Source: https://www.nature.com/articles/s41541-018-0095-z?error=cookies_not_supported&code=c4616df9-c97a-4bb7-af56-0f7c820d7aa5
Timestamp: 2019-04-21 05:28:08+00:00

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In recent years, therapeutic monoclonal antibodies have made impressive progress, providing great benefit by successfully treating malignant and chronic inflammatory diseases. Monoclonal antibodies with broadly neutralizing effects against specific antigens, or that target specific immune regulators, manifest therapeutic effects via their Fab fragment specificities. Subsequently therapeutic efficacy is mediated mostly by interactions of the Fc fragments of the antibodies with their receptors (FcR) displayed on cells of the immune system. These interactions can trigger a series of immunoregulatory responses, involving both innate and adaptive immune systems and including cross-presentation of antigens, activation of CD8+ T cells and CD4+ T cells, phagocytosis, complement-mediated antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The nature of the triggered effector functions of the antibodies is markedly affected by the glycosylation patterns of the Fc fragments. These can cause differences in the conformation of the heavy chains of antibodies, with resultant changes in antibody binding affinity and activation of the complement system. Studies of the Fc glycosylation profiles together with the associated Fc effector functions and FcR/CR interactions promoted interest and progress in engineering therapeutic antibodies. Furthermore, because antigen–antibody immune complexes (ICs) have shown similar actions, in addition to certain novel immunoregulatory mechanisms that also reshape immune responses, the properties of ICs are being explored in new approaches for prevention and therapy of diseases. In this review, both basic studies and experimental/clinical applications of ICs leading to the development of preventive and therapeutic vaccines are presented.
Antibodies have been used for >100 years as effective therapies for infectious diseases. In the 1890s, pioneering studies from the laboratory of Robert Koch demonstrated that administration of sheep antiserum against diphtheria toxin to a girl dying from diphtheria led to her rapid recovery and ultimate survival.1 Later, more patients were treated with antibody therapy using horse antiserum against diphtheria toxin by von Behring and Kitasato, who were awarded the Nobel Prize. Since then, antimicrobial antibodies have also been used for the treatment of other infectious diseases, including bacterial pneumonia, staphylococcus infections, and septicemia.
Since the discovery of toxoid vaccines for prevention of tetanus and diphtheria, and the success of treating infections with antimicrobial drugs and antibiotics, the use of antibody therapies has been largely replaced by new and efficient therapies. To date, antitoxins against tetanus, and botulism, and pooled anti-rabies antibodies are still in use for prevention and treatment of the corresponding diseases. Pooled hyper-immune immunoglobulins for hepatitis B are recommended as passive immunization in combination with preventive vaccination for blocking perinatal transmission. Polyclonal immunoglobulins for hepatitis A and measles are used in people at risk or under emergency exposure. Respiratory syncytial virus (RSV) antibodies are used in infants born with low body weight, who may undergo a life-threatening episode of infection.
Development of murine monoclonal antibodies led to renewed interests in antibody therapy. However, low efficacy and the development of a human anti‐murine antibody (HAMA) response in patients has hampered the general use of these antibodies in clinics. During the last two decades, new technologies for generating mouse/human chimeric monoclonal antibodies and humanized monoclonal antibodies have resulted in more successful clinical antibody applications. Interest in antibody therapies has been further stimulated by the development of broadly neutralizing monoclonal antibodies against infections and monoclonal antibodies that target immune checkpoints for treatment of inflammation and immune disorders. Furthermore, rapid developments from studies on antibody structures and functions, from genetic engineering technology for mass production of proteins and from novel methods of applying therapeutic antibodies have further boosted interest. Studies of the immune mechanisms initiated in cells by Fc–FcR interactions, have resulted in perception of the immune regulatory roles of antigen–antibody immune complex (IC) as a double-edged sword being revisited and studied in more detail. Despite their potential for pathological effects, ICs have been explored as preventive in addition to therapeutic vaccines, first in poultry breeding, and later in human diseases. This review summarizes the background, the mechanistic studies on Fc–FcR functions, the translational research on Fc–FcR and the prospects of IC-based vaccines.
In early use as immunotherapies, rodent-derived monoclonal antibodies were relatively inefficient in human hosts. Most importantly, because mouse proteins are foreign to the human immune system, a human anti-mouse antibody (HAMA) response is elicited resulting in a rapid clearance of the mouse antibody and adverse reactions.3,4 Additionally, the Fc fragments of murine monoclonal antibodies are relatively inefficient in engaging in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are critical for immunological therapeutic effects. To overcome these disadvantages, engineered antibodies have been developed via multiple approaches. For example, to reduce immunogenicity of therapeutic mouse monoclonal antibodies, either the mouse Fc fragment or the whole antibody constant regions (CH1–CH3) were replaced with the human counterparts by means of genetic manipulations, whereas the mouse Fab or Fv (VH-VL) fragments retained the original epitope specificity.5 By these means, the immunogenicity to the human immune system is reduced by ≥70%.6 The first chimeric human–mouse monoclonal antibody, rituximab, was approved by Federal Drug Administration (FDA) in 1997.7 An alternative approach for production of chimeric human–animal antibodies is by using a humanized-rodent such as OmniRat that carries a chimeric human/rat IgH locus and a fully human Igκ or Igλ locus.8 In addition, fully human monoclonal antibodies can be produced after fusion of peripheral blood lymphocytes from immunized individuals, or immune B cells obtained at a disease recovery period, with human lymphoblastoid or lymphoma cell lines (human hybridomas).9 These important technologies have all contributed to facilitate the development of antibody therapy.
The rapid emergence of drug-resistant microbes, and newly emerging infectious diseases, together with the ever- increasing number of difficult-to-treat persistent infections, have shown an urgent need for the development of effective preventive and therapeutic antibodies for infectious diseases. Previously, a number of preventive and therapeutic polyclonal and monoclonal antibodies have been under research in academic laboratories, aimed at viral infections caused by rotavirus, Hantaan virus, parvovirus, yellow fever virus.23 To date, a number of polyclonal antibodies or immunoglobulins versus hepatitis B virus (HBV), hepatitis C virus, varicella zoster virus, RSV and cytomegalovirus, West Nile Virus and human immunodeficiency virus (HIV) are already being used in diverse applications. Monoclonal antibodies with high neutralizing potency, especially broadly neutralizing antibodies against these infectious agents have been explored. However, their preventive or therapeutic efficacies need further improvement. Importantly, monoclonal antibodies against infections can have a great impact in increasing our capability for rapid response to the public health challenges presented by newly emerging and re-emerging infectious diseases. Indications for the use of antibody therapies in endemic or epidemic of infectious disease have been advised, for treatment of infected individuals, for targeted prophylaxis to protect high-risk individuals, and for targeted prophylaxis to interrupt transmission to average-risk populations.24 During the 2014–2016 Zaire ebola virus outbreak in West Africa, ZMapp, a “cocktail” of three mouse–human chimeric antibodies, showed efficacy in nonhuman primates, but it has not been used in humans.24 In a recent outbreak of Ebola in Guinea, pooled convalescent plasma was used as an emergency treatment without identifying the neutralizing titer. Totally 84 patients received two consecutive transfusions of 200–250 ml of ABO-compatible convalescent plasma.25 Though results showed no improvement in survival, the limited data showed that under outbreaks of lethal infections, antiviral antibody therapies may be considered.
Antigen–antibody ICs can either cause immune pathological effects or potentiate beneficial immune effects, depending on various factors, including the subclasses of the antibody, the ratio between the antigen and the antibody forming the IC, the biological characteristics of the IC components, the sites where the ICs were formed, the cells involved and how the ICs were introduced into hosts etc. Table 1 shows comparisons between ICs causing pathological outcomes versus ICs inducing immune regulatory effects.
With the evolving progress of using therapeutic antibodies or immunoglobulins for treatment, in recent years, the immunopathological effects of ICs alongside with their therapeutic efficacies have been studied in depth. The conventional concept of IC-mediated immunological pathogenesis has been that, when ICs were not cleared by phagocytosis system, they remained in blood circulation and deposited on small vessel walls of various organs. These deposited ICs could exert damaging effects by binding to complement receptors on innate immune effector cells and result in inflammation and tissue injury. However, through studies on soluble ICs and their effects, it was observed that the fate of ICs in blood circulation is either to initiate immunopathological outcomes, or to react with receptors on immune cells initiating immunological regulations. Decreased binding of ICs to Fc receptors could affect biological outcomes. In a study to analyze elements involved in ICs binding to Fc receptors, the size of IC, IgG subclasses, glycosylation of IgG, all were found of relevance.45 Mechanistic study of the pathological injuries in arthritis patients and IC-induced nephritis revealed that binding of ICs to FcγRI (CD64) contributed to the severity of arthritis and hypersensitivity responses.46 In lupus nephritis, intra-capillary IC deposits selectively accumulated a proinflammatory population of 6-sulfo LacNAc+ (slan) monocytes (slanMo), which locally expressed TNF-α.47 The recruitment of slanMo from the microcirculation was via interaction with Fc γ receptor IIIA (CD16) and the slanMo then induced the production of neutrophil-attracting chemokine CXCL2, as well as TNF-α.
In microbial infections, more pathogenic mechanisms have been described. When ICs formed between non-neutralizing IgG and microorganisms that can replicate in macrophages, increased intracellular infections can occur and this was named intrinsic antibody-dependent enhancement (ADE) of infections.48 This ADE of infection modulates the severity of diseases such as dengue hemorrhagic fever and leishmaniasis. Intrinsic ADE is distinct from extrinsic ADE, because intrinsic ADE leads to an increased number of infected cells.48 The mechanism manifests as suppression of host innate immunity through idiosyncratic Fcγ, increased production of IL-10, a bias of Th1 responses towards Th2 responses and increased numbers of infected cells.
Recently, another new immune inhibitory mechanism of ICs was reported in a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection.49 The increased amounts of IC in the circulation during persistent infections, competed with FcγR binding and suppressed multiple aspects of FcγRs-dependent responses in vivo. The FcγR-mediated processes that were suppressed in vivo included activation of innate cells such as NK cells. By using transgenic mice expressing human CD20 and chronically infected with LCMV, virus antibody IC in circulation was shown to hamper the depletion of B cells by an anti-CD20 antibody (rituximab), a drug for treatment of B-cell lymphoma. In addition, FcR-dependent activation of dendritic cells by agonistic ant-CD40 antibody was decreased by the persistence of IC in these mice.50 Though these findings are not directly associated with IC pathogenicity, the data suggest that ICs could limit the effectiveness of therapeutic antibodies in humans.
In addition to their immune regulatory functions, ICs can effectively inhibit inflammatory responses. ICs were shown to inhibit the adaptive immune responses in an NLRP3-dependent model during priming of immune responses in vivo,67 suppression of both inflammasome activation and the generation of IL-1 alpha and IL-1 beta from antigen-presenting cells were observed. Recently, IL-2/IL-2 antibody IC was found to regulate HSV-induced inflammation through induction of IL-2 receptors alpha, beta, and gamma in a mouse model.68 The anti-inflammatory function has been widely employed in therapeutics for various diseases. A favored approach has been to use ICs in combination with cytokines and their antibodies. IL-2 complex treatment expanded both the NK and CD8+ T memory cell pool, including preexisting memory-phenotype T cells. In a renal ischemia–reperfusion injury (IRI) mouse model, IL-2 IC reduced expression of inflammatory cytokines and attenuated the infiltration of neutrophils and macrophages in renal tissue.69 IL-2 IC treatment has also been studied in experimental renal cancer.69 In experimental atherosclerosis, IL-2 IC in combination with anti-CD3 antibody markedly reduced atherosclerosis lesions.70 This effect was accompanied by a striking increase in the Treg/Teff ratio in the T cells in lymphoid organs and atherosclerotic lesions. Naive mice treated with a short course of IL-2 complexes showed enhanced protection from newly encountered bacterial and viral infections.71 However, increased IL-2 complex treatment generated CD8+ T cells and NK cells with a reduced capacity to produce IFN-γ, potentially suggesting some form of exhaustion occurred. Figure 1 summarizes the various known immunological functions of ICs (Fig. 1).
The content of this section has been published in a previous review,72 herein a short summary of IC vaccines and new developments is presented.
The first application of an IC vaccine was in the prevention of infectious bursa disease (IBD) in poultry. This viral infection targets the bursa of Fabricius and kill developing B cells. More recently, in an in ovo application of the IC vaccine against Newcastle Disease Virus (NDV) in maternal antibody-positive chickens, the birds were protected against clinical disease. An IC-based vaccine has also been used to protect pigs against pig parvovirus infections. This vaccine was shown to be both safe and ecologically convenient.
The first glimmer of success with an IC vaccine in HIV infections was reported by Hioe et al., who demonstrated that gp120 antigenicity and immunogenicity were significantly enhanced when gp120 was presented as an IC with anti-CD4 mAb 654-D. This enhanced the antigenicity and immunogenicity of gp120s from different HIV-1 strains and elicited neutralizing antibodies in mice.73 Later, Gp120/654 complex was shown to not only induce anti-gp120 antibodies to higher titers, they were also cross-reactive with V3 peptides from most subtype B and some subtype C isolates.74 Recently, a prime/boost immunization strategy was shown to facilitate Fc-mediated phagocytosis. Another research group used an SIV model to explore an IC vaccine as a topical preventive vaccine for women.75 They showed that an Simian Immunodeficient Virus (SIV) -specific IC could interact with the FcγRIIb receptor on the epithelium lining the cervix and block target cell recruitment.
The global prevalence of chronic HBV infection (CHB) is estimated to be around 250 million. Defects in cell-mediated immune responses and immune tolerance towards HBV are the key issues for chronicity. Restoration of effective cell-mediated immune responses has been explored in different Immunotherapeutic approaches.78 A recent review presented approaches to developing more effective therapeutic vaccines,79 suggesting to use more potent immunogens that can stimulate both T- and B-cell responses, developing a better prime and boost strategy, or employing immune checkpoint inhibitors in combination therapy.
The main obstacles for the development of therapeutic cancer vaccines are: tumor evasion from recognition by the host immune system, tumor inhibition of immune responses, and defective induction of adaptive immunity.90 In experimental studies, antitumor monoclonal antibody could generate antibody–tumor antigen ICs to initiate host immune responses.59 and IC-loaded DCs were shown to be superior to soluble ICs in tumor immunotherapy.56 More recently, scientists demonstrated that antibody–tumor antigen ICs engaged the hFcγRIIIA expressed by phagocytes to initiate ADCC, and engage the hFcγRIIA to stimulate DC maturation and presentation of tumor antigens to T cells.91 Despite all these excellent experimental studies, no IC cancer vaccine is currently under clinical trial. One potential candidate IC for cancer patients is IL-2-anti-IL-2 complex (IL-2 IC), which could extend IL-2 bioactivity from hours to days.92 Furthermore, the antibody component in the IC can be manipulated to interact with specific cellular receptors, focusing IL-2 towards specific cells such as CD8+ T cells, NK cells, and Treg cells.
Previously, a major handicap for developing IC vaccines for human use was the lack of appropriate human monoclonal antibodies for the construction of IC vaccines that would function properly through human Fc receptors. With the rapid development and production of different human monoclonal antibodies for therapeutic purposes, switching from polyclonal human immunoglobulin to specific human monoclonal antibody may significantly improve the efficacies of IC therapies. In addition, the use of ICs with modifications in the glycosylation of IgG can be employed to generate broadly neutralizing antibodies for protection against viruses that are prone to mutate.
With the experience gained in producing ICs with HBsAg and influenza HA and their respective antibodies, appropriate ratios and methodologies for the manufacture of ICs can be standardized to fulfill the regulatory requirements for clinical application. Furthermore, the recent development of a simple cellular assay of IC-mediated T-cell activation in vitro using human peripheral blood mononuclear cells, may help to evaluate the efficacy of ICs prior to clinical trials.95 Notably, due to the small dosage of monoclonal antibodies used to generate ICs, it will also be intrinsically less expensive to produce ICs than therapeutic antibodies. Furthermore, the tedious and expensive process of separately producing qualified antigen and antibody may be avoidable. Recombinant ICs can also be generated by fusing antigens with the Fc fragment of IgG into one molecule and expressing the construct in appropriate vectors.96 This experimental approach has been tested using plant biotechnology and immunization in mice.87 In addition, as shown in a recent study on allosteric communications in antibody–antigen recognition and FcR activation,97 more effective IC constructs may be generated.
Although extensive experimental studies have shown the immune regulatory effects of ICs, the application of ICs in vaccinology has only just started. As IC therapy is mediated through immune regulation, and immune responses initiated by IC can be pathological, as shown by transient elevation of ALT in certain IC-treated CHB patients. Careful monitoring of side effects during IC clinical trials is crucial. More field/clinical trials are clearly merited to finally substantiate and verify ICs’ contribution to vaccinology.
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This work was supported by the National Science and Technology Major Projects (2008ZX10002003, 2012ZX10002002004, 2012ZX10004701, 2013ZX1000200, and 2017ZX10202201002). Y.-M.W. has been supported by the 863 and mega scientific grant from 1988 till now. In particularly, we are grateful to Dr. Tian-Lei Ying of the Key Laboratory of Medical Molecular Virology of MoE & MoH, Shanghai Medical College, Fudan University for preparing the figure.
X.-Y.W., B.W., and Y.-M.W. worked on the development of antibody–antigen immunocomplex hepatitis B therapeutic vaccine, and conceived the manuscript. Y.-M.W. drafted the manuscript, X.-Y.W. organized the references and table, B.W. prepared the figure.

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