Fc-Binding Antibody-Recruiting Molecules Targeting Prostate-Specific Membrane Antigen: Defucosylation of Antibody for Efficacy Improvement

<div> <div> <div> <p>Synthetic small molecules that redirect endogenous antibodies to target cells are promising drug candidates because they overcome the potential shortcomings of therapeutic antibodies, such as immunogenicity. Previously, we reported a novel class of bispecific molecules targeting the antibody Fc region and folate receptor, named Fc-binding antibody-recruiting molecules (Fc-ARMs). Fc-ARMs can theoretically recruit most endogenous antibodies, inducing cancer cell elimination via antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we describe new Fc-ARMs that target prostate cancer (Fc-ARM-Ps). Fc-ARM-Ps recruited antibodies to cancer cells expressing prostate membrane-specific antigen but did so with lower efficiency compared with Fc-ARMs targeting folate receptor. Upon recruitment by Fc-ARM-P, defucosylated antibodies efficiently activated natural killer cells and induced ADCC, whereas antibodies with intact N-glycans did not. The results suggest that the affinity between recruited antibodies and CD16a, a type of Fc receptor expressed on immune cells, could be a key factor controlling immune activation in the Fc-ARM strategy. </p> </div> </div> </div>

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HobPre: accurate prediction of human oral bioavailability for small molecules

Journal of Cheminformatics ◽

10.1186/s13321-021-00580-6 ◽

2022 ◽

Vol 14 (1) ◽

Author(s):

Min Wei ◽

Xudong Zhang ◽

Xiaolin Pan ◽

Bo Wang ◽

Changge Ji ◽

...

Keyword(s):

Drug Development ◽

Small Molecules ◽

Oral Bioavailability ◽

Computational Models ◽

Experimental Tests ◽

New Drugs ◽

Drug Candidates ◽

Drug Molecules ◽

Key Factor ◽

Input Variables

AbstractHuman oral bioavailability (HOB) is a key factor in determining the fate of new drugs in clinical trials. HOB is conventionally measured using expensive and time-consuming experimental tests. The use of computational models to evaluate HOB before the synthesis of new drugs will be beneficial to the drug development process. In this study, a total of 1588 drug molecules with HOB data were collected from the literature for the development of a classifying model that uses the consensus predictions of five random forest models. The consensus model shows excellent prediction accuracies on two independent test sets with two cutoffs of 20% and 50% for classification of molecules. The analysis of the importance of the input variables allowed the identification of the main molecular descriptors that affect the HOB class value. The model is available as a web server at www.icdrug.com/ICDrug/ADMET for quick assessment of oral bioavailability for small molecules. The results from this study provide an accurate and easy-to-use tool for screening of drug candidates based on HOB, which may be used to reduce the risk of failure in late stage of drug development. Graphical Abstract

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Fc-Binding Antibody-Recruiting Molecules for Cancer Therapy: Exploiting Endogenous IgG Without antigen–Fab Interactions

10.26434/chemrxiv.9761633.v1 ◽

2019 ◽

Author(s):

Koichi Sasaki ◽

Minori Harada ◽

Yoshiki Miyashita ◽

Hiroshi Tagawa ◽

Akihiro Kishimura ◽

...

Keyword(s):

Small Molecules ◽

Cancer Cells ◽

Ternary Complex ◽

Human Cancer ◽

Folate Receptor ◽

Xenograft Model ◽

Effector Functions ◽

Mouse Xenograft Model ◽

Clinical Benefits ◽

Binding Antibody

<div><div><div><p>Small molecules emulating the effector functions of antibodies have potential clinical benefits because of their low immunogenicity. Antibody-recruiting molecules (ARMs) are bispecific molecules designed to redirect endogenous antibodies to targets. However, endogenous antibodies show intra/inter-patient differences regarding their concentrations and affinities, limiting the potential of ARMs. We sought to address this issue using a Fc-binding peptide instead of an antigen for antibody redirection. Fc-binding ARM (Fc-ARM) targeting folate receptor-α (FR-α) expressed on cancer cells, formed a ternary complex of Fc-ARM, FR-α, and antibody on cancer cells. The ability of this ternary complex to activate natural killer cells was positively correlated with its Fc affinity, and did not require the Fab region. Fc-ARM hitchhiked on pooled human IgG to enhance its blood retention, and suppressed tumor growth in a mouse xenograft model of human cancer. Thus, Fc-ARM has the potential to be employed as a less immunogenic alternative to therapeutic antibodies.</p></div></div></div>

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Cellular Targeting of Oligonucleotides by Conjugation with Small Molecules

Molecules ◽

10.3390/molecules25245963 ◽

2020 ◽

Vol 25 (24) ◽

pp. 5963

Author(s):

Manuel Hawner ◽

Christian Ducho

Keyword(s):

Small Molecules ◽

Cell Types ◽

Target Cells ◽

Specific Cell ◽

Cell Type ◽

Drug Candidates ◽

Cellular Targeting ◽

Related Proteins ◽

High Polarity

Drug candidates derived from oligonucleotides (ON) are receiving increased attention that is supported by the clinical approval of several ON drugs. Such therapeutic ON are designed to alter the expression levels of specific disease-related proteins, e.g., by displaying antigene, antisense, and RNA interference mechanisms. However, the high polarity of the polyanionic ON and their relatively rapid nuclease-mediated cleavage represent two major pharmacokinetic hurdles for their application in vivo. This has led to a range of non-natural modifications of ON structures that are routinely applied in the design of therapeutic ON. The polyanionic architecture of ON often hampers their penetration of target cells or tissues, and ON usually show no inherent specificity for certain cell types. These limitations can be overcome by conjugation of ON with molecular entities mediating cellular ‘targeting’, i.e., enhanced accumulation at and/or penetration of a specific cell type. In this context, the use of small molecules as targeting units appears particularly attractive and promising. This review provides an overview of advances in the emerging field of cellular targeting of ON via their conjugation with small-molecule targeting structures.

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Fc-Binding Antibody-Recruiting Molecules for Cancer Therapy: Exploiting Endogenous IgG Without antigen–Fab Interactions

10.26434/chemrxiv.9761633 ◽

2019 ◽

Author(s):

Koichi Sasaki ◽

Minori Harada ◽

Yoshiki Miyashita ◽

Hiroshi Tagawa ◽

Akihiro Kishimura ◽

...

Keyword(s):

Small Molecules ◽

Cancer Cells ◽

Ternary Complex ◽

Human Cancer ◽

Folate Receptor ◽

Xenograft Model ◽

Effector Functions ◽

Mouse Xenograft Model ◽

Clinical Benefits ◽

Binding Antibody

<div><div><div><p>Small molecules emulating the effector functions of antibodies have potential clinical benefits because of their low immunogenicity. Antibody-recruiting molecules (ARMs) are bispecific molecules designed to redirect endogenous antibodies to targets. However, endogenous antibodies show intra/inter-patient differences regarding their concentrations and affinities, limiting the potential of ARMs. We sought to address this issue using a Fc-binding peptide instead of an antigen for antibody redirection. Fc-binding ARM (Fc-ARM) targeting folate receptor-α (FR-α) expressed on cancer cells, formed a ternary complex of Fc-ARM, FR-α, and antibody on cancer cells. The ability of this ternary complex to activate natural killer cells was positively correlated with its Fc affinity, and did not require the Fab region. Fc-ARM hitchhiked on pooled human IgG to enhance its blood retention, and suppressed tumor growth in a mouse xenograft model of human cancer. Thus, Fc-ARM has the potential to be employed as a less immunogenic alternative to therapeutic antibodies.</p></div></div></div>

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Cell-Specific Chemical Delivery Using a Selective Nitroreductase–Nitroaryl Pair

10.26434/chemrxiv.6447683.v1 ◽

2018 ◽

Author(s):

Todd D. Gruber ◽

Chithra Krishnamurthy ◽

Jonathan B. Grimm ◽

Michael R. Tadross ◽

Laura M. Wysocki ◽

...

Keyword(s):

Small Molecules ◽

Mammalian Cells ◽

Target Cells ◽

Specific Chemical ◽

E Coli ◽

Enzyme Substrate ◽

Cell Specificity ◽

General Chemical ◽

Increased Activity ◽

Enzyme Variant

<p>The utility of<b> </b>small molecules to probe or perturb biological systems is limited by the lack of cell-specificity. ‘Masking’ the activity of small molecules using a general chemical modification and ‘unmasking’ it only within target cells could overcome this limitation. To this end, we have developed a selective enzyme–substrate pair consisting of engineered variants of <i>E. coli</i> nitroreductase (NTR) and a 2‑nitro-<i>N</i>-methylimidazolyl (NM) masking group. To discover and optimize this NTR–NM system, we synthesized a series of fluorogenic substrates containing different nitroaromatic masking groups, confirmed their stability in cells, and identified the best substrate for NTR. We then engineered the enzyme for improved activity in mammalian cells, ultimately yielding an enzyme variant (enhanced NTR, or eNTR) that possesses up to 100-fold increased activity over wild-type NTR. These improved NTR enzymes combined with the optimal NM masking group enable rapid, selective unmasking of dyes, indicators, and drugs to genetically defined populations of cells.</p>

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Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

Current Molecular Pharmacology ◽

10.2174/1874467213666200422090135 ◽

2020 ◽

Vol 13 (4) ◽

pp. 273-294 ◽

Cited By ~ 2

Author(s):

Elahe Zarini-Gakiye ◽

Javad Amini ◽

Nima Sanadgol ◽

Gholamhassan Vaezi ◽

Kazem Parivar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Small Molecules ◽

Clinical Trial Design ◽

Treatment Approaches ◽

Drug Candidates ◽

Novel Treatments ◽

Approved Drugs ◽

Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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CYTOTOXICITY MEDIATED BY SOLUBLE ANTIGEN AND LYMPHOCYTES IN DELAYED HYPERSENSITIVITY

Journal of Experimental Medicine ◽

10.1084/jem.128.6.1237 ◽

1968 ◽

Vol 128 (6) ◽

pp. 1237-1254 ◽

Cited By ~ 96

Author(s):

Nancy H. Ruddle ◽

Byron H. Waksman

Keyword(s):

Lymph Node ◽

Genetic Difference ◽

Specific Antigen ◽

Delayed Hypersensitivity ◽

Target Cells ◽

Soluble Antigen ◽

Rat Embryo ◽

Egg Albumin ◽

Lymph Node Cells ◽

Electronic Particle Counter

In the presence of specific antigen, lymph node cells from inbred rats with delayed hypersensitivity to tuberculoprotein, bovine gammaglobulin, and egg albumin produced progressive destruction of monolayers of rat embryo fibroblasts in tissue culture, first apparent at 48 hr and maximal at 72 hr. The effect was specific and did not depend on a genetic difference between the lymph node cells and target cells. It required antigen concentrations equal to or greater than 1.25 µg/ml and lymphocyte: target cell ratios of approximately 10 or 20:1. It could be evaluated both by a plaquing technique and by cell enumeration with an electronic particle counter.

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Chimeric Maternal Cells with Tissue-Specific Antigen Expression and Morphology Are Common in Infant Tissues

Pediatric and Developmental Pathology ◽

10.2350/08-07-0499.1 ◽

2009 ◽

Vol 12 (5) ◽

pp. 337-346 ◽

Cited By ~ 26

Author(s):

Anne M. Stevens ◽

Heidi M. Hermes ◽

Meghan M. Kiefer ◽

Joe C. Rutledge ◽

J. Lee Nelson

Keyword(s):

Islet Cells ◽

Tissue Injury ◽

Specific Antigen ◽

Antigen Expression ◽

Cell Types ◽

Target Cells ◽

Specific Cell ◽

Tissue Specific ◽

Renal Tubular Cells ◽

Parenchymal Cells

Maternal microchimerism (MMc) has been purported to play a role in the pathogenesis of autoimmunity, but how a small number of foreign cells could contribute to chronic, systemic inflammation has not been explained. Reports of peripheral blood cells differentiating into tissue-specific cell types may shed light on the problem in that chimeric maternal cells could act as target cells within tissues. We investigated MMc in tissues from 7 male infants. Female cells, presumed maternal, were characterized by simultaneous immunohistochemistry and fluorescence in situ hybridization for X- and Y-chromosomes. Maternal cells constituted 0.017% to 1.9% of parenchymal cells and were found in all infants in liver, pancreas, lung, kidney, bladder, skin, and spleen. Maternal cells were differentiated: maternal hepatocytes in liver, renal tubular cells in kidney, and β-islet cells in pancreas. Maternal cells were not found in areas of tissue injury or inflammatory infiltrate. Maternal hematopoietic cells were found only in hearts from patients with neonatal lupus. Thus, differentiated maternal cells are present in multiple tissue types and occur independently of inflammation or tissue injury. Loss of tolerance to maternal parenchymal cells could lead to organ-specific “auto” inflammatory disease and elimination of maternal cells in areas of inflammation.

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Bioactive Secondary Metabolites of the Genus Diaporthe and Anamorph Phomopsis from Terrestrial and Marine Habitats and Endophytes: 2010–2019

Microorganisms ◽

10.3390/microorganisms9020217 ◽

2021 ◽

Vol 9 (2) ◽

pp. 217

Author(s):

Tang-Chang Xu ◽

Yi-Han Lu ◽

Jun-Fei Wang ◽

Zhi-Qiang Song ◽

Ya-Ge Hou ◽

...

Keyword(s):

Secondary Metabolites ◽

Small Molecules ◽

Host Plants ◽

Plant Pathogens ◽

Bioactive Metabolites ◽

Drug Candidates ◽

The Past ◽

Marine Habitats ◽

Bioactive Secondary Metabolites ◽

Unidentified Species

The genus Diaporthe and its anamorph Phomopsis are distributed worldwide in many ecosystems. They are regarded as potential sources for producing diverse bioactive metabolites. Most species are attributed to plant pathogens, non-pathogenic endophytes, or saprobes in terrestrial host plants. They colonize in the early parasitic tissue of plants, provide a variety of nutrients in the cycle of parasitism and saprophytism, and participate in the basic metabolic process of plants. In the past ten years, many studies have been focused on the discovery of new species and biological secondary metabolites from this genus. In this review, we summarize a total of 335 bioactive secondary metabolites isolated from 26 known species and various unidentified species of Diaporthe and Phomopsis during 2010–2019. Overall, there are 106 bioactive compounds derived from Diaporthe and 246 from Phomopsis, while 17 compounds are found in both of them. They are classified into polyketides, terpenoids, steroids, macrolides, ten-membered lactones, alkaloids, flavonoids, and fatty acids. Polyketides constitute the main chemical population, accounting for 64%. Meanwhile, their bioactivities mainly involve cytotoxic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, anti-algae, phytotoxic, and enzyme inhibitory activities. Diaporthe and Phomopsis exhibit their potent talents in the discovery of small molecules for drug candidates.

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