Recent advances in neonatal Fc receptor targeted drug delivery systems / 药学学报

The neonatal Fc receptor (FcRn) was first found to be a membrane protein that maternal antibodies transmitted to fetuses and newborns, and also expressed in multiple organs and tissues for whole life in adults. It plays a significant role to central regulate the lifespan of immunoglobulin G and serum albumin, as well as its involvement in innate and adaptive immune responses. In modern biopharmaceuticals, FcRn is a great potential drug delivery target and a highlighted subject for current research. This paper briefly describes the basic biological properties and action mechanism of FcRn, as well as the commonly used drug carrier design strategies of FcRn, especially the functional applications of prolonging half-life, targeted drug delivery, transmembrane and antigen presentation and so on. We propose that these distribution in different tissues and the diverse biological activities may have significant implications of targeting FcRn for novel drug delivery systems and immunotherapy.

Therapy of myasthenia gravis: looking forward to the era of targeted immunotherapy / 中华神经科杂志

Myasthenia gravis is mainly acetylcholine receptor antibody-mediated, T cells-dependent and complement participated acquired autoimmune disease characterized by impairment of the neuromuscular transmission. The main clinical feature of the disease is the presence of fatigability or muscle weakness. Most patients can be successfully managed with nonspecific immunotherapies such as corticosteroid and non-steroidal immunosuppressants. However, the side effects caused by long-term corticosteroid therapy are still a hurdle in the treatment of myasthenia gravis (MG). Oral non-steroidal immunosuppressants, as add-on therapy, can greatly reduce the relapse of the disease, but some drugs have a slow onset of action and the potential for significant toxicity, and even increase the risk of infection and neoplasms with long-term treatment. Despite these therapies, a minority of patients can be refractory because of incompletely responding or not well tolerated to available therapies. Thus, the need to avoid the use of corticosteroids, or at least reduce their use as much as possible should concern all patients with MG. Targeted immunotherapy is a therapeutic monoclonal antibody or antibody fragment targeting immune cells, complement, neonatal Fc receptor and cytokines. Recently, targeted immunotherapy has completed phase Ⅱ and Ⅲ clinical trials in patients with MG, and some of them have been approved by Food and Drug Administration. These promising biologics showed efficacy in symptoms persistent improvement, steroids reduction and were well tolerated, now evolving into powerful tools changing the algorithm of MG. This paper summarizes the results of clinical trials of new biologics in MG and looks forward to the prospect of MG treatment.

IgG Fc engineering to modulate antibody effector functions

Therapeutic monoclonal antibodies are among the most effective biotherapeutics to date. An important aspect of antibodies is their ability to bind antigen while at the same time recruit immune effector functions. The majority of approved recombinant monoclonal antibody therapies are of the human IgG1 subclass, which can engage both humoral and cellular components of the immune system. The wealth of information generated about antibodies has afforded investigators the ability to molecularly engineer antibodies to modulate effector functions. Here, we review various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype. Further, we will discuss proposed mechanisms by which engineering approaches led to modified interactions with immune components and provide examples of clinical studies using next generation antibodies.

The effect of pH and ligand density on the endocytosis and exocytosis process of FcBP decorated PEG-PCL micelles on Caco-2 cells / 药学学报

The difference in pH between apical and basolateral side of intestinal epithelial and pH dependence character of the combination of FcRn (neonatal Fc receptor) and ligand might improve the delivery of hydrophobic drugs by facilitating the transcytosis of nanocarriers. Here we designed FcBP (IgG Fc domain-binding peptides) decorated coumarin 6 (C6) loaded poly(ethyl ethylene phosphate)-co-poly(ε-caprolactone) (PEG-PCL) micelles with different ligand densities to study the effect of pH and ligand density on the endocytosis and exocytosis process of micelles on human colon adenanocaricinoma cell lines (Caco-2). Active micelles with different ligand densities and passive micelles were prepared using the thin-film hydration method. The size of the micelles was characterized by dynamic light scattering analysis and the morphology was observed by transmission electron microscope. The endocytosis and exocytosis of the micelles at pH 7.4 and pH 6.0, as well as the effect of FcRn on the endocytosis, were investigated by flow cytometry. The results showed that the size of micelles was about 30 nm, which was not affected by FcBP decoration. We found that pH and ligand density could both influence the endocytosis. The uptake of active micelles was higher at pH 6.0 than at pH 7.4, and an optimal ligand density of endocytosis was appeared in both pH environment. Then we proved that FcBP decorated micelles could be endocytosed at pH 6.0 and exocytosed at pH 7.4, and the exocytosis process was also related to ligand density. Micelles with 10% ligand density had the largest exocytosis, showing the potentiality to deliver drugs through the intestinal epithelial. In addition, the competitive inhibition experiments illustrated that the interaction between FcRn and FcBP were essential to endocytosis. The results will enhance the understanding on the FcBP decorated PEG-PCL micelles for transmemberane drug delivery.