Phase 1 trial supports safety and mechanism of action of peptide immunotherapy for peanut allergy.

BACKGROUND: Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy. METHODS: Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment. RESULTS: PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment. CONCLUSION: This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.

Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches.

Atopic dermatitis (AD) is a chronic, systemic, inflammatory disease that affects the skin and is characterized by persistent itch and marked redness. AD is associated with an increased risk of skin infections and a reduced quality of life. Most AD treatment options to date were not designed to selectively target disease-causing pathways that have been established for this indication. Topical therapies have limited efficacy in moderate-to-severe disease, and systemic agents such as corticosteroids and immunosuppressants present with tolerability issues. Advances in the understanding of AD pathobiology have made possible a new generation of more disease-specific AD therapies. AD is characterized by the inappropriate activation of type 2 T helper (Th2) cells and type 2 innate lymphoid (ILC2) cells, with a predominant increase in type 2 cytokines in the skin, including interleukin (IL)-13 and IL-4. Both cytokines are implicated in tissue inflammation and epidermal barrier dysfunction, and monoclonal antibodies targeting each of these interleukins or their receptors are in clinical development in AD. In March 2017, dupilumab, a human anti-IL-4Rα antibody, became the first biologic to receive approval in the United States for the treatment of moderate-to-severe AD. The anti-IL-13 monoclonal antibodies lebrikizumab and tralokinumab, which bind different IL-13 epitopes with potentially different effects, are currently in advanced-stage trials. Here, we briefly review the underlying pathobiology of AD, the scientific basis for current AD targets, and summarize current clinical studies of these agents, including new research to develop both predictive and response biomarkers to further advance AD therapy in the era of precision medicine.

Broad neutralization coverage of HIV by multiple highly potent antibodies.

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.

Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses.

Influenza remains a serious public health threat throughout the world. Vaccines and antivirals are available that can provide protection from infection. However, new viral strains emerge continuously because of the plasticity of the influenza genome, which necessitates annual reformulation of vaccine antigens, and resistance to antivirals can appear rapidly and become entrenched in circulating virus populations. In addition, the spread of new pandemic strains is difficult to contain because of the time required to engineer and manufacture effective vaccines. Monoclonal antibodies that target highly conserved viral epitopes might offer an alternative protection paradigm. Herein we describe the isolation of a panel of monoclonal antibodies derived from the IgG(+) memory B cells of healthy, human subjects that recognize a previously unknown conformational epitope within the ectodomain of the influenza matrix 2 protein, M2e. This antibody binding region is highly conserved in influenza A viruses, being present in nearly all strains detected to date, including highly pathogenic viruses that infect primarily birds and swine, and the current 2009 swine-origin H1N1 pandemic strain (S-OIV). Furthermore, these human anti-M2e monoclonal antibodies protect mice from lethal challenges with either H5N1 or H1N1 influenza viruses. These results suggest that viral M2e can elicit broadly cross-reactive and protective antibodies in humans. Accordingly, recombinant forms of these human antibodies may provide useful therapeutic agents to protect against infection from a broad spectrum of influenza A strains.

Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target.

Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from about 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses.

Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12.

Allergens are capable of polarizing the T cell immune response toward a Th2 cytokine profile in a process that is mediated by dendritic cells (DCs). Proteases derived from Aspergillus species (Aspergillus proteases; AP) have been shown to induce a Th2-like immune response when administered directly to the airway and without adjuvant or prior priming immunizations at sites remote from the lung in models of allergic airway disease. To explore mechanisms that underlie the Th2 immune response, we have investigated the effect of AP on DC function. We found that human DCs derived from CD14(+) monocytes from healthy donors underwent partial maturation when incubated with AP. Naive allogeneic T cells primed with AP-activated DCs proliferated and displayed enhanced production of IL-4 and reduced expression of IFN-gamma as compared with naive T cells primed with LPS-activated DCs. Global gene expression analysis of DCs revealed relatively low expression of IL-12p40 in AP-activated DCs as compared with those activated by LPS, and this was confirmed at the protein level by ELISA. Exogenous IL-12p70 added to cocultures of DCs and T cells resulted in reduced IL-4 and increased IFN-gamma expression when DCs were activated with AP. When the proteolytic activity of AP was neutralized by chemical inactivation it failed to up-regulate costimulatory molecules on DCs, and these DCs did not prime a Th2 response in naive T cells. These findings provide a mechanism for explaining how proteolytically active allergens could preferentially induce Th2 responses through limited maturation of DCs with reduced production of IL-12.

Amphiregulin expression in human mast cells and its effect on the primary human lung fibroblasts.

BACKGROUND: Amphiregulin is a member of the epidermal growth factor family and has been shown to stimulate the proliferation of human keratinocytes in an autocrine manner. OBJECTIVE: The aim of the present study was to examine the expression change of growth factors, especially amphiregulin, in human mast cells induced by IgE cross-linking. METHODS: Microarray analysis and RT-PCR were used to analyze the gene expression profile of human cord blood-derived mast cells (CBMCs) stimulated with IgE cross-linking. Protein secretion in the supernatants of CBMCs was measured by means of ELISA. Double-immunofluorescence staining was used to analyze the expression in the lung mast cells. RESULTS: Of the 64 different growth factor genes analyzed, 5 were found to be substantially upregulated. Among them, amphiregulin mRNA was induced by 44-fold in CBMCs on activation through IgE cross-linking. Secretion of amphiregulin protein was evident in CBMCs 8 hours after stimulation. Amphiregulin was also expressed in human lung mast cells from patients with asthma, as demonstrated by means of double-immunofluorescence staining. Amphiregulin promoted the proliferation of the primary human lung fibroblasts, and amphiregulin-treated primary human lung fibroblasts showed a marked increase in the expression of c-fos , a proto-oncogene that facilitates or is required for the proliferation of a wide variety of cells. CONCLUSION: Human CBMCs secreted amphiregulin on IgE cross-linking, and the amphiregulin induced proliferation of primary human lung fibroblasts. These data suggest that local release of amphiregulin by human mast cells could play an important role in lung fibrosis by promoting the proliferation of primary human lung fibroblasts.