The review evaluates the use of in vitro C assays and the porcine liposome-induced cardiopulmonary distress model for predicting CARPA. It is concluded that CARPA may become a frequent safety issue in the upcoming era of nanomedicines, necessitating its prevention at an early stage of nanomedicine R&D.

KW - Adverse drug effects

KW - Allergy

KW - Cancer chemotherapy

KW - CARPA

KW - Hypersensitivity reactions

KW - Immune toxicity

KW - Nanomedicines

UR - http://www.scopus.com/inward/record.url?scp=80052174164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052174164&partnerID=8YFLogxK

U2 - 10.1016/j.addr.2011.06.017

DO - 10.1016/j.addr.2011.06.017

M3 - Article

VL - 63

SP - 1020

EP - 1030

JO - Advanced Drug Delivery Reviews

JF - Advanced Drug Delivery Reviews

SN - 0169-409X

IS - 12

ER -