Complement Activation, Immunogenicity, and Immune Suppression as Potential Side Effects of Liposomes

Janos Szebeni3 and Yechezkel (ChezyJ BarenhoIzb

*Nanomedicine Research and Education Center,

Semmelweis University and BayZoitan Foundation for Applied Research, Budapest, and Faculty of Health Sciences, Miskolc University, Miskolc, Hungary bLaboratory of Membrane and liposome Research,

Institute of Medical Research Israel Canada,

The Hebrew University-Hadassah Medical School, Jerusalem, Israel This email address is being protected from spam bots, you need Javascript enabled to view it , This email address is being protected from spam bots, you need Javascript enabled to view it , This email address is being protected from spam bots, you need Javascript enabled to view it

Some therapeutically relevant liposomes are recognized by the immune system as foreign, and the resulting innate or specific immune response can be adverse to the host. The innate response can involve the activation of the complement (C) system, which, via liberation of anaphylatoxins (C5a, C3a), underlies an acute hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA represents a potential barrier to the clinical use of reactogenic

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ISBN 978-981-4800-90-7 (Hardcover), 978-1-003-12525-9 (eBook) liposomes in cardiac patients, as a main manifestation of C activation in the body may be cardiopulmory distress. The adverse immune response to liposomes involving specific immunity is exemplified by PEGylated nanoliposome-induced transient IgM production, which causes accelerated blood clearance (ABC). Immunosuppression occurs mostly with anticancer and antifungal liposomes. This chapter updates the information on CARPA, accelerated blood clearance (ABC phenomenon), and immunosuppression; highlights their common and specific causes; and discusses their mechanisms.


Today, 46 years after the discovery of liposomes [10, 25], 34 years after their first injection in man against Gaucher's disease [12] and with more than 10 liposomal drugs in clinical use [63, 92, 93], the adverse effects of liposomes on the immune system represent a relatively poorly explored territory within "liposomology."

This, however, will likely change in the near future as the rising number of advanced liposome-based drugs reach in vivo testing. These advanced nano-liposomes include targeting ligands and/or proteins or nucleic acids as the active ingredient, making the particles more complex than the currently approved liposomal drugs. Therefore, they may carry increased risk of recognition by the immune system as foreign. Unless we understand the cellular and molecular processes underlying the ensuing protective/defensive response, the absence of adverse effects — a unique asset of simple liposomes — will probably become the exception rather than the rule. The immunological effects of liposomes will extend its present focus, from the use of liposomes as vaccines, to mapping an uncharted network of hypersensitivity and immunogenicity reaction pathways. As the safety of medicinal nanoparticles comes more to the fore, reactogenicity and immunogenicity testing may join the list of toxicity and QC assays required by regulatory agencies. A deeper insight into the fine immunomodulatory effects of such complex nano-particles may also lead to a need to revise our views on immune suppression, not as a side effect but as contributor to therapeutic benefit. This seems to be the case with Doxil, the first nano-drug approved by the US FDA, which is the subject of Chapter 12.

It looks like future nano-particle based drugs will have a less smooth path of safety clearance compared with what we used to have so far, a toll we may need to pay for nursing small-molecular-weight conventional drugs into the nano dimension, which is surveyed by the immune system with "eager eyes” (Figure 11.1).

Immune recognition of nanoparticles

Figure 11.1 Immune recognition of nanoparticles. Map of different nanoparticles on a diameter vs. Mw chart; blue shaded area is the region of immune recognition. Liposomes and carbon nanotubes, with their length, fall into the "sight" of the immune system, while smaller nanoparticles (fullerenes, dendrimers, micelles and complex polymeric particles (e.g., nanolatex) are, in theory, below the size and Mw thresholds of immune recognition. The green "Lipinsky box" shows the position of traditional small-molecular weight drugs [62].

Types and Features of Immune Responses to Liposomes

The immune effects of liposomes can be stimulatory or inhibitory, weak, moderate or severe, all with a broad individual variation in the time of onset and duration (Table 11.1). In additions to the above time-related differences, the immune effects of liposomes also differ in the part of the immune system primarily affected, i.e., whether the nonspecific, innate, or the specific, adaptive arm of immunity undergoes stimulation or suppression. The term reactogenicity is used to imply a broad activation process that involves the innate as well as the adaptive arm of the immune system, while immunogenicity usually refers to specific antibody induction with the involvement of В and T cells. Of note, antigenicity, i.e., the capability of liposomes to expose antigens, does not necessarily mean reactogenicity or immunogenicity, as antigens may remain unrecognized or can induce immune suppression (tolerance).

Table 11.1 Types of liposome-induced immune changes according to the time of onset and duration

Type of change

Time of onset


Example and reference


Immediate (within seconds to minutes) Delayed (within hours)

Minutes to hours

Hypersensitivity (infusion) reactions caused by liposomes [84-86,89]

Late (within days to months)

Weeks to years

Immunity to liposomal antigens, e.g. influenza or hepatitis В [2,13]



Hours to days

Liposomal alendronate [21]


Days to months

Doxil-induced immunosuppression [1, 37, 79]

To date, two aspects of the impact of liposomes on the immune system were explored: first, in the 1970s, the late-onset, long-lasting immunogenic properties of phospholipid bilayers were recognized and utilized as antigen carriers and adjuvants. Since then, numerous vaccine candidates have reached advanced clinical trials, and two products, an influenza (Inflexal® V) and a hepatitis A vaccine (Epaxal®) have reached the market; both are based on influenza virus-like liposomes ("immune-potentiating reconstituted influenza virosomes"). Another proteoliposome-based hepatitis-B vaccine in current testing worldwide is based on yeast derived or mammalian recombinant, 22 nm-hepatitis В surface antigen particles carried by multilamellar liposomes [26, 27].

The second "bad" aspect of immune stimulation by liposomes, i.e., the rise of immune responses with adverse consequences, emerged only some 20 years later, after clinical studies started with liposome- based antifungal and anticancer drugs (Ambisome and Doxil) [11,

18, 34, 36, 66, 77]. The rest of the chapter focuses only on the latter, adverse immune responses to liposomes. It was our goal to highlight the common grounds of immune stimulation, to provide examples of reactogenicity, immunogenicity and immune suppression, and to outline recent theories about the mechanism of these phenomena.

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