Role of Complement Activation in Hypersensitivity Reactions to Doxil and Hynic Peg Liposomes: Experimental and Clinical Studies

Szebeni, János; Baranyi, Lajos; Sávay, Sándor; Milosevits, János; Bünger, Rolf; Laverman, Peter; Metselaar, Josbert M.; Storm, Gert; Chanan‐Khan, Asher; Liebes, Leonard; Fm, Muggia; Cohen, Rivka; Barenholz, Yechezkel; Alving, Carl R.

doi:10.1081/lpr-120004790

Cited by 184 publications

(126 citation statements)

References 10 publications

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“…Also, it is important to note that no adverse reactions were observed in the animals from the final 3-mg/kg dose when antibodies were present. This result contrasts with the adverse reactions observed with repeated administration of lipid-based systems that are associated with the presence of antibodies (22,23,(25)(26)(27)(28).…”

Section: Multiple Doses Of Targeted Nanoparticles Safely Administered Incontrasting

confidence: 52%

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Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Heidel

Liu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

357

226

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The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-␥ in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17-18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.systemic administration ͉ RNA interference

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Section: Multiple Doses Of Targeted Nanoparticles Safely Administered Incontrasting

confidence: 52%

“…PEGylated lipid systems carrying small molecule drugs have been used clinically for years, and these lipid-based systems are capable of causing hypersensitivity reactions and complement activation (22,23). Additionally, repeated administration of lipid-based delivery vehicles has the potential to cause phospholipidosis (24) and other lipidrelated toxicities.…”

mentioning

confidence: 99%

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Heidel

Liu

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

357

226

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show abstract

“…These results show that the multicycle animal data are predictive of the multicycle data observed in humans. In contrast, PEGylated liposomes have produced hypersensitivity reactions, complement activation, and other side effects that are not observed from the drug alone (23,24). Additionally, cycle-dependent PK parameters have been observed for PEGylated doxorubicin in humans (i.e., the clearance decreased over three cycles of treatment) (25).…”

Section: Discussionmentioning

confidence: 99%

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Eliasof

Lazarus

Peters

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

124

114

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Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20-to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.nanomedicine | clinical translation | interspecies scaling | pharmacodynamics | Nanoparticles

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“…Further studies are needed to establish the impact of dose and size dependency of a liposome, e.g., Doxil (Speth et al, 1988) on CBF/blood volume changes and the potential overlapping of CBF autoregulation and direct vasoactive effect of complement activation (Szebeni et al, , 2002.…”

Section: Resultsmentioning

confidence: 99%

Cerebrovascular Involvement in Liposome - Induced Cardiopulmonary Distress in Pigs

Bodó¹,

Szebeni²,

Baranyi³

et al. 2005

J. of Liposome Res.

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The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing the burden, 14. ABSTRACT Intravenous administration of liposomes, including Doxil, can cause severe life threatening hemodynamic changes in pigs. The reaction is due to complement activation, and it is characterized by massive pulmonary hypertension, systemic hypotension and severe cardiac abnormalities including falling cardiac output, tachy-or bradycardia with arrhythmia. There were no data suggesting the involvement of cerebrovascular changes in this reaction, however clinical observations allowed this hypothesis. Here we measured the accompanying changes during liposome infusion by monitoring pulsatile electrical impedance (rheoencephalogram -REG) on the skull (n = 24 pigs, 57 trials, 19 types of liposomes). A transient but significant decrease of REG pulse amplitudes followed the injection of liposomes (78.43 % in the total sample, and 91.66 % in the Doxil subgroup; P = 0.003, n = 12), indicating the involvement of cerebrovascular reaction during liposome infusion.

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Role of Complement Activation in Hypersensitivity Reactions to Doxil and Hynic Peg Liposomes: Experimental and Clinical Studies

Cited by 184 publications

References 10 publications

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

Cerebrovascular Involvement in Liposome - Induced Cardiopulmonary Distress in Pigs

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