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The Mechanisms and Implications of IgM-mediated Pseudoallergy for Drug Delivery

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Pseudoallergy refers to hypersensitivity reactions that resemble allergic reactions but are not mediated by IgE antibodies. Instead, they involve activation of the complement system, especially via IgM antibodies. A prime example is C activation-related pseudoallergy (CARPA) induced by intravenous administration of liposomal drugs. Understanding the mechanisms of IgM-mediated pseudoallergy reactions has important implications for engineering safer nanoparticle drug delivery systems. Liposomes are spherical vesicles composed of phospholipid bilayers that can encapsulate hydrophobic drugs or hydrophilic compounds in the core or membrane. Pegylation with polyethylene glycol (PEG) on the surface increases liposome circulation time by reducing recognition by the mononuclear phagocytic system. However, repeat injections of PEGylated liposomes leads to accelerated blood clearance (ABC phenomenon) due to anti-PEG IgM antibodies that activate complement.

Mechanisms of IgM-Mediated Pseudoallergy

IgM is the first antibody produced during an initial exposure to an antigen. IgM pentamers with 10 binding sites are highly efficient at activating the classical complement pathway. Anti-PEG IgM is generated by B-1 cells in the spleen in a T-cell independent manner. The ABC phenomenon is due to anti-PEG IgM binding causing C3 opsonization, leading to clearance by Kupffer cells in the liver. This hypersensitivity-like reaction is termed CARPA. The complement system consists of plasma proteins that react to pathogens or antibody complexes. Activation of early components C1-C4 generates C3 convertase, which cleaves C3 into C3a and C3b. C3b tags pathogens and immune complexes for elimination. C5 convertase then cleaves C5 into C5a and C5b, with the latter assembling the membrane attack complex. C3a and C5a are anaphylatoxins that trigger mast cell and basophil degranulation, releasing histamine and other inflammatory mediators.

Complement activation-related pseudoallergy.Fig 1. Complement activation-related pseudoallergy.1

Selective Depletion of Anti-PEG IgM for CARPA Treatment

In CARPA, complement activation by anti-PEG IgM on PEGylated liposomes generates anaphylatoxins that bind receptors on effector cells. This leads to acute cardiopulmonary distress with symptoms like hypertension, edema, and bronchospasm mimicking anaphylaxis. However, tryptase levels are normal since mast cells are not activated. Risk factors for CARPA include faster blood circulation of liposomes and higher levels of preexisting anti-PEG antibodies. Several strategies are being pursued to mitigate CARPA triggered by anti-PEG IgM. Limiting the PEG content can reduce immunogenicity and ABC reaction severity. Attaching PEG via a degradable linker allows its removal prior to a second injection. Lower molecular weight PEG is less likely to provoke IgM responses. Alternative polymers like polysarcosine in place of PEG avoid ABC reactions in preclinical models. Modifying the liposome composition, such as increasing cholesterol content, can also decrease complement activation. Another approach is selective depletion of anti-PEG IgM using an extracorporeal immunoadsorption device containing PEGylated particles to capture IgM. In a test of its safety and efficacy, treating CARPA-sensitive pigs with the immunoadsorber lowered anti-PEG IgM levels by more than 90% and enabled repeated administration of PEGylated liposomes without triggering pseudoallergy reactions.

In summary, IgM-mediated pseudoallergy is an obstacle for clinical translation of nanomedicines like PEGylated liposomes. Elucidating the molecular mechanisms involving anti-PEG IgM and complement activation has guided engineering strategies to reduce this hypersensitivity risk. Further innovations to limit IgM responses or selectively remove anti-PEG IgM could enable safe, repeated dosing of nanoparticle drugs. A deeper understanding of pseudoallergy pathways may also shed light on other unexplained infusion reactions to pegylated biopharmaceuticals.

At Creative Biolabs, our team of professionals provides a wide range of non-IgG antibody development services to clients around the globe. In addition, we can provide a full range of IgM antibodies from different species, such as rat, mouse, and Armenian hamster for different applications. If you have any related needs, please feel free to contact us for more information and a detailed quote.


  1. Szebeni, Janos. "Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals." Molecular immunology 61.2 (2014): 163-173.

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