New drug solution use nanoparticles to induce immune tolerance

More than 100 approved drugs in the U.S. warn of immune-related side effects on their labels.

Countless others never make it onto shelves because of unwanted immune responses that can harm patients and limit the effectiveness of drug candidates.

Most gene therapies, for instance, use viruses to enter a person’s cells and alter their DNA.

But those viruses often elicit immune responses that can have unpredictable consequences and, in some cases, eliminate potential benefits associated with the treatment.

Selecta Biosciences is working to overcome those problems with a nanoparticle-based system, called ImmTOR, that has been shown to control human immune responses in preliminary clinical data.

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The central function of the immune system is the maintenance of immunological tolerance to self-components and innocuous exogenous antigens while eliminating malignant cells and dangerous pathogens.

Immunological tolerance, defined as the absence of immunity to an antigen even in the presence of otherwise immunogenic stimuli, is achieved through a combination of processes that lead to the elimination or inactivation of immune cells specific for the antigen and the development of regulatory T cells (Tregs).

The first and most impactful selection process, called central tolerance, eliminates lymphocytes recognizing self-antigens or leads to the differentiation of natural Tregs in the thymus.

Autoreactive cells can escape this process and survive to join the repertoire of mature circulating lymphocytes.

This pool of potentially dangerous cells can be further tolerized by encountering their cognate antigen in absence of immunogenic signals leading to anergy or the induction of adaptive Tregs and the establishment of peripheral tolerance (1).

For example, autoreactive lymphocytes specific for components of the nervous system can be identified in the circulation of animals and humans (2, 3).

These cells remain dormant and checked by regulatory T and B cells. Similarly, most “foreign” gut-associated antigens (microbial or dietary) are well tolerated and do not trigger pathogenic immune responses.

However, in presence of strong and persistent stimuli, lymphocytes specific for these antigens can break tolerance and launch attacks against self-components and innocuous antigens triggering disorders such as autoimmune diseases and food allergies, respectively.

Antigen-presenting cells (APCs), such as dendritic cells (DCs), are at the crossroads of immunity and tolerance (Figure ​(Figure1).1).

APCs sample and process antigens in the context of multiple complex cues from their environment.

The pivotal signals allowing APCs to instruct lymphocytes to acquire the expression of costimulatory molecules and support the development of immunity have been categorized as “danger signals.”

Such signals include pathogen-associated molecular patterns (4), damage-associated molecular patterns (5), changes in the tissue metabolic state (6), inflammatory cytokines (7), and costimulatory-molecule ligands (8).

Stimulation of APCs triggers a “maturation” program that includes activation of the NF kappa B (NF-κB) and mammalian target of rapamycin (mTOR) pathways and leads to metabolic changes and upregulation of costimulatory molecules, such as such as CD80, CD86, and CD40, and production of pro-inflammatory cytokines (9–11).

By contrast, antigen presentation in the absence of such costimulatory signals results in anergy and tolerance (12, 13).

APCs capable of tolerance induction include macrophages, B cells and DCs (14–17). Animals lacking DCs have a general failure in the establishment of self-tolerance, resulting in autoimmune conditions (18–22).

Whether an immature or steady-state phenotype is required for DCs to induce tolerance is still a matter of debate.

Recently the notion that tolerance is established by DCs that undergo incomplete maturation has been challenged by findings that tolerogenic DCs require transcriptional and epigenetic programs distinct from both steady-state (immature) and activated (mature) DCs (14, 19, 22–24).

Furthermore, there is conflicting evidence about the phenotypic characteristics that define tolerogenic DCs induced by immunomodulatory drugs.

For example, induction of tolerogenic capacities by treating DCs in vitro or in vivo with free or encapsulated rapamycin results in induced tolerogenic DCs (itDCs) of different phenotypes and maturation characteristics (e.g., expression of MHC-CLII and costimulatory molecules) (14, 25–30).

Regardless of the specifics of their phenotype, APCs constitute an ideal target to manipulate immune responses (Figure ​(Figure1).1).

Nanoparticles have unique properties that make them well suited to target APCs and deliver instructions that can modulate the nature of an antigen-specific immune response in vivo (31–35).Go to:

Why Nanoparticles?

The immune system has evolved to capture and interrogate virus-like (nanosized) particles (36, 37).

Such nanoparticulates are filtered out and accumulate in lymphoid organs, such lymph nodes and the spleen, and the liver.

This scavenger task is performed by APCs that are adept at phagocytosing and eliminating debris in the extracellular environment.

Synthetic nanoparticles of a wide array of materials in the range of 50 nm to 1 µm of size are readily phagocytosed by APCs (31, 32, 36–38).

The display of multimerized antigen on nanoparticles has been shown to be inherently immunogenic, similar to particulate or aggregated antigen (36, 37, 39).

Encapsulation or conjugation of antigens (both peptides and entire proteins) can lead to their presentation as a multimerized complex that has the potential to directly engage and cross-link of B cell receptors (BCRs), resulting in the activation of humoral immunity.

Indeed, many particle-based vaccines exploit these principles (encapsulation and multimeric display) to induce protective humoral immunity (38).

To engineer nanocarriers for the induction of tolerance, we and others have use materials and components that provide tolerogenic signaling to APCs or harness natural tolerogenic processes to override the inherently immunogenic nature of antigen-bearing nanocarriers.

The usage of synthetic tolerogenic nanoparticles (tNPs) confers several important advantages compared with other strategies to induce tolerance (Table ​(Table1).1).

Nanoparticles can employ a wide range of materials that can be optimized for various functions and can carry a diverse payload of antigens and immunomodulators to deliver coordinated messages to the immune system.

Table 1

Tolerogenic nanoparticle (tNP) composition, mechanism, and characteristics.

tNP composition	Mechanism	Characteristics	Reference
Peptide–major histocompatibility complex (MHC) complexes on metal-oxide NPs or peptide–MHC complexes plus anti-Fas ligand antibody	Antigen presentation w/o costimulation on synthetic antigen-presenting cell. Anti-FAS ligand antibody delivers apoptotic signal	Direct action on effector T cells, but requires complex manufacturing. Restricted to peptide antigens (antigen selection risk). Non-biodegradable	(40–42)
Protein or DNA-encoded antigen in poly(lactic-co-glycolic acid) (PLGA) or chitosan NPs	Oral tolerance	Ease of delivery via oral route. However, poor history of translation for oral tolerance	(43–45)
Peptides conjugated to polystyrene, PLGA, or poly(maleic anhydride-alt-1-octadecene) nanoparticles	Mimic apoptotic cells; target tolerogenic niche via MARCO+ macrophages in spleen or liver sinusoidal cells	Simple composition, but restricted to peptides and i.v. dosing. Potential to be stimulatory in inflammatory setting	(46–52)
Antigen encapsulated in liposomes containing phosphatidylserine (PS)	Mimic apoptotic cells TAM? Scavenger receptor-mediated uptake by macrophages	PS-binding scavenger receptors trigger TAM? receptors and tolerogenic response	(53–57)
NPs encapsulating tolerogenic cytokines and antigen	Anti-inflammatory cytokines create a tolerogenic microenvironment?	Complex manufacturing. Potential to create autoreactive immune response to endogenous cytokines	(58–60)
Liposomes presenting antigen and CD22 ligand	Induce antigen-specific B cell tolerance and deletion	Direct action on specific B cells. CD22 ligand is a complex sugar that is difficult to manufacture. Requires protein antigen	(61, 62)
Gold particles presenting peptide antigen and aryl hydrocarbon agonist	Trigger aryl hydrocarbon receptor (AHR) pathway	Utilizes an immunomodulator (AHR agonist) to lock in tolerogenic response. Restricted to peptides? Non-biodegradable	(63, 64)
Liposomes containing peptide antigen and antigen	Inhibit NF kappa B (NF-κB) pathway	Utilizes an immunomodulator (NF-κB inhibitor) to lock in tolerogenic response. Works with protein antigens and s.c. or i.v. route	(65)
Polylactic acid/PLGA NPs containing rapamycin + antigen (encapsulated or free)	Induce tolerogenic dendritic cells by inhibition of mammalian target of rapamycin pathway	Utilizes an immunomodulator (rapamycin) to lock in tolerogenic response. Works with both protein and peptide antigens and s.c. or i.v. route. Human proof of clinical activity demonstrated	(30, 66–72)

This review will focus on nanoparticle approaches for the induction of antigen-specific immune tolerance.

We define antigen-specific tolerance as the absence of immune response against an immunogenic target antigen, maintenance of tolerance after cessation of treatment, and retention of the ability to mount an immune response to an unrelated antigen.

There have been three broad approaches to achieving antigen-specific immune tolerance with nanoparticles (Figure ​(Figure2):2): (1) tNPs that provide antigen alone to harness natural tolerogenic processes or environments, (2) tNPs that provide antigen while targeting pro-tolerogenic receptors, and (3) tNPs that use pharmacological immunomodulators to force or “lock-in” a tolerogenic immune response against a target antigen.

Nanoparticle delivery of immunomodulators, in the absence of a specific target antigen, for the treatment of autoimmune diseases and prevention of graft rejection is beyond the scope of this review, although it is notable that this approach has demonstrated durable disease modification in animal models (73–76).

Similarly, nanoparticles that skew the immune response in an antigen-specific manner, such as Th1 polarizing nanoparticles for the treatment of Th2-mediated allergic diseases (77), are also not included in this review.

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The company is pairing its ImmTOR technology with biological drugs that can cause unwanted immune responses, to increase the drugs’ effectiveness and safety.

“Any time you’re faced with giving a drug that could be great but might lead to an immune response that leads to rejection or neutralization, this is a potential way to change that,” says Robert Langer, Selecta co-founder and the David H. Koch Institute Professor at MIT. “

Immune responses could be a good thing, but they could also be a bad thing.

With Selecta’s platform, you can modulate the immune system, turn it up or down.

It would really be the first time you could do that.”

The company’s lead drug candidate, currently in a phase 2 trial with the U.S. Food and Drug Administration, is aimed at treating a painful inflammatory condition called chronic gout.

Beyond that trial, Selecta is focused on enabling the repeated dosing of gene therapies, which it has already accomplished in mice and detailed in a recent Nature Communications paper.

Selecta’s team of researchers has made important progress in advancing the nanoparticle technology since the start of the company in 2008.

The foundations of the company, however, were largely laid at MIT.

Tiny particles with massive potential

The science behind Selecta’s ImmTOR technology has its roots in a 1994 paper published by Langer and others in the journal Science.

paper outlined a method for using biodegradable nanoparticles as a vehicle to control the circulation of drugs in the body.

Omid Farokhzad MBA ’15 came to Langer’s lab in 2001 as a postdoc and improved the technology’s ability to target specific types of cells.

Farokhzad also demonstrated the technology’s potential in a living organism for the first time.

Farokhzad joined the faculty of Harvard Medical School in 2004, where he is currently a professor and the director of the Center for Nanomedicine at Brigham and Women’s Hospital, but he and Langer have continued collaborating to this day.

In 2006, the two researchers published a highly cited paper showing how to use synthesized nanoparticles to deliver drugs to cancer cells.

In 2008, they founded Selecta Biosciences with Harvard immunologist Ulrich von Andrian, after von Andrian and Farokhzad realized it might be possible for the nanoparticles to control the immune system if they had the same shape and size as specific viruses.

The three founders began by working with MIT’s Technology Licensing Office to secure a significant portion of Selecta’s founding intellectual property.

Meanwhile, Langer leveraged his legendary network (nearly 1,000 scientists worldwide have been trained in his laboratory on campus) to help get the company off the ground.

To secure seed funding, he turned to two former-students-turned-investors, Polaris Venture Partners managing partner Amir Nashat Ph.D. ’03 and Noubar Afeyan Ph.D. ’87, the founder of investment fund Flagship Pioneering. The founders’ first hire was Lloyd Johnston SM ’92 Ph.D. ’96, who had previously worked for another company founded by Langer.

“I think of these companies as kind of like children growing up,” Langer says.

“In the beginning, the first year or two, you help on almost everything, and as the company gets older, they need – and often want – less and less support from you.”

At first, the company worked on developing vaccines by using the nanoparticles to activate the immune system in response to specific antigens.

But it later pivoted to use its technology to induce immune tolerance.

Farokhzad says tolerance is a much riskier, less explored path, but the rewards can be much higher if drugs earn FDA approval.

Today, Selecta’s team has optimized the nanoparticle technology to encapsulate specific compounds that regulate the immune system, known as “immunomodulators.”

The nanoparticles are injected into the body, accumulating in organs where immune responses are coordinated, and delivering the immunomodulator to specialized immune cells.

Then the drug is administered.

The immunomodulator makes the immune system tolerate the drug, mitigating the formation of antibodies against it and increasing the drug’s effectiveness and safety.

When paired with gene therapies, Selecta’s ImmTOR nanoparticle platform contains rapamycin, an immunomodulator that’s currently approved to prevent organ rejection after kidney transplants.

The rapamycin prevents the formation of antibodies that normally attack the virus, allowing the virus to effectively enter cells and edit genes.

The approach is a big upgrade compared to some other immunomodulators, which simply suppress the formation of all immune cells in the body.

Farokhzad likens Selecta’s technology to “engineering, or teaching,” the immune system to tolerate specific drugs.

The added sophistication brings a number of advantages.

For instance, the immune responses triggered by many gene therapies can cause harm to patients or wipe out the effectiveness of a second dose.

In Selecta’s recent Nature Communications paper, the company used ImmTOR to successfully re-administer these gene therapies in animals.

Redosing holds particular promise for children who may benefit from continued gene therapy treatment later in life.

Overall, Selecta believes unwanted immune responses are the biggest reason that drug candidates fail.

Company officials are hoping their technology can dramatically expand the applications of treatments like gene therapy and lead to better patient outcomes for every drug that’s hampered by immune responses.

Anywhere else, the company’s ambitious goals would stand out.

But in the greater Boston area, Selecta is just one of an ever-growing number of biotech companies with a past that can be traced back to MIT and a radical plan to transform the future.

Langer doesn’t think the booming biotech sector around MIT is a coincidence.

“MIT has great graduates, and people love to stay around here and see the things they do lead to products,” Langer says.

“That’s been great for Selecta and great for Cambridge and it’s why the Boston area is what it is today.”

More information: Amine Meliani et al. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration, Nature Communications (2018). DOI: 10.1038/s41467-018-06621-3

Journal information: Nature Communications , Science
Provided by Massachusetts Institute of Technology