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Biomimetic Nanosponges for Treating Antibody-Mediated Autoimmune Diseases Yao Jiang, Ronnie H. Fang, and Liangfang Zhang Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.7b00814 • Publication Date (Web): 22 Jan 2018 Downloaded from http://pubs.acs.org on January 23, 2018

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Bioconjugate Chemistry

Biomimetic Nanosponges for Treating Antibody-Mediated Autoimmune Diseases Yao Jiang, Ronnie H. Fang* and Liangfang Zhang* Department of NanoEngineering and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA. *

Corresponding authors: [email protected] or [email protected]

ABSTRACT Autoimmune diseases are characterized by overactive immunity, where the body’s defense system launches an attack against itself. If left unchecked, this can result in the destruction of healthy tissue and significantly affect patient wellbeing. In the case of type II autoimmune hypersensitivities, autoreactive antibodies attack the host’s own cells or extracellular matrix. Current clinical treatment modalities for managing this class of disease are generally nonspecific and face considerable limitations. In this review, we cover emerging therapeutic strategies, with an emphasis on novel nanomedicine platforms. Specifically, the use of biomimetic cell membrane-coated nanosponges that are capable of specifically binding and neutralizing pathological antibodies will be explored. There is significant untapped potential in the application of nanotechnology for the treatment autoimmune diseases, and continued development along this line may help to eventually change the clinical landscape.

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INTRODUCTION Under normal functioning, the immune system is in a state of dynamic equilibrium between pro-inflammatory and anti-inflammatory responses. Autoimmune diseases result from pathological immune responses targeted against an individual’s own healthy cells due to aberrant activities of autoreactive T cells or B cells.1 The susceptibility, onset, and progression of various autoimmune diseases are determined by a mixture of genetic and environmental factors, and many of the underlying mechanisms are still poorly understood. About 5% of the United States population is affected by more than 80 different kinds of autoimmune diseases,2 the most prevalent of which are Graves’ disease and rheumatoid arthritis.3 Interestingly, autoimmune diseases are not distributed evenly among genders, and 60% to 80% of patients affected by major ones like systemic lupus erythematosus (SLE) and multiple sclerosis are female.2, 4 Overall, quality of life can be significantly lowered due to the chronic nature of most these diseases. Autoimmune diseases, which generally include type II, III, and IV hypersensitivity reactions, can be classified as either systemic or organ-/tissue-specific.1 A significant portion of the latter fall under the umbrella of type II hypersensitivity reactions, which are mediated by antibodies that bind to non-soluble, self-antigens on cell surfaces or the extracellular matrix (ECM). These autoreactive antibodies trigger pathological effects in a variety of ways (Figure 1). In many cases, damage is induced when cell surface-bound IgG or IgM antibodies activate complement pathways, which can lead to the insertion of a membrane attack complex into the cell membrane and cause cytolysis. Otherwise, antibody opsonization can facilitate clearance and destruction of the target by immune cells. One example is Goodpasture's syndrome, in which specific domains of type IV collagen distributed in the ECM of the glomerular basement membrane are attacked, causing glomerulonephritis.5


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Figure 1. Mechanisms of antibody-mediated cell destruction in type II immune hypersensitivities. After opsonization by autoantibodies, the target cell is destroyed either by the complement system or by recruited immune cells.

Autoreactive antibodies can also cause the disruption of important cellular functions in a non-cytotoxic manner by binding to and blocking specific surface receptors. In the case of Myasthenia gravis, a long-term neuromuscular disease, antibodies target acetylcholine receptors on the postsynaptic membrane of muscle cells, preventing binding of the neurotransmitter acetylcholine and causing muscle weakness and fatigue.6 In contrast, the autoantibodies in patients with Graves' disease, a common autoimmune disease featuring hyperthyroidism, bind to thyrotropin receptor on thyroid tissues and act as agonists, which leads to the overproduction of thyroid hormones.7 It is worth pointing out that type II hypersensitivities not only arise from



intrinsic autoimmunity, but can also be induced by extrinsic factors when haptens from infections or drugs are attached to cell surface proteins, thus enhancing their immunogenicity. One example is drug-induced hemolytic anemia, where antibodies are developed against red blood cells (RBCs) after administration of certain drugs (i.e. cephalosporin, methyldopa, and penicillin) and cause intravascular hemolysis.8 Taken together, these autoimmune diseases place a significant burden on public health, and there is a great need for treatments that are both potent and specific. In this review, we begin by discussing current clinical standards, as well as other more experimental therapies for addressing type II autoimmune hypersensitivities. This is followed by an overview of nanomedicine and how such platforms have been applied towards managing autoimmunity. Finally, we highlight a recently developed cell membrane-coated nanosponge platform, which has been used for the direct neutralization of pathological autoantibodies. This new biomimetic nanotechnology offers a unique approach for addressing autoimmune diseases, and it may provide avenues for the future development of treatment modalities that can either supplant or supplement more traditional, nonspecific therapies.

CURRENT AND EMERGING TREATMENTS When it comes to autoimmune diseases, glucocorticoids have been clinically used for over 60 years to achieve broad-spectrum immunosuppression. Such treatments can be highly potent and affect multiple aspects of immunity, including the innate and humoral immune responses.9 They are cost-efficient, highly accessible, and can be used for symptom relief when the disease is idiopathic. However, due to their nonspecific nature, glucocorticoids systemically downregulate immune surveillance and thus increase a patient’s susceptibility to opportunistic


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infections, such as tuberculosis or pneumonia. In addition, they have other well-established side effects, including hyperglycemia, osteoporosis, and drug resistance after long-term treatment.10, 11

In addition to glucocorticoids, intravenous immunoglobulin (IVIg), which consists of pooled

serum IgG from thousands of donors, has also been used for many years to ameliorate immune thrombocytopenia purpura (ITP) and autoimmune hemolytic anemia (AIHA).12 The mechanism of its broad efficacy in immunosuppression, especially at high dosages, is still under investigation.13 Cytotoxic drugs such as cyclophosphamide are also used, in spite of their significant iatrogenic risks, as complements to glucocorticoids to achieve comprehensive immunosuppression.14 Generally, the potential adverse effects posed to the host immune system are directly related to the potency of the broad-spectrum immunosuppressant used.15 In extreme cases when the disease doesn’t respond to immunomodulatory drugs, surgery can be a last resort; this is the case for refractory immune thrombocytopenia purpura (ITP) or Graves’ disease, where clinicians perform splenectomies or thyroidectomies, respectively, to control symptoms.16, 17 More recently, there have been efforts to develop targeted therapies, exemplified by antibodies (i.e. adalimumab, infliximab, and natalizumab) that target critical pathological pathways. Tumor necrosis factor (TNF), a cytokine, and α4β1 integrin, an adhesion molecule critical for lymphocyte homing, are two of the most common targets; these proteins are produced in low amounts and are rate-limiting steps in inflammatory processes.18 Similarly, belimumab is an antibody that inhibits soluble B cell activating factor (BAFF), a potent B cell stimulant belonging to the TNF family of cytokines, and it has been approved for the treatment of SLE.19 One of the more current strategies directly relevant to type II hypersensitivity reactions is the administration of antibodies that deplete B cells. These generally target CD20, a B cell surface marker that has increasing expression levels throughout the maturation process.20 These



antibodies have variable efficacy, depending on an individual’s B cell status and CD20 expression levels.21 The most widely used is rituximab, a murine/human chimeric IgG1 antibody that promotes B cell lysis through complement-dependent cytotoxic effects.22, 23 Around 50% of ITP patients have a partial or complete response to initial infusions of rituximab, but only a portion sustain the response for longer than 6 months.24, 25 Unfortunately, more aggressive dosing has no additional benefit, and resistance to repeated therapy may exist in patients with relapsed ITP.25 To achieve higher response rates, computational design methods have been used to enhance binding affinity.26 To achieve longer response duration, improved pharmacokinetic halflives have been achieved via antibody modifications or employing humanized CD20-targeting antibodies.27, 28 Beyond their use for treating antibody-dominant autoimmune diseases like ITP, these depletion therapies have also recently been clinically approved for certain systemic autoimmune diseases in which autoreactive B cells significantly contribute to disease exacerbation, such as multiple sclerosis and SLE.22 While more specific than glucocorticoids, depletion of all CD20+ cells runs the risk of inducing hypogammaglobulinemia and can increase susceptibility to infections.29 Indeed, the current view is that a low level of autoreactivity actually has physiological significance,1 and the deletion of entire B cell populations or other important immune cell subsets may affect the delicate balance of the immune system.

NANOMEDICINE FOR AUTOIMMUNE DISEASES The last several decades have witnessed significant progress made in the application of nanotechnology towards the prevention, diagnosis, and treatment of diseases.30-33 Nanoparticles display unique properties at their small size scale and can be precisely engineered to carry out specific functions.34-38 With the appropriate surface modifications, nanoparticles can achieve


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prolonged circulation half-life while specifically targeting a site of interest in vivo.39-41 They can also be used to load a wide range of cargoes, including potent therapeutic drugs, and their material properties can be modulated to achieve sustained payload release over time or to bestow environmental sensitivity.42-44 These advantages have made them particularly well-suited for the drug delivery field, where numerous nanoformulations have been successfully translated to the clinic. More recently, nanoparticles have also been extensively studied for a wide range of other purposes, including detoxification and immune modulation.45-47 The application of nanoparticles towards autoimmune disease treatment is an emerging topic of study. The work in this area can be seen as a natural extension of immune-activating nanoplatforms, which have demonstrated impressive utility for applications like vaccination and cancer immunotherapy.46, 47 To date, nanoparticle-based immunosuppression has been implemented in several ways. Along the lines of traditional drug delivery, encapsulation of immunosuppressive agents can enable targeted delivery, high drug loading capacity, and controlled drug release, which can lower dosing frequency and reduce side effects from systematic exposure. All of this can help to improve patient compliance, especially given that most autoimmune diseases are chronic in nature. Additionally, many common immunosuppressants are hydrophobic, and their formulation into a long-circulating nanocarrier can greatly enhance bioavailability. For example, intravenously administered polymeric nanoparticles loaded with glucocorticoids have enabled better remission of inflammatory responses compared with free drug at three times the dosage in an anti-type II collagen antibodyinduced arthritis mouse model.48 Similarly, glucocorticoid-loaded liposomes ameliorated experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis, at a much lower dosing frequency than the corresponding free drug formulation.49



Beyond the use of immunosuppressive payloads, it has been discovered that some nanoparticles themselves can have tolerogenic properties. In one example, gold nanoparticles demonstrated specific inhibitory effects on toll-like receptor 9 signaling in macrophages in a size-dependent manner.50 Similarly, carboxylated polystyrene particles with negative zeta potential have been shown to prevent circulating monocytes from trafficking to sites of inflammation.51 This was shown to be dependent on the macrophage receptor with collagenous structure, and administration of the particles was able to ameliorate disease symptoms in numerous murine models of inflammation, including EAE. More recently, there has been significant interest in using nanoparticle-based systems for inducing specific immune tolerance (Figure 2). In cases where the target antigen is known, employing such a strategy can help to significantly reduce side effects common with broad immunosuppression. In one case, polymeric particles were using to deliver peptide or protein antigens along with the immunosuppressant rapamycin.52 These tolerogenic particles were able to inhibit cellular immune responses and induced long-term B cell tolerance in animal models of multiple sclerosis and hemophilia A. Co-administration of unencapsulated free rapamycin mixed together with antigen-bearing nanoparticles did not show the same tolerogenic effect, which highlighted the importance of co-delivery. Similarly, 60 nm gold nanoparticles with a polyethylene glycol (PEG) stealth coating carrying both EAE-relevant myelin peptide antigens and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, a tolerance-inducing molecule, suppressed EAE progression.53 This effect was mediated by a significant expansion of FoxP3+ regulatory T cells. The same platform was later used to deliver peptide antigens for use in treating a murine model of type I diabetes.54


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Figure 2. Nanoparticle-based platforms for inducing specific immune tolerance. (A) Schematic of polymeric tolerogenic nanoparticles (tNPs) co-encapsulating antigens and rapamycin. (B) When used to treat a murine model of hemophilia A, the tNP formulation is able to significantly reduce autoantibody titers compared with an empty nanoparticle (NP) formulation. Adapted with permission from ref 52. Copyright 2015 National Academy of Sciences. (C) Schematic of a tolerogenic PEG-coated gold nanoparticle formulation incorporating 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) and a myelin oligodendrocyte glycoprotein (MOG) peptide. (D) When used to treat an animal model of experimental autoimmune encephalomyelitis (EAE), the formulation is able to significantly control disease symptoms. Adapted with permission from ref 53. Copyright 2012 National Academy of Sciences.

Another nanoparticle-based strategy for inducing specific tolerance involves surface functionalization with tolerizing protein signals that engage receptors on immune cells. For example, liposomes displaying both B cell-specific antigens and ligands for CD22, an inhibitory 9 ACS Paragon Plus Environment


co-receptor, promoted apoptosis of antigen-specific autoreactive B cells.55 Particle-based killer artificial antigen presenting cells (KaAPCs) displaying multiple signals, including a specific peptide-MHC complex and Fas ligand (FasL), engage T cells in a similar fashion.56 The interaction between Fas and FasL can induce T cell apoptosis, thus achieving selective depletion of self-reactive T cells. Activated T cells, which are more pathogenic than their resting form, express more Fas on their surface, and are thus more susceptible to KaAPCs. More than 80% cytotoxic T cell elimination has been achieved in an antigen-specific fashion in vitro,57 and intravenous administration of KaAPCs prolonged graft survival for 43 days in a murine alloskin transplantation model.58

BIOMIMETIC ANTIBODY NANOSPONGES Within the field of nanomedicine, there has recently been significant interest in the development of biomimetic nanoparticles, which take inspiration from nature and allow synthetic materials to better interface with biological systems.59-62 Along this direction, cell membranecoated nanoparticles are an emerging platform, and they have shown promise for treating a wide range of different diseases.62-66 They are generally fabricated by cloaking a synthetic nanoparticulate core with naturally derived cell membranes. The resulting membrane-coated nanoparticles exhibit cell-specific properties that would otherwise be hard to replicate using purely synthetic approaches. Of note, employing this strategy can help to greatly enhance the biocompatibility of synthetic nanomaterials and reduce their immune clearance.67, 68 The nonimmunogenic nature of membrane-coated nanoparticles mitigates concerns regarding acute immune reactions as well as chronic immunity that can decrease performance over time. Depending on the type of membrane used, nanocarriers that are capable of effectively targeting


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different disease substrates can be fabricated.41, 65, 66 As such, membrane-coated nanoparticles have been extensively explored for the delivery of therapeutic and imaging payloads.62, 69 They have also demonstrated great utility for immunomodulation, aiding the design of potent vaccine formulations against cancer and bacterial infections.70-73 A unique application that has been enabled by the development of cell membrane-coated nanoparticles is biodetoxification.45 In a notable example, these nanoparticles have demonstrated utility for combating bacterial infections via an antivirulence mechanism.74 Virulence factors are employed by bacteria and exert toxic effects to facilitate survival and host colonization.75 Neutralizing these toxic secretions can help the immune system to more effectively fight off infection. Mechanistically, these protein-based toxins must interact with their cellular targets through their membranes, and this interaction is often mediated by lipid, protein, or carbohydrate receptors found on the cell surface.45 As such, this makes cell membrane-coated nanoparticles ideal for serving as toxin decoys. In essence, they can act as “nanosponges” that bind and neutralize toxins, sparing healthy cells from attack. By utilizing a function-based approach for achieving broad-spectrum neutralization, the nanosponge platform differentiates itself from traditional nanomaterial-based approaches that work by complementary structures.76 This concept has been demonstrated for a variety of different pore-forming toxins, including α-toxin from methicillin-resistant Staphylococcus aureus, streptolysin O from group A Streptococcus, and melittin from bee venom.74, 77 In each of these cases, incubation of the toxin with red blood cell (RBC) membrane-coated nanosponges was able to completely abrogate their toxic effects, reducing cytolysis and cytotoxicity in a dose-dependent manner. The presence of the nanoparticulate core serves to stabilize the membrane vesicles, which can otherwise be fusogenic and alone are unable to neutralize toxins.74, 78 In animal models of lethal toxin challenge,



administration of RBC nanosponges, either before or after, could significantly improve survival compared with no treatment. Subsequent studies have demonstrated that nanosponges can also neutralize toxic secretions of unknown composition,79 as well as small molecule chemical agents,80 making this strategy widely applicable and generalizable. Nanosponges for the treatment of type II immune hypersensitivities Instead of being used to neutralize exogenous toxins, the nanosponge concept has more recently been expanded for use against autoimmune antibodies. This novel approach has the potential to enable the targeted treatment of many forms of type II immune hypersensitivity, especially when the precise antigen eliciting autoimmunity is unknown. Much like their toxinneutralizing counterparts, the antibody nanosponge works by leveraging the natural interactions between the pathological antibodies and their cellular targets (Figure 3).

Figure 3. Antibody nanosponges for treating type II immune hypersensitivities. Under normal circumstances, autoantibodies will attack a target cell, leading to cellular destruction. Antibody nanosponges, which are coated with cell membrane containing the same antigens as the target cell, are capable of binding the autoantibodies, protecting the healthy cells from destruction.


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In the first example, an RBC-based nanosponge formulation was developed for treating AIHA (Figure 4), a typical type II hypersensitivity reaction in which anti-RBC IgG antibodies are produced by the host immune system.81 Fabricated by coating RBC membrane around a polymeric core, RBC antibody nanosponges were able to bind anti-RBC antibodies with the same affinity as native RBC ghosts, and this effect was not observed for control PEGylated nanoparticles. In vitro, the nanosponges were able to prevent the binding of anti-RBC autoantibodies to healthy RBCs in both pre-incubation and competitive scenarios. To test the in vivo stability of RBC antibody nanosponges complexed with anti-RBC antibodies, the two components were incubated together and then administered intraperitoneally into mice. In this case, no significant drop in major RBC-related parameters, including RBC count, hemoglobin concentration, and hematocrit, were seen. In contrast, mice administered with anti-RBC without the nanoparticles displayed a significant drop in all of the above parameters over the course of 4 days. In a more clinically relevant setup, a low dose of anti-RBC antibodies was administered intraperitoneally every day to induce anemia over time. Mice treated daily using intravenous injections of RBC nanosponges witnessed only a slight decline in RBC-related parameters. In contrast, the administration of PEGylated nanoparticles, which may actually potentiate anti-RBC reactions,82 did not receive any therapeutic benefit, demonstrating that the activity of the RBC antibody nanosponges resulted largely from the presence of membrane coating derived from the target cell.



Figure 4. RBC antibody nanosponges for treating autoimmune hemolytic anemia. (A) Electron microscopy image of RBC antibody nanosponges (RBC-ANS). Scale bar = 150 nm. (B) Dosedependent protection of RBCs by RBC-ANS from fluorescently labeled anti-RBC antibodies in vitro. (C) In vivo binding stability between RBC-ANS and anti-RBC antibodies. Anti-RBC antibodies were incubated with RBC-ANS before intraperitoneal administration. (D) Therapeutic efficacy of RBC-ANS when used to treat a murine model of antibody-induced anemia. AntiRBC was administered intraperitoneally, followed by intravenous administration of the RBCANS or a PEG-NP control. Adapted with permission from ref 81. Copyright 2014 National Academy of Sciences.

The antibody nanosponge concept was also demonstrated using platelet membranecoated nanoparticles for the treatment of ITP (Figure 5), another hematological autoimmune disorder that can lead to blood clotting dysfunction and uncontrolled bleeding upon injury.83 Like with RBC nanosponges, the platelet-based formulation was able to specifically bind anti-platelet antibodies. In vitro, the platelet nanosponges were able to significantly reduce binding of anti14 ACS Paragon Plus Environment

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platelet antibodies to intact platelets. Upon complexation of the nanosponges with anti-platelet antibodies, the biological activity of the antibodies was almost completely eliminated. After intraperitoneal injection of the complexes into mice, a majority had blood platelet counts in line with baseline levels, whereas antibody alone almost completely eliminated circulating platelets in a majority of mice. In a therapeutic scenario, anti-platelet antibodies were administered intraperitoneally, followed by platelet nanosponge intravenously. The mice treated with the nanosponge formulation had significantly improved platelet counts compared with untreated mice as well as those treated with PEGylated nanoparticles, demonstrating the specific effect of the platelet membrane coating. Impressively, all mice treated with the platelet antibody nanosponges had normal clotting function as assessed via a tail tip excision experiment.



Figure 5. Platelet antibody nanosponges for treating immune thrombocytopenia. (A) Electron microscopy image of platelet antibody nanosponges, referred to as PNPs. Scale bar = 75 nm. (B) Dose-dependent protection of platelets by PNPs from fluorescently labeled anti-platelet antibodies in vitro. (C) Therapeutic efficacy of PNPs when used to treat a murine model of antibody-induced thrombocytopenia. Anti-platelet antibodies were administered intraperitoneally, followed by intravenous administration of the PNPs or a PEG-NP control. (D) The bleeding times of the mice in (C) were evaluated by tail tip excision. Adapted with permission from ref 83. Copyright 2016 Elsevier.

Overall, these antibody nanosponge formulations have demonstrated considerable potential for addressing antibody-mediated type II hypersensitivities in a manner that is unique from any current treatment. A significant advantage of this approach is that, by simply knowing the cellular target, an appropriate formulation capable of binding polyspecific antibodies can be developed without the need for identifying specific self-antigens. This is especially important when considering that autoimmune diseases are highly heterogeneous and target a complicated mixture of generally unknown self-antigens.84 For example, glycophorin and protein band 3 are well-recognized targets on RBCs in AIHA, but anti-RBC autoantibodies do not exclusively react with these antigens. There have also been studies showing that the target antigen can shift throughout the progression of autoimmune diseases.85, 86 Unlike with other tolerogenic nanoformulations, nanosponges do not require the use of an immunosuppressive cargo, which may mitigate concerns about nonspecific immune downregulation and opportunistic infections. As these nanosponges can be fabricated from biocompatible and biodegradable materials, there is also little concern of toxicity associated with treatment. This is in contrast to some cell replacement therapies, which may lead to the production of toxic byproducts that can worsen a patient’s overall health.87


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CONCLUSIONS Autoimmune diseases, including type II hypersensitivities, oftentimes lead to chronic illness that can significantly affect quality of life or even lead to death. While current treatments like broad-spectrum immunosuppressive drugs and cell-depleting therapies can be effective, they carry significant side effects and iatrogenic risks. Through the advent of nanomedicine, emerging platforms for targeted delivery or specific antigen tolerance can help to address many of these issues. Antibody nanosponges are a novel biomimetic platform that takes a unique approach towards addressing antibody-mediated immune diseases, particularly those that lead to the destruction of cellular targets. By directly targeting the pathological autoreactive antibodies, nanosponges can specifically bind and neutralize the agents responsible for disease symptoms. This is made possible by the fact that they display the exact same surface receptors as the cells targeted by the autoimmunity, enabling them to serve as decoys that can divert away the autoantibodies. The use of these nanoparticles does not rely on prior knowledge of specific antigenic targets, which makes this strategy easily generalizable. It can be foreseen that, by employing different cell types as the source of the membrane coating, a wide range of type II autoimmune hypersensitivities can be treated using this approach. With their unique mode of action and broad applicability, antibody nanosponges may one day serve as a potent tool for helping clinicians better manage hard to treat autoimmune diseases.

ACKNOWLEDGEMENTS This work was supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense under Grant Number HDTRA1-14-10064.



AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail: [email protected] ORCID Liangfang Zhang: 0000-0003-0637-0654 Notes The authors declare no competing financial interest.


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