Schematic of Selecta’s immune-tolerance SVPs, which are designed to program the immune system to tolerate a specific antigen without impacting the rest of the immune system. Courtesy of Selecta.
Schematic of Selecta’s immune-tolerance SVPs, which are designed to program the immune system to tolerate a specific antigen without impacting the rest of the immune system. Courtesy of Selecta.

Biological drugs promise a new era in more targeted treatments, but many therapies produce a strong response from the body’s immune system. When the immune system encounters a foreign agent or potential threat it produces antibodies. In the case of drugs or biologics, the formation of anti-drug antibodies (ADAs) can reduce efficacy and lead to allergic or extreme anaphylactic reactions. 

But researchers from Selecta Biosciences in Massachusetts believe that if polymer nanoparticles carrying an immune-suppressing agent are administered at the same time and in the same way as biological drugs, the immune response can be attenuated [Kishimoto et al., Nature Nanotechnology (2016), DOI: 10.1038/ nnano.2016.135].

“Today there is no comprehensive solution to the problem of immunogenicity,” says Peter Keller of Selecta. “Clinicians [have to] switch to other drugs [or] increase the dose of the biologic and use antihistamines or steroids to mitigate allergic reactions.”

The approach developed by Selecta, however, uses nanoparticles made from poly(lactic-co-glycolic acid) (or PLGA) – known as synthetic vaccine particles (SVPs) – to carry the immune-suppressing agent rapamycin. When the rapamycin-carrying nanoparticles are introduced into the body at the same time and by the same route as the biological agents or proteins,the combination appears to side step the immune system’s response.

“The nanoparticles are selectively taken up by antigen presenting cells in lymphoid organs and induce regulatory T cells which maintain immune tolerance to specific antigens,” explains Keller.

The rapamycin-carrying nanoparticles also reduce B cell activation, which signals the arrival of foreign agents to the body, and germinal center formation, where lymphocytes are produced in response to an infection. Taken together, these are tell tale signs that the rapamycin-carrying nanoparticles are inducing immunological tolerance (Fig. 1).

The team tested the approach with two biological drugs – an enzyme-based treatment for gout (pegloticase) and an anti-inflammatory drug adalimumab, which is used to help sufferers of rheumatoid arthritis. In both cases, the addition of rapamycin-carrying nanoparticles suppresses the normal development of ADAs enabling the active agents to work to their full capacity.

Giving rapamycin-carrying nanoparticles at the same time as the active biological agent appears much more effective than multiple daily doses of free rapamycin, which only suppresses the response of the immune system transiently. The researchers believe that the reason for this difference is that rapamycin-carrying nanoparticles are taken up lymphatic organs like the spleen, which play an important role in the immune response.

Federico Mingozzi of the French National Research Institute INSERM and team leader at non-profit research institute Généthon believes this is an important finding.

“The technology has the potential to change the safety and efficacy profile of protein-based therapeutics by changing dramatically their immunogenicity profile,” he says. “Additionally, the work demonstrates how nano-delivery of certain drugs, in this case rapamycin, completely changes their bioavailability and pharmacological profile.”

The approach is now being put into preclinical trials for the gout treatment pegloticase on human patients. “Beyond that, we have identified a number of drugs and several novel technologies for which [our approach] could drastically improve therapeutic outcomes and broaden the number of patients benefiting from these biologics,” says Keller.

This article was originally published in Nano Today (2016), doi:10.1016/j.nantod.2016.08.001