2020-03-02 17:17:47
Mechanism of the ABC phenomenon
According to Dams et al. [39], in animal models, a second dose of PEGylated liposomes, injected within a time interval of 5 and 21 days, was cleared very rapidly from the blood circulation. The ABC phenomenon showed two distinct phases: the induction phase and the effectuation phase. The induction phase followed the initial dose of PEGylated liposomes in which the biological system is ‘primed’. The effectuation phase occurs at day 3–7 after the initial dose in which a subsequent dose of PEGylated liposomes is rapidly cleared from systemic circulation [42].
Dams et al. [39] demonstrated that serum transfu- sions into normal rats from rats pretreated with PEGylated liposomes also elicited the enhanced blood clearance of a first dose of PEGylated liposomes. In addition, they reported that the phenomenon was abolished either when the rat serum was preheated at 56°C for 30 min prior to transfusion, which inactivate complement system, or when antibodies in the rat serum were removed by other means. These results support the existence of a circulating opsonizing factor that is a heat labile non-antibody molecule, which results in the rapid clearance of a second dose via phagocytosis by liver macrophages [39].
Our group has been intensively studying the mechanism behind the ABC phenomenon. We have confirmed that the ABC phenomenon against PEGylated liposomes occurred in mice [43], rats [43], minipigs [44] and beagle dogs [45] for empty liposomes (containing no drug). We further showed that anti-PEG IgM production and the resulting ABC phenomenon triggered by PEGylated liposomes occurred in BALB/c nu/nu (T cell-deficient) mice, but not in SCID (T and B cells-deficient) mice. A similar observation was reported by Semple et al.
[46] with nude and SCID-Rag2 mice. They showed that B cells and immunoglobulins, but not T cells, are critical in the development of immune responses against PEGylated liposomes containing oligonucleo- tides. These data prove that anti-PEG IgM, produced by the splenic B cells that are independent of T-cell involvement, could play a significant role in the induction of the ABC phenomenon.
The so-called class-2 of thymus-independent antigens (TI-2) may provide an additional explanation for the mechanism of the ABC phenomenon induced by PEGylated liposomes. TI-2 antigens can induce an immunological response by extensively cross-linking the cell surface immunoglobulins of specific B cells, resulting in secretion of massive amounts of neutralizing antibodies including IgM and IgG from the B cells [47,48]. Cheng and co-workers [49,50] have demon- strated that anti-PEG antibody (IgM) obtained following immunization with PEGylated β-glucuronide recognizes the repeating -(O-CH2-CH2)n- subunit (16 units) of PEG. This raises the assumption that PEG polymer in PEGylated nanocarriers acts as a TI-2 antigen and the repeating subunit may be an immunogenic epitope of PEG and a binding site for the derived anti-PEG IgM.
Based on all the above-mentioned reports, we con- firmed that the ABC phenomenon is divided into two phases: the induction phase and effectuation phase. In the induction phase, the biological system is ‘primed’ by promoting the proliferation and differentiation of specific B cells (responsible for the antibody produc- tion and cell-mediated immune responses) in the marginal zone of the spleen in T-cell independent manner, resulting in anti-PEG IgM formation [51– 54]. The delayed effectuation phase is manifested from day 5 to day 21 after the initial dose, which is closely correlated with the time course for anti-PEG IgM production in response to initial dose. In this effectuation phase, a subsequent dose of PEGylated liposomes is rapidly opsonized by C3 fragments and cleared from the systemic circulation by the Kupffer cells in coordination with anti-PEG IgM and the complement system, as shown in Figure 1. Further, the magnitude of the ABC phenomenon is closely linked to the magnitude of anti-PEG IgM production by splenic B cells in response to an initial injected dose of PEGylated liposomes [55,56]. However, although removal of spleen from mice reduced anti- PEG IgM production, it failed to completely reverse the rapid clearance of PEGylated liposomes to normal control levels. This suggests that another serum factor(s) or cell(s) may contribute to this phenom- enon [43].
Once the PEGylated liposomes (first dose) reach the spleen, they bind and crosslink to surface immunoglo- bulins on reactive B cells in the splenic marginal zone and consequently trigger the production of an anti-PEG IgM that is independent of T-cell help. Upon adminis- tration of the second dose, if anti-PEG IgM, produced in response to the first dose, still exists in the blood circulation, it binds to the PEG on the liposomes, and subsequently activates the complement system, result- ing in opsonization by C3 fragments and enhanced uptake by Kupffer cells via complement receptor- mediated endocytosis.
Factors affecting the ABC phenomenon
There are many factors that have an impact on the ABC phenomenon including: animal species, lipid dose, time interval between injections, nanoparticle physicochemical properties and type of encapsulated drug (Figure 2).
Animal species
In various types of animal models (rats, rabbits, mice, guinea pigs, minipigs and beagle dogs), repeated intra- venous injection of PEGylated liposomes has been reported to elicit the ABC phenomenon [39,42]. However, the magnitude of the elicited ABC phenom- enon varied with the animal species. Suzuki et al. [44] reported that anti-PEG IgM production and the ABC phenomenon were not detected in mice treated with Doxil® (2 and 20 mg DXR/m2), while in minipigs trea- ted with Doxil® (2 mg DXR/m2), anti-PEG IgM produc- tion and the ABC phenomenon were significantly increased. Beagle dogs seemed to be more sensitive to Doxil® than rodents in triggering anti-PEG IgM and the ABC phenomenon [45]. This might be due to variations in the sensitivity of the immune system between dogs and rodents or due to differences in the pharmacoki- netics of the initial dose of PEGylated liposomes [45].
Lipid dose
There appears to be a strong inverse relationship between the extent of the ABC phenomenon and the phospholi- pid dose for the initial dose of PEGylated liposomes, regardless of liposomal phospholipid composition. The higher the lipid dose, the lower the ABC phenomenon [57,58]. We speculate that low concentrations of phos- pholipid could activate marginal zone B cells (MZ-B), and trigger anti-PEG IgM production, while higher initial doses of PEGylated liposomes could cause MZ-B to elicit immunological tolerance or anergy [59,60]. MZ- B cells are a specialized population of B cells that are located in the marginal zone of the spleen. They secrete antibodies that help to protect against blood-borne viruses and bacteria. Rats injected intravenously with doses higher than 5 μmol phospholipid/kg did not exhi- bit increased levels of anti-PEG IgM and the subsequent ABC phenomenon. On the other hand, the ABC phe- nomenon was significantly increased at phospholipid doses less than 1 μmol phospholipid/kg [58,61,62]. Such difference also might be due to difference in the pharmacokinetics of PEGylated liposomes and/or reac- tivity of MZ-B with PEGylated liposomes in different species as described above.
Time interval between injections
The induction and the magnitude of the ABC phenom- enon were dependent on the time between injections. Some reports demonstrated that no alteration in the clearance of encapsulated drugs was observed with repeat injections of PEGylated liposomes when the interval between the initial and subsequent injection was less than 2 days or more than 4 weeks [63,64]. Actually, Dams et al. [39] and our group [51,53,58] showed that the extent of the ABC phenomenon was highest when the interval between two injections was from 4 to 7 days. This could be explained by the fact that the production of anti-PEG IgM occurred by 3–4 days after the initial dose [54,57] and the IgM disappeared within its biological half-life of 3 weeks [65].
Physicochemical properties of liposomes
The physicochemical properties of PEGylated liposomes such as size, lipid composition, extent of PEGylation and surface charge, all affected the extent of the ABC phenomenon. It has been reported that ‘classical’ (non- PEGylated) liposomes also induced the ABC phenom- enon when PEGylated liposomes were given as a subsequent dose [66]. We investigated the influence of surface charge and liposome size on the occurrence of the ABC phenomenon in mice. The ABC phenomenon was not induced when the initial dose of liposomes exhibited three different mean particle sizes (100, 400 and 800 nm) and three different surface potentials (+13,15, – 46.15 and −1.51 mV) [66]. On the other hand, the lipid composition of the liposomes did affect the appearance of the ABC phenomenon, e.g. use of phospholipids with long satu- rated acyl chains and inclusion of membrane stabilizers such as cholesterol and PEGylated lipid. In rats, the effect of phospholipid types in the initial dose of PEGylated liposomes on the ABC phenomenon was investigated using five different types of phospholipids (hydrogenated soy phosphatidylcholine, egg sphingomyelin, soybean phosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phos- phocholine and egg phosphatidylcholine). All PEGylated liposomes composed of different phospholipids signifi- cantly induced the ABC phenomenon. The PEGylated liposomes composed of unsaturated phospholipid induced the phenomenon more than the PEGylated lipo- somes composed of saturated phospholipid [66,67].
Encapsulated drug
It has been reported that the drugs encapsulated in PEGylated liposomes strongly affected the ABC phe- nomenon. PEGylated liposomes containing anticancer drugs such as DXR, oxaliplatin (l-OHP) and mitoxan- trone result in no induction of the ABC phenomenon [68–71]. We can hypothesize that chemotherapeutic agents encapsulated in liposomes accumulate in immune cells and hinder anti-PEG IgM production by inhibiting B cell proliferation and/or by damaging B cells in the marginal zone [70]. Indeed, there is no evidence that the clinical use of Doxil® causes the ABC phenomenon. However, Suzuki et al. [44] reported that intravenous injection of Doxil® at very tiny doses (0.2 mg/m2) triggers the ABC phenomenon in various animal species. These small doses contain very low total doses of lipids and low total doses of the drug. The low levels of DXR in small amounts of injected Doxil® may be below the threshold for inhibiting B cell secretion of anti-PEG IgM. A similar observation was reported by Nagao et al. [57] who demonstrated that intravenous injection of l-OHP- containing PEGylated liposomes at low doses (0.023 μg l-OHP/kg) could trigger a relatively high anti-PEG IgM response. On the other hand, at higher doses of l-OHP- containing PEGylated liposomes (2.3–2300 μg l-OHP/ kg), the l-OHP tended to inhibit the anti-PEG IgM response. Hence, low doses of PEGylated liposomal for- mulations in Phase 1 dose-escalation trials could concei- vably induce anti-PEG IgM and the ABC phenomenon confounding analysis of the Phase I pharmacokinetics. Furthermore, since low total doses of lipids trigger the ABC phenomenon to a greater extent than higher doses, this may also play a role in Suzuki’s observations.
Recent reports have demonstrated that multiple injections of PEGylated liposomes containing topotecan in beagle dogs and Wistar rats could trigger the ABC phe- nomenon [72,73]. Topotecan is a cell cycle-specific drug that exerts its inhibitory action in the S phase of the cell cycle. One can hypothesize that topotecan might not affect the B cell proliferation for B cells in other phases of the cell cycle and still allow them to produce some anti-PEG IgM. Another, more convincing hypothesis is that the rapid release of topotecan from liposomes could result in empty (drug-free) liposomes or drug-depleted liposomes in the blood circulation. The interaction of such drug-free or drug-depleted liposomes with the B cells in spleen could induce the production of anti- PEG IgM, rather than inhibiting its production, and lead to the induction of the ABC phenomenon upon repeated intravenous administration.
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