Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil®): possible role in hypersensitivity reactions
Open accessAbstract
Background Pegylated liposomal doxorubicin (Doxil) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date.Patients and methods Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate.Results Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate.Conclusions C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors.
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DOXIL has shown the ability to induce ABC in human patients mainly due to anti-PEG antibodies after initial treatment.
“The clinically approved doxorubicin liposome formulation, DOXIL®, has also shown the ability to induce the ABC phenomenon in human patients mainly due to the development of anti-PEG antibodies in the body after the initial treatment of DOXIL® [82].”
From Polymeric micelles for the delivery of poorly soluble drugs: From nanoformulation to clinical approval. (2020) · cites this paper as [82]
The Introduction says Doxil hypersensitivity reactions occur mostly at first exposure, without prior sensitization. The Patients and Complement activation by Doxil in vivo sections study first-time recipients and report complement activation after infusion, not accelerated blood clearance (ABC) after an initial treatment. The cited paper therefore describes a different reaction and does not support anti-PEG antibodies as the claimed mechanism. (LLM, conf=0.87)
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- Authors
- Chanan-Khan, A., Szebeni, J., Savay, S., Liebes, L., Rafique, N. M., Alving, C. R., & Muggia, F. M.
- Affiliations
- New York University (US)
- Walter Reed Army Institute of Research (US)
- Corresponding author
- Chanan-Khan, A.
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 14
- Issue
- 9
- Pages
- 1430-1437
- ISSN
- 0923-7534 (ISSN-L)
- OpenAlex
- W2106088947
- Cited by
- 479
- References
- 27
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 22 · 2023: 26 · 2022: 28 · 2021: 32 · 2020: 38 · 2019: 33 · 2018: 26 · 2017: 26 · 2016: 33 · 2015: 25 · 2014: 21 · 2013: 30 · 2012: 17
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- pegylated liposomal doxorubicin, hypersensitivity, complement activation, sC5b-9, immediate hypersensitivity, non-IgE-mediated allergy, dose rate, solid tumors, chemotherapy side effects
- MeSH terms
- Adult, Aged, Antibiotics, Antineoplastic, Complement Activation, Dose-Response Relationship, Drug, Doxorubicin, Drug Hypersensitivity, Female, Humans, Hypersensitivity, Immediate, Male, Middle Aged, Neoplasms
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