Selecta Bioscience Inc. published preclinical data this week suggesting its immune tolerance therapy SVP-Rapamycin (SEL-110), which is in a phase I trial to prevent the formation of antidrug antibodies (ADAs) to enzyme therapy for gout, could be broadly useful to prevent ADA formation to different types of biologics.

The results were published in the Aug. 1, 2016, online issue of Nature Nanotechnology.

Immune reactions to therapeutic proteins can run the gamut from annoying, to frustrating, to truly dangerous. But they are certainly common.

The reasons for an immune response depend on the nature of the therapeutic. Sometimes, proteins that are manufactured at very large production capacities can form microaggregates. For enzyme replacement therapies, the enzyme that is being replaced may not be produced by the body, which thus legitimately sees it as a foreign protein.

And with certain core complex biologics, such as viral vectors for gene therapy, "there is only so much humanization you can do," Selecta's chief business officer Peter Keller told BioWorld Today.

According to the FDA's 2014 industry guidance on "immunogenicity assessment for therapeutic protein products, premedication, desensitization, or immune tolerance induction procedures" can be explored as potential mitigation strategies for immune reactions to therapeutic proteins, though the agency also cautioned that given the risks of the approach, "the appropriateness of such procedures will depend on the nature of the specific indication, the target patient population, and the stage of development."

Some such strategies, such as pegylation and glycosylation, are in routine clinical use. But there's certainly room for improvement.

Some biological therapeutics rapidly lose their effectiveness due to the development of ADAs in the majority of patients. One example – though admittedly an extreme one – is the enzyme uricase, which can be used to treat refractory gout. Krystexxa (pegloticase, Horizon Pharma llc.) is a pegylated form of uricase that is approved for the treatment of refractory gout. Despite its pegylation, 90 percent of patients develop ADAs to Krystexxa.

Selecta has its own version of pegylated uricase, pegsiticase, in clinical development. (See BioWorld Today, June 19, 2016.)

In a phase Ia trial, pegsiticase was safe and reduced uric acid levels. But like Krystexxa, it induced ADAs in individuals receiving the treatment.

The company is currently comparing the immunogenicity of pegsiticase to SEL-212, which is a combination of pegsiticase and SEL-110, a tolerance-inducing nanoparticle.

The immune system, Selecta Chief Scientific Officer Kei Kishimoto told BioWorld Today, "has evolved to interrogate nanoparticulates," because any given nanoparticulate could be a virus – "it's something the immune system has to deal with."

As a result, nanoparticles are selectively taken up by antigen-presenting cells, which ultimately decide whether the immune system mounts a stimulatory or tolerizing immune response.

SEL-110 consists of a nanoparticle carrier made of poly(lactic-co-glycolic acid) (PLGA), and rapamycin. PLGA is a material with a long track record in biomedical applications – dissolvable sutures, among other things, are made from PLGA.

Rapamycin is a potent immunosuppressant. For tolerization, however, the goal is not immunosuppression – which does not outlast the presence of the drug – but resetting the immune system to permanently view another stimulus – in this case, the biological therapeutic – as benign.

For a tolerizing response, delivering rapamycin as part of a nanoparticle "because it focuses the activity in the antigen-presenting cells," Kishimoto explained.

In the studies now published in Nature Nanotechnology, the team showed that rapamycin-carrying nanoparticles, but not free rapamycin, could induce immune tolerance to both pegsiticase and anti-TNF alpha antibody Humira (adalimumab, Abbvie Inc.).

The effects of the nanoparticles were specific to the drugs, which needed to be co-administered with the nanoparticles for tolerance to develop. Once tolerance was induced by antigen-presenting cells, it was sustained by increased numbers of regulatory T cells and reduced activation of B cells.

Pegsiticase is administered intravenously, while Humira is administered subcutaneously. "Because we're giving the particle added on . . . we don't have to change the dose route," Kishimoto said, so particles are broadly applicable.

The approach could also be useful for treating autoimmunity. Selecta has partnered with Sanofi for two programs on food allergy and celiac disease, and has grant funding from Sanofi and the Juvenile Diabetes Research Foundation to work on type I diabetes.

The company plans to expand into gene therapy next, and announced in July that it will be testing SEL-110s ability to enable repeat dosing in two rare genetic metabolic disorders, methylmalonic acidemia (MMA) and ornithine transcarbamylase deficiency (OTC).

Currently, gene therapy that is not delivered to immunoprivileged sites – the eye or the brain "is very much restricted to a single application of the gene therapy," Keller explained, because of the immune reaction to the vectors when the first dose is delivered.

Preventing such antibody formation, Keller said, could "broaden the space in which you can apply gene therapy to many more indications."