ISR Platform

Today, biologics represent one of the fastest growing markets within the pharmaceutical industry.

The pipeline of biological drugs is growing at a rapid pace with a global market expected to reach approximately 380 billion USD in 2024.(1)

In order to bypass gastric metabolism, biologics are usually designed for the parenteral route of administration. However, this solution is cost intensive and tends to lower patient compliance.

On that note, subcutaneous injection offers a variety of benefits including self-medication, shorter administration time and therefore a better adhesion to the treatment as well as reduction of costs.

Today, 4,959 clinical candidates (2) are being investigated for subcutaneous routes, either new candidates or approved therapeutic products currently available for parenteral routes.

However, subcutaneous injection comes with some drawbacks.

Part of them are side effects that can dramatically decrease patient compliance making treatments less effective than they are supposed to be.

Frequently, the injection of some therapeutics formulation can lead to a fast and local inflammatory response characterized by swelling, erythema and pain.

Such a reaction is commonly known as injection site reaction (ISR), the most common reported adverse effect upon injection of a biologic drug (3), (4).

Immediate ISR are pseudo-allergic reactions recently reported to be triggered through a mast cells receptor, MRGPRX2, the human ortholog to the mouse MrgprB2 (5).

MRGPRX2 was found to be activated by a broad range of cationic substances such as neuropeptides, but also therapeutic drugs including beta-lactam antibiotics, chemotherapy agents, among others (6).

Delayed injection site reactions (happening within days post injection) can also be observed and are known to be driven by additional inflammatory mechanisms, most notably the recruitment of peripheral blood immune cells at the site of injection.

Therefore, identifying new drug-candidates that do not trigger mast cell dependent or independent ISR-like inflammatory responses ahead of clinical trials becomes crucial to ensure patient safety, comfort and compliance toward an injectable treatment.

Discovered over a century ago by Paul Ehrlich (7), mast cells are becoming a hot topic with more than 180,000 publications over the past 6 years (8).

They play a central role in allergic reactions and have an important implication in the defense against pathogens. Therefore, they are an asset in developing new drugs or improving existing ones.

To date, research on mast cells can be performed using rodent cell lines or human cell lines as well as human primary mast cells derived from peripheral blood (PB) or cord blood (CB). Mast cells can also be studied in situ, directly in living immunocompetent skin models.

Mast cells express various activatory receptors (some of them are described in Figure 1), and scientists are getting better at understanding the metabolism and molecular mechanisms behind their biological functions.

We describe below two key mast cell receptors involved in allergic and pseudoallergic reactions.

Mast cells are known for their implication in IgE-mediated disorders through their expression of the FcRI.

IgE antibodies can be found bound to FcRI circulating in the peripheral blood. The contact between an antigen and surface-bound IgE (specific of such antigen) will result in the crosslinking of FcRI and activation of mast cell degranulation. This will then trigger the release of pre-stored inflammatory mediators (9) such as histamine and proteases, and the secretion of de novo mediators9 such as cytokines or eicosanoids (10).

Briefly presented earlier, Human Mass-related G protein-coupled receptor X2 (MRGPRX2) is strongly present in connective tissue-type mast cells mainly located in the human skin. MRGPRX2 has been recently described as a major player in immediate injection site reaction, a severe hypersensitivity reaction that occurs in a significant number of patients treated with biological drugs. IgE-dependent or MRGPRX2-dependent mast cell activation typically results in an increase of vascular permeability, formation of oedema which will lead to different kinds of symptoms depending on the location of the mast cells. In the skin, typical symptoms will be urticarial reaction with itchiness and pain.