Nanosponges Clean up Antibody-mediated Autoimmune Disease
What does lupus, rheumatoid arthritis, type I diabetes, multiple sclerosis, and rheumatic heart disease have in common? All of these (and many other) apparently unrelated disorders are caused by autoimmunity, in which the immune system produces antibodies that attack normal, healthy cells and tissues. Currently considered incurable, these autoimmune diseases can be managed, but to varying degrees and not without serious side effects. Moreover, autoimmune diseases include a wide range of dysfunctional immune responses known as type II, type III, and type IV immune hypersensitivity reactions.
Recently researchers demonstrated a novel pathophysiologically-inspired nanoengineering approach to the management of type II hypersensitivity reactions — Type II is caused when antibodies produced by the immune response bind to intrinsic or extrinsic antigens on the surfaces of healthy cells. (Antigens, typically microorganisms and chemicals, provoke an immune response and, if foreign or toxic, bind to a specific antibody.)
The researchers demonstrated in a murine model (mice) of antibody-induced anemia that by successfully acting as alternative targets for anti-RBC antibodies, polymeric nanoparticles coated with intact red blood cell (RBC) membranes – which the scientists term RBC antibody nanosponges ( or ANS for short and yes, nanosponges) – counteracted the effect of pathological antibodies without requiring pharmaceutical immune suppression and thereby protected circulating healthy RBCs.
The nanosponges reduced antibody binding to healthy RBCs by up to 95% in a test tube study, and mice injected with anemia-inducing antibodies followed by injection with the nanosponges showed improvements in anemia-related parameters compared with mice injected with antibodies and nanoparticles not coated with an RBC membrane.
“In type II immune hypersensitivity, the antibodies produced by the immune system bind to the antigens on the patients’ own cells, thus causing the cells to be destroyed,” said Prof. Liangfang Zhang, head researcher.
“While current treatment is largely relying on broadly suppressing the immune system, which is non-specific and likely to induce adverse side effects, RBC nanosponges serve as an ideal decoy to absorb these pathological antibodies and thus divert them away from the cellular targets,” he continued.
In so doing, the RBC nanosponges can deplete the level of circulating antibodies, and so save natural RBCs without introducing any therapeutic drugs – and more importantly, Zhang adds, these particles themselves are completely biocompatible and biodegradable, so they can be broken down to small molecules and leave nothing that is harmful to the body.
In addition, the team has developed an established protocol to fabricate these biomimetic nanoparticles consisting of synthetic polymeric cores surrounding by natural RBC membranes: the core ensures mechanical stability by supporting the RBC membrane shell, while membrane provides an ideal stealth coating that evades immune recognition.
Since the major challenge to achieving long circulation is attack by the immune system, this “stealth” feature allows the nanoparticles to circulate in the bloodstream for longer periods of time, which has significant clinical impact in sustained systemic cargo delivery or toxicant clearance.
That said, there is another major challenge of using the nanosponges to absorb pathological antibodies. That is to determine how many antibody nanosponges — in other words, the dosage — are needed in order to remove sufficient amount of the antibodies and thus to reduce symptoms.
While the scientists were inspired by antibody-driven pathology in general, they are particularly interested in type II immune hypersensitivity, where the antibodies produced by the immune system bind to the antigens on the patient’s own cells and thereby cause the cells’ destruction.
“The key innovation was to create a biomimetic nanoparticle that serves as an antibody decoy to absorb and arrest the pathological antibodies that otherwise will bind to natural cells and destroy them,” Zhang says. “These biomimetic nanoparticles are about 120 nm in size, circulate for days in the blood stream to absorb pathological antibodies, and are eventually broken down safely by the liver, leaving nothing toxic.”
In addition to how nanosponges clear pathological antibodies from the bloodstream in the RBC protocol discussed in the paper, the team was quick to point out that for other types of type II immune hypersensitivities it depends on the cell types the autoantibodies target.
“The reported RBC nanosponges can be applied to clear all autoantibodies that target RBCs. If they target other types of cells, we can use those cells to fabricate the types of nanosponges needed to treat those particular type II hypersensitivities.”
Moving forward, the scientists are focused on further validation of RBC antibody nanosponges for the treatment of RBC-related type II immune hypersensitivity in different animal models – the goal being human clinical trials – and are investigating other antibody nanosponges fabricated from various cell types.
“This study certainly advances the development of nanotechnology and bioengineering research by providing a unique and robust nanoparticle platform that combines the strengths of both synthetic nanoparticles and natural cellular membranes,” Zhang concludes. “It will therefore also benefit a broad range of biomedicine research by providing a new therapeutic option that offers opportunities for selective disease intervention while minimizing risk and side effects associated with many traditional drug-based therapies.”
For anyone suffering from an autoimmune disease, this might just be the news they were waiting on. Anyone who suffers from one can tell you, it can be a very personal brand of hell with little to no relief. Fingers crossed that this pans out and we can start better treating the problem.
Copp JA, Fang RH, Luk BT, Hu CM, Gao W, Zhang K, & Zhang L (2014). Clearance of pathological antibodies using biomimetic nanoparticles. Proceedings of the National Academy of Sciences of the United States of America, 111 (37), 13481-6 PMID: 25197051