Selecta Biosciences is a precommercial drug developer focused on the emerging area of immune tolerance. Most investors probably haven’t heard of immune tolerance – and it certainly isn’t trending on FinTwit or being talked up by famous fund managers – but such tools hold significant potential to reduce one of the biggest limiting factors in drug development: Immunogenicity.

Immunogenicity is the ability of a substance to trigger an immune response. These substances, called antigens, aren’t inherently good or bad. Pet dander, pollen, respiratory viruses, and vaccines can each be an antigen. The determination of “good or bad” is made by interpreting the desirability of the immune response. When humans react to pollen it’s considered an inconvenient nuisance. When humans react to a virus or vaccine it’s considered an evolutionary marvel.

These immune responses tend to follow similar biomolecular sequences independent of the type of antigen encountered:

An antigen enters the bloodstream. The substance is interrogated by dendritic cells, a unique group of immune cells. If the antigen is labeled a threat, then dendritic cells send an immunogenic message – “prepare for battle!” – to the rest of the immune system. The body’s first line of defense against new threats are naïve T cells. These immune cells are on call 24/7 and exist prior to encountering an antigen. However, your immune system randomly creates billions of naïve T cells capable of binding to billions of unique threats. When a new threat is encountered naïve T cells rush in to interact with the antigen. Most will be ineffective, but some will bind tightly to the antigen – it’s purely a numbers game. These naïve T cells get to survive as memory T cells and helper T cells that are optimized for the new threat. Helper T cells travel throughout the immune system to control the activity of other immune cells by handing off accurate blueprints of the antigen. For example, these instructions are presented to B cells, which become factories for creating neutralizing antibodies (NAbs) optimized for a specific threat. The biomolecular cascade summarized above essentially explains how and why vaccines work. Unfortunately, it also explains why many biologic drugs don’t work.

Many biologic drugs are immunogenic, which means they trigger the creation of NAbs. Instead of neutralizing an antigen that’s an actual threat, these NAbs neutralize a drug that’s intended to help patients. The resulting immune response to an immunogenic drug (the mere process of creating helper T cells and B cells and NAbs) can also trigger side effects that reduce the safety of biologic drugs.

Don’t think immunogenicity is a major problem to drug development? Think again. An estimated 70% of individuals who receive the world’s best-selling drug, Humira (adalimumab), develop NAbs after a single dose. Only 4% of individuals who develop adalimumab NAbs achieve long-term remission, compared to 34% of individuals who don’t develop unwanted immune responses. And that’s Humira. Many drug candidates never make it through clinical trials due to immunogenicity challenges.

The global drug development industry spends tens of billions of dollars each year to engineer less immunogenic drug candidates. It’s a necessary component of modern drug development, but it’s not so simple. Many characteristics that make biologic drugs – monoclonal antibodies, enzymes, gene therapies, and so on – effective also make them immunogenic.

Immune tolerance presents another promising solution. What if, instead of triggering dendritic cells to send out an immunogenic (“prepare for battle!”) message, it was possible to send out a tolerogenic (“no threat detected!”) message? This is possible through a slightly different biomolecular cascade:

An antigen enters the bloodstream. The substance is interrogated by dendritic cells, which determine the antigen is not a threat. Naïve T cells receive the message and differentiate into regulatory T cells (Tregs) that promote a passive response by the immune system to that specific antigen. Selecta Biosciences is developing an immune tolerance technology platform based on ImmTOR, which can be co-administered with biologic drugs to mitigate the formation of NAbs against the drug. The platform could rescue drug candidates that were abandoned in clinical trials due to immunogenicity, help more patients respond to treatment, enable re-dosing of AAV gene therapies, or be used to restore self-tolerance in autoimmune disorders.

A recently unveiled next-generation tool called ImmTOR-IL appears to have considerable advantages over ImmTOR – and is likely to be swapped in for almost every pipeline program. ImmTOR-IL promises to (finally) put immune tolerance and Selecta Biosciences on the map.