Microencapsulation of therapeutic bispecific antibodies producing cells: immunotherapeutic organoids for cancer management

Regardless of the important therapeutic advances developed over the last years for the management of cancer, the fact is that many patients still suffer from a tremendous reduction on their quality of life due to lack of complete selectivity of conventionally administered chemotherapeutic drugs. In the search of more efficacious tumor-targeted therapies, the use of bispecific antibodies (bsAbs) capable of simultaneous binding to tumor-associated antigens and to an activating receptor, such as CD3, has emerged as a promising approach. With the intention to complementing and improving this cancer immunotherapy, human HEK-293 cells have been genetically modified ex vivo to secrete a recombinant anti-CEA (carcinoembryonic antigen)?×?anti-CD3 bsAb. After encapsulation in alginate-poly-l-lysine microcapsules, bsAb-secreting HEK-293 cells were monitorized for several weeks. This system has proved to be feasible for the maintenance of cell growth and recombinant antibody production giving proof-of-concept of its use as immunotherapeutic organoids in cancer treatment.     

Cancer immunotherapy using anti-TIM3/PD-1 bispecific antibody: a patent evaluation of EP3356411A1

Introduction: TIM3 and PD-1 are checkpoint inhibitors in cancer that coordinate the downregulation of the proliferation of antigen-specific lymphocytes. There is a great need to discover and develop new therapies focused on inhibiting the action of TIM3 and PD-1 and consequently improving the immune response in the various types of cancer. The authors of patent EP3356411A1 propose several anti-TIM3/anti-PD-1 bispecific antibodies, as well as the method for producing them and their pharmacological application in the treatment of cancer.

Areas covered: Patent EP3356411A1 describes a method by producing anti-TIM3/anti-PD-1 bispecific antibodies and their potential in cancer treatment.

Expert opinion: Data supporting the patent demonstrate the ability by producing anti-TIM3/anti-PD-1 bispecific antibodies. Although the proposed methodology is very interesting and promising, further studies are necessary to assess the clinical applicability of the inventions on cancer.     

Murine models of psoriasis and their usefulness for drug discovery

Introduction: Psoriasis is an autoimmune skin disease characterized by red plaques with silver or white multilayered scales with a thickened acanthotic epidermis. Using mouse models of cutaneous inflammation, IL-23/Th17 was identified to have a potential key role in psoriasis. New treatments to slow this inflammatory skin disorder are urgently needed. To aid their discovery, a psoriasis animal model mimicking human psoriasis is urgently needed for their early preclinical evaluation.

Areas covered: The authors review animal models of psoriasis and analyze the features and molecular mechanisms involved in these mouse models. The application of various mouse models of psoriasis for drug discovery and development has also been reviewed and the possible molecular targets in psoriasis for future anti-psoriatic drug design is discussed.

Expert opinion: So far, it has been difficult to create an animal model that exactly simulates a human disease or condition. The xenotransplantation model is regarded as the closest to incorporating the complete genetic, phenotypic, and immunopathogenic processes of psoriasis. However, the imiquimod (IMQ)-induced model is the most prevalent among psoriatic mouse models due to its ease of use, convenience, and low cost. Further efforts to develop psoriasis-like skin models in mice are needed for the study and treatment of this complex disease.     

A reporter gene assay for determining the biological activity of therapeutic antibodies targeting TIGIT

T cell immunoglobulin and ITIM domain (TIGIT) is a novel immune checkpoint that has been considered as a target in cancer immunotherapy. Current available bioassays for measuring the biological activity of therapeutic antibodies targeting TIGIT are restricted to mechanistic investigations because donor primary T cells are highly variable. Here, we designed a reporter gene assay comprising two cell lines, namely, CHO-CD112-CD3 scFv, which stably expresses CD112 (PVRL2, nectin-2) and a membrane-bound anti-CD3 single-chain fragment variable (scFv) as the target cell, and Jurkat-NFAT-TIGIT, which stably expresses TIGIT as well as the nuclear factor of activated T-cells (NFAT) response element-controlled luciferase gene, as the effector cell. The anti-CD3 scFv situated on the target cells activates Jurkat-NFAT-TIGIT cells through binding and crosslinking CD3 molecules of the effector cell, whereas interactions between CD112 and TIGIT prevent activation. The presence of anti-TIGIT mAbs disrupts their interaction, which in turn reverses the inactivation and luciferase expression. Optimization and validation studies have demonstrated that this assay is superior in terms of specificity, accuracy, linearity, and precision. In summary, this reliable and effective reporter gene assay may potentially be utilized in lot release control, stability assays, screening, and development of novel TIGIT-targeted therapeutic antibodies.     

A safety evaluation of guselkumab for the treatment of psoriasis

Introduction: Guselkumab is a fully human monoclonal IgG1λ antibody for the treatment of plaque psoriasis that inhibits interleukin (IL)-23p19 subunit, reducing the proliferation of type 17 helper T (Th-17) cells and thus production of Th-17-derived pro-inflammatory cytokines, especially IL-17 and IL-22.

Areas covered: In the following article, the mechanism of action and mainly the efficacy and safety profile of guselkumab available from results of trials will be discussed. We summarized these data after a literature review including PubMed search, relating proceedings and abstracts from relevant international conferences, assessment reports from European and United States regulatory agencies and treatment guidelines up to April 2018.

Expert opinion: The central role of IL-23 in psoriasis pathogenesis is supported by genetic links of IL-23 and IL-23R alleles to psoriasis susceptibility; early clinical trials have demonstrated that sufficient inhibition of IL-23p19 results in rapid resolution of the disease. Targeting IL-23, may be responsible for the high efficacy and durable responses of guselkumab, avoiding some adverse effects of IL-17A blockade, like mucocutaneous candida infections or triggering/worsening of inflammatory bowel disease, experienced with agents acting selectively against this molecule and that seem to be class related.     

A promising therapeutic target for psoriasis: Neuropeptides in human skin

Psoriasis is a chronic inflammatory skin disease featured by excessive proliferation of keratinocytes, clearly defined round erythema and dry, scaly plaques, long-term inflammatory cells infiltration in skin lesions. However, the physiopathological mechanism of psoriasis is still not clearly understood. Neuropeptides, a class of peptides secreted by the nervous system, may play important roles in promoting excessive proliferation of keratinocyte, enhancing angiogenesis, vasodilation, plasma extravasation and chemotaxis of inflammatory cells during the development of psoriasis. To understand the pathogenesis of neuropeptides in psoriasis, we summarized the function of several common neuropeptides in psoriasis and hypothesize neuropeptides may serve as therapeutic potential novel targets in psoriasis.     

New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents

Introduction: Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA.

Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs.

Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti-IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease.     

Naphthoquinones: A continuing source for discovery of therapeutic antineoplastic agents

Naturally occurring naphthoquinones, usually in forms of botanical extracts, have been implicated with human life since ancient time, far earlier than their isolation and identification in modern era. The long use history of naphthoquinones has witnessed their functional shift from the original purposes as dyes and ornaments toward medicinal benefits. Hitherto, numerous studies have been carried out to elucidate the pharmacological profile of both natural and artificial naphthoquinones. A number of entities have been identified with promising therapeutic potential. Apart from the traditional effects of wound healing, anti‐inflammatory, hemostatic, antifertility, insecticidal and antimicrobial, etc., the anticancer potential of naphthoquinones either in combination with other treatment approaches or on their own is being more and more realized. The molecular mechanisms of naphthoquinones in cells mainly fall into two categories as inducing oxidant stress by ROS (reactive oxygen species) generation and directly interacting with traditional therapeutic targets in a non‐oxidant mechanism. Based on this knowledge, optimized agents with naphthoquinones scaffold have been acquired and further tested. Hereby, we summarize the explored biological mechanisms of naphthoquinones in cells and review the application perspective of promising naphthoquinones in cancer therapies.     

Clinical Pharmacology 2008: Practical Information for Physicians,Nurses and Pharmacists

This annual Clinical Pharmacology update was sponsored by the UC Davis Health System, Office of Continuing Education and by the Department of Pharmacy and was located in the beautiful Napa Valley (CA, USA). The diverse and talented faculty of physicians and clinical pharmacists reviewed new medications and advances in state-of-the-art therapeutics, which are important in the treatment of disease.     

Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review

Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents.

Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004–2014).

Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI.

Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors.

Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.     

A novel therapeutic approach for Helicobacter pylori infection: the bismuth-based triple therapy monocapsule

Helicobacter pylori infection causes peptic ulcer disease and must be regarded as a serious infectious disease. Over the past two decades treatment of the infection has been a controversial issue. Treatment is purely empirical and based on combinations of two, three or four existing drugs. Antimicrobial resistance is important and an observed increase in the prevalence of resistance may change the relative importance of certain antibiotics. Bismuth-based triple therapy with bismuth, tetracycline and metronidazole is a well investigated, cheap and FDA approved regimen to cure the infection. Adding a proton pump inhibitor (PPI) increases efficacy. A novel monocapsule (‘Helicide^®’) that contains bismuth, tetracycline and metronidazole simplifies the regimen. This new and patient-friendly drug has been investigated in clinical studies and is expected to be released in North America in 2002.     

JAK-STAT inhibitors: Immersing therapeutic approach for management of rheumatoid arthritis

Rheumatoid arthritis is a world leading cause of musculoskeletal disease. With the introduction of biological agents as treatment alternatives the clinical possibilities have grown exponentially. Currently most common Disease-modifying anti-rheumatic drugs (DMARDs) treatment option involves intravenous or subcutaneous injection, and some patients struggle to respond to DMARDs or lose their primary reaction. An oral drug formulation with lowered costs of manufacturing and flexibility for healthcare workers to preferably perform treatment will result in decreased healthcare expenditures and increased medication compliance. The JAK-STAT inhibitors, a new class of small molecules drugs, fulfills these criteria and has recently shown efficacy in rheumatoid arthritis. Here we give a summary of how JAK-STAT inhibitors function and a detailed review of current clinical trials. Convincing clinical results suggest that therapeutic inhibition of the JAK proteins can effectively modulate a complex cytokine-driven inflammation.     

Redox-responsive smart nanogels for intracellular targeting of therapeutic agents: applications and recent advances

Abstract

Redox-responsive nanogels (NGs) can encapsulate appropriate amount of active ingredient, deliver drugs to the target cells by the enhanced permeability and retention (EPR) effect or specific targeted groups, and finally, rapidly release the loaded drug at the site of action when the redox-stimulus is applied. These programmed site-specific drug delivery features cause unique drug delivery control in the stimuli-responsive NGs and lead to superior in vitro and/or in vivo anti-cancer efficacy. Because of the high difference between the concentration of oxidative species in normal and tumour tissues, which is very important for biomedical applications particularly cancer therapy, the redox-responsive NGs have received much attention among various stimuli-responsive NGs. Thus, in this review, we attempt to summarise recent efforts to prepare innovative redox-responsive NGs and discuss recent advances in the interface between drug delivery and stimuli-responsive NGs that are able to control drug biodistribution in response to specific stimuli, with a particular emphasis on their design, drug release performance and therapeutic benefits.     

Changing therapeutic paradigms for exudative age-related macular degeneration: antiangiogenic agents and photodynamic therapy

Age related macular degeneration (AMD) is the leading cause of irreversible visual loss in the United States. Overall, approximately 10 - 20% of patients with AMD exhibit the exudative form, which is responsible for most of the estimated 1.2 m cases of severe visual loss from AMD. Visual loss develops in the exudative form of AMD due to abnormal choroidal neovascular membranes (CNVM) that develop under the retina, leak serous fluid and blood, and ultimately cause a blinding disciform scar in, and under, the retina. Currently, the only well-studied and widely accepted method of treatment is laser photocoagulation of the CNVM. However, only a minority of patients with exudative AMD show well-demarcated ‘classic’ CNVM amenable to laser treatment, and at least half of these patients suffer persistent or recurrent CNVM formation within two years. In addition, since the treatment itself causes a blinding central scotoma when the CNVM is located subfoveally, many clinicians do not treat subfoveal CNVM. With these treatment limitations, there has been a great deal of interest in alternative therapies for AMD, including anti-angiogenic agents and photodynamic therapy. Angiogenesis involves a complex interplay of cellular events involving a cascade of factors that are both inhibitory and stimulatory. Soluble growth factors have been the best-known cell modulating agents in ophthalmology, but there are a multitude of potential sites for inhibition of angiogenesis by pharmacological agents. With regard to photodynamic therapy, a photosensitising dye is injected intravascularly and low power laser light is used to activate the dye within the CNVM to cause vascular occlusion by a photochemical reaction. Closure of the CNVM is achieved without severe collateral damage to the non-vascular tissues as occurs with laser photocoagulation.     

Th17 cells: a promising therapeutic target for Parkinson’s disease?

Introduction: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder caused by the progressive loss of neurons in the midbrain and other brain regions. Only symptomatic treatment is currently available. Mounting evidence suggests that T cells are a key contributor to PD pathogenesis and neurodegeneration by a mechanism that requires further elucidation.

Areas covered: We discuss the evidence of imbalanced activation of effector T cell populations in PD and summarize the data of Th17 involvement and Th17-regulated mechanisms in PD pathology. Moreover, possible Th17-related molecular targets as possible neuroprotective immunomodulatory therapeutic targets for PD are examined.

Expert Opinion: Existing data show that Th17 cells, their effector molecules, and signaling pathways are potentially effective therapeutic targets for neuroprotective immunomodulation in PD treatment. However, specificity of action within Th17-mediated signaling pathways for PD requires careful consideration.     

Transdermal delivery of therapeutic agents using dendrimers (US20140018435A1): a patent evaluation

A method of treating CXCL13-mediated inflammatory diseases by the co-administration of a CXCL13 antagonist and a TNF-α antagonist is claimed. Their use is claimed to provide methods of treating asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis and systemic lupus erythematosus. The reported activity of such combinations in animal models provides evidence for the CXCR5 chemokine receptor as a potential drug target in such diseases.     

Thiazolyl‐N‐substituted amides: A group of effective anti‐inflammatory agents with potential for local anesthetic properties. Synthesis,biological evaluation,and a QSAR approach

A series of thiazolyl‐N‐substituted amides were synthesized and tested for anti‐inflammatory activity. Their R_M values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and log D_7.4 was also performed. The effect of the synthesized compounds on inflammation, using the carrageenan‐induced mouse paw edema model was studied. In general, the studied compounds were found to be potent anti‐inflammatory agents (23.2–72.1%). Anti‐inflammatory activity was influenced by some structural characteristics of the synthesized compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure–activity relationship approach (QSAR). A parabolic dependence of activity from clog D_7.4 and a linear dependence from surface tension were found. The anti‐inflammatory activity of the thiazolyl‐amides were found to a great extent to be under pharmacokinetic control. Drug Dev. Res. 48:53–60, 1999. © 1999 Wiley‐Liss, Inc.