Keun Ah Ryu

Bio: Keun Ah Ryu is an academic researcher from Merck & Co.. The author has contributed to research in topics: Dendritic cell & Immune system. The author has an hindex of 11, co-authored 22 publications receiving 584 citations. Previous affiliations of Keun Ah Ryu include Pohang University of Science and Technology & Calvin College.

In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity

Abstract: The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

Ammonium Fluoride Mediated Synthesis of Anhydrous Metal Fluoride-Mesoporous Carbon Nanocomposites for High-Performance Lithium Ion Battery Cathodes

Abstract: Metal fluorides (MFx) are one of the most attractive cathode candidates for Li ion batteries (LIBs) due to their high conversion potentials with large capacities. However, only a limited number of synthetic methods, generally involving highly toxic or inaccessible reagents, currently exist, which has made it difficult to produce well-designed nanostructures suitable for cathodes; consequently, harnessing their potential cathodic properties has been a challenge. Herein, we report a new bottom-up synthetic method utilizing ammonium fluoride (NH4F) for the preparation of anhydrous MFx (CuF2, FeF3, and CoF2)/mesoporous carbon (MSU–F–C) nanocomposites, whereby a series of metal precursor nanoparticles preconfined in mesoporous carbon were readily converted to anhydrous MFx through simple heat treatment with NH4F under solventless conditions. We demonstrate the versatility, lower toxicity, and efficiency of this synthetic method and, using XRD analysis, propose a mechanism for the reaction. All MFx/MSU–F–C prep...

Directing the immune system with chemical compounds.

Abstract: Agonists of immune cell receptors direct innate and adaptive immunity. These agonists range in size and complexity from small molecules to large macromolecules. Here, agonists of a class of immune cell receptors known as the Toll-like receptors (TLRs) are highlighted focusing on the distinctive molecular moieties that pertain to receptor binding and activation. How the structure and combined chemical signals translate into a variety of immune responses remain major questions in the field. In this structure-focused review, we outline potential areas where the tools of chemical biology could help decipher the emerging molecular codes that direct immune stimulation.

Stimulation of innate immune cells by light-activated TLR7/8 agonists.

Abstract: The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-κB production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population.

Guidelines and trends for next-generation rechargeable lithium and lithium-ion batteries.

Abstract: Commercial lithium-ion (Li-ion) batteries suffer from low energy density and do not meet the growing demands of the energy storage market. Therefore, building next-generation rechargeable Li and Li-ion batteries with higher energy densities, better safety characteristics, lower cost and longer cycle life is of outmost importance. To achieve smaller and lighter next-generation rechargeable Li and Li-ion batteries that can outperform commercial Li-ion batteries, several new energy storage chemistries are being extensively studied. In this review, we summarize the current trends and provide guidelines towards achieving this goal, by addressing batteries using high-voltage cathodes, metal fluoride electrodes, chalcogen electrodes, Li metal anodes, high-capacity anodes as well as useful electrolyte solutions. We discuss the choice of active materials, practically achievable energy densities and challenges faced by the respective battery systems. Furthermore, strategies to overcome remaining challenges for achieving energy characteristics are addressed in the hope of providing a useful and balanced assessment of current status and perspectives of rechargeable Li and Li-ion batteries.

Towards personalized, tumour-specific, therapeutic vaccines for cancer

Abstract: Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific. As a result of the diversity of tumour neoepitopes between individuals, the development of personalized cancer vaccines is warranted. Here, we review the emerging field of personalized cancer vaccination and discuss recent developments and future directions for this promising treatment strategy.

TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy.

Abstract: Tumour-associated macrophages are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet, macrophages are highly plastic and can also acquire an anti-tumorigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNP-R848) lead to efficient drug delivery to tumour-associated macrophages in vivo. As a monotherapy, the administration of CDNP-R848 in multiple tumour models in mice altered the functional orientation of the tumour immune microenvironment towards an M1 phenotype, leading to controlled tumour growth and protecting the animals against tumour rechallenge. When used in combination with the immune checkpoint inhibitor anti-PD-1, we observed improved immunotherapy response rates, including in a tumour model resistant to anti-PD-1 therapy alone. Our findings demonstrate the ability of rationally engineered drug-nanoparticle combinations to efficiently modulate tumour-associated macrophages for cancer immunotherapy.

Big opportunities for small molecules in immuno-oncology

Abstract: Small-molecule drugs have several advantages that are complementary to, and possibly synergistic with, biologic approaches for anticancer immunotherapy. This Review provides an overview of immunological pathways that can best be targeted with small molecules and discusses how these approaches fit into the armamentarium of immunotherapeutic strategies for cancer. The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein–protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms — modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration — are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.

Acid-Activatable Versatile Micelleplexes for PD-L1 Blockade-Enhanced Cancer Photodynamic Immunotherapy

Abstract: Photodynamic therapy (PDT) has emerged as a promising clinical modality for cancer therapy due to its ability to initiate an antitumor immune response. However, PDT-mediated cancer immunotherapy is severely impaired by tumor-cell immunosuppression of host T cell antitumor activity through the programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) (PD-L1–PD-1) immune checkpoint pathway. Here, we demonstrate that PDT-mediated cancer immunotherapy can be augmented by PD-L1 knockdown (KD) in tumor cells. We rationally designed a versatile micelleplex by integrating an acid-activatable cationic micelle, photosensitizer (PS), and small interfering RNA (siRNA). The micelleplex was inert at physiological pH conditions and activated only upon internalization in the acidic endocytic vesicles of tumor cells for fluorescence imaging and PDT. Compared to PDT alone, the combination of PDT and PD-L1 KD showed significantly enhanced efficacy for inhibiting tumor growth and distant metastasis i...