Drug delivery targets and strategies to address mast cell diseases

Abstract

Introduction: Current and developing mast cell therapeutics are reliant on small molecule drugs and biologics, but few are truly selective for mast cells. Most have cellular and disease-specific limitations that require innovation to overcome longstanding challenges to selectively targeting and modulating mast cell behavior. This review is designed to serve as a frame of reference for new approaches that utilize nanotechnology or combine different drugs to increase mast cell selectivity and therapeutic efficacy.

Areas covered: Mast cell diseases include allergy and related conditions as well as malignancies. Here, we discuss the targets of existing and developing therapies used to treat these disease pathologies, classifying them into cell surface, intracellular, and extracellular categories. For each target discussed, we discuss drugs that are either the current standard of care, under development, or have indications for potential use. Finally, we discuss how novel technologies and tools can be used to take existing therapeutics to a new level of selectivity and potency against mast cells.

Expert opinion: There are many broadly and very few selectively targeted therapeutics for mast cells in allergy and malignant disease. Combining existing targeting strategies with technology like nanoparticles will provide novel platforms to treat mast cell disease more selectively.

Keywords: Mast cells; allergy; cancer; cell targeting; mastocytosis; nanoparticles.

Figure 1.

Non-FcεRI-associated mast cell activating pathways (black lines) and their inhibition (red lines) by various drugs. G protein-coupled receptors are antagonized by a variety of small molecules that interfere with ligand binding or with intracellular signaling components. Phosphatases SHP and SHIP play a significant role in several inhibitory pathways involving kinases important to mast cell signaling.

Figure 2.

Examples of small molecules and antibodies used to inhibit (red lines) various activating pathways (black) associated with FcεRI signaling. Kinases tend to be the most frequently targeted components of mast cell activating pathways and are exclusively inhibited by small molecule drugs of varying selectivity. Antibody-based therapeutics can be used to inhibit (KIT and ST2/IL-1RAcP) or trigger inhibitory signals (Siglecs).

Figure 3.

Examples of malignant mast cell therapeutic strategies. Current clinical methods largely rely on small molecule kinase inhibitors (e.g. midostaurin, avapritinib, etc) which target and inhibit (red lines) mutant KIT activity (black lines). Historically, these drugs had broad kinase antagonistic activity responsible for many of their side effects. Recent iterations have resulted in more selective and better tolerated drugs. Receptor targeting strategies such as KIT or Siglec antibodies and antibody-drug conjugates have shown promise as potential therapeutic methods as well.

Figure 4.

Advantages of nanoparticles as drug delivery vehicles in the treatment of mast cell disease. (A) Nanoparticles can harbor and protect internal drug payloads from physiological threats such as enzymes, differences in pH, and unintended uptake by non-target cells. (B) Multivalent conjugation and surface presentation of targeting species enhance cell selective uptake by specific cell surface receptors. (C) The material composition and geometry of nanoparticles impacts cellular interactions and pharmacokinetics to allow optimization of drug delivery and cell selectivity. Nanoparticle composition, geometry, and morphology can range from small solid core micelles to larger more complex architectures such as vesicles, nanocages and filaments, each with unique degradation, pharmacokinetic, and pharmacodynamic properties. (D) Nanoparticle surface chemistry, size and payloads can be optimized to avoid unwanted cellular interactions such as innate inflammatory reactions or non-specific payload delivery.