Immunology and Microbiology › Immunology

Toxin Mechanisms and Immunotoxins

Works Count: 46813

Wikipedia

Description

This cluster of papers focuses on the development and efficacy of immunotoxin therapy for cancer treatment, with a particular emphasis on ricin poisoning, ribosome-inactivating proteins, and targeted therapy using recombinant immunotoxins. It also explores the use of IL-13 receptor and mistletoe extract in cancer therapy.

Keywords

Immunotoxin; Ricin Poisoning; Ribosome-Inactivating Proteins; Cancer Therapy; Diphtheria Toxin; Targeted Therapy; Recombinant Immunotoxin; IL-13 Receptor; Ricinus communis; Mistletoe Extract

The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes. The site and the characteristics of the modification in 28 S ribosomal RNA caused by the toxins.

1987-04-01

Yaeta Endo , Kazuhiro Mitsui , Mitsuyoshi Motizuki +1 more

Ricin is a potent cytotoxic protein derived from the higher plant Ricinus communis that inactivates eukaryotic ribosomes.In this paper we have studied the mechanism of action of ricin A-chain on … Ricin is a potent cytotoxic protein derived from the higher plant Ricinus communis that inactivates eukaryotic ribosomes.In this paper we have studied the mechanism of action of ricin A-chain on rat liver ribosomes in uitro.Our findings indicate that the toxin inactivates the ribosomes by modifying both or either of two nucleoside residues, G43,s and A43249 in 28 S rRNA.These nucleotides are located close to the asarcin cleavage site and become resistant to all ribonucleases tested.The examination of the lability of phosphodiester bonds of these nucleotides to both mild alkaline digestion and aniline treatment at acidic pH suggests that the base of A4324 is removed by the toxin.This unique activity of ricin A-chain was also observed when naked 28 S rRNA is used as a substrate, indicating that the toxin directly acts on the RNA.Similar activity on 28 S rRNA is also exhibited by abrin and modeccin, ricin-related toxins, suggesting a general mechanistic pathway for ribosome inactivation by lectin toxins.

The interleukin‐1 family: 10 years of discovery 1

1994-12-01

Charles A. Dinarello

Ten years ago the cloning of two interleukin-1 molecules (IL-1 alpha and IL-1 beta) resolved the question of whether a single polypeptide could evoke a wide variety of biological effects. … Ten years ago the cloning of two interleukin-1 molecules (IL-1 alpha and IL-1 beta) resolved the question of whether a single polypeptide could evoke a wide variety of biological effects. During the past decade, the biology of IL-1 has greatly expanded our understanding of how the host responds to external challenges, such as injury and infection, as well as its role in several diseases. We learned of the remarkable potency of IL-1 in the femtomolar range and of its ability to induce a response by triggering only one or two receptors per cell. Unexpectedly, the IL-1 family of genes, receptors and associated molecules have been linked to those of Drosophila, nematodes, and microorganisms and IL-1 signal transduction is similar to that observed after cellular stress. The cloning of IL-1 opened other avenues of fundamental biological interest. For example, in addition to the two agonist molecules IL-1 alpha and IL-1 beta, a third member of the IL-1 gene family is a specific, high affinity receptor antagonist (IL-1 receptor antagonist). That this third member of the IL-1 family inhibits the other two is characteristic of the tight control over production and activity exerted on IL-1. Although IL-1 contributes to the pathogenesis of many diseases, a small amount appears to be needed to combat infection and initiate healing processes. This article highlights 10 years of discoveries on IL-1.

A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles.

1982-02-01

Stanley Cohen , Hiroshi Ushiro , C M Stoscheck +1 more

A method is presented for the preparation of a 'hative" epidermal growth factor (EGF) receptor-kinase complex of molecular weight 170,000 from A-431 cells.Although this receptor complex is capable of binding … A method is presented for the preparation of a 'hative" epidermal growth factor (EGF) receptor-kinase complex of molecular weight 170,000 from A-431 cells.Although this receptor complex is capable of binding EGF, noncovalently, in quantities similar to the previously isolated 150,000 complex (Cohen, S., Carpenter, G., and King, L., Jr. (1980) J. BioZ.Chem 255, 4834-4842), the 170,000 preparation has 5 t o 10 times the intrinsic kinase activity (autophosphorylation).However, the 170,000 kinase activity toward other proteins is lower than that of the 150,000 preparation.Both the 170,000 and 150,000 kinase activities are enhanced by

RNA N-glycosidase activity of ricin A-chain. Mechanism of action of the toxic lectin ricin on eukaryotic ribosomes.

1987-06-01

Yaeta Endo , Kunio Tsurugi

The modification reaction of 28 S rRNA in eukaryotic ribosomes by ricin A-chain was characterized.To examine whether ricin A-chain release any bases from 28 S rRNA, rat liver ribosomes were … The modification reaction of 28 S rRNA in eukaryotic ribosomes by ricin A-chain was characterized.To examine whether ricin A-chain release any bases from 28 S rRNA, rat liver ribosomes were incubated with a catalytic amount of the toxin, and a fraction containing free bases and nucleosides was prepared from the postribosomal fraction of the reaction mixture by means of ion-exchange column chromatography.Thin-layer chromatographic analysis of this fraction revealed a release of 1 mol of adenine from 1 mol of ribosome.When the ribosomes or naked total RNAs were treated with ricin A-chain in the presence of [32P] phosphate, little incorporation of the radioactivity into 28 S rRNA was observed, indicating that the release is not mediated by phosphorolysis.Thus, considering together with the previous result (Endo, Y., Mitsui, K.,

Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase.

1994-05-01

Garth Powis , Rosanne Bonjouklian , Margareta Berggren +7 more

Phosphatidylinositol-3-kinase is an important enzyme for intracellular signaling. The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. The 50% inhibitory concentration … Phosphatidylinositol-3-kinase is an important enzyme for intracellular signaling. The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. The 50% inhibitory concentration for inhibition by wortmannin is 2 to 4 nM. Kinetic analysis demonstrates that wortmannin is a noncompetitive, irreversible inhibitor of phosphatidylinositol-3-kinase, with inactivation being both time- and concentration-dependent. Wortmannin has previously been reported to be an inhibitor of myosin light chain kinase but with an inhibitory concentration of 0.2 microM. Wortmannin was found not to be an inhibitor of phosphatidylinositol-4-kinase, protein kinase C, or protein tyrosine kinase. Wortmannin inhibited the formation of phosphatidylinositol-3-phosphates in intact cells. The results of the study suggest that wortmannin and its analogues may have utility as pharmacological probes for studying the actions of phosphatidylinositol-3-kinase.

Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production.

1994-08-15

Chet Nastala , Howard Edington , T G McKinney +7 more

Recent evidence supports the critical and proximate role of IL-12 in regulating both T and NK cell function during inflammation. In these studies, we evaluated the in vivo antitumor activity … Recent evidence supports the critical and proximate role of IL-12 in regulating both T and NK cell function during inflammation. In these studies, we evaluated the in vivo antitumor activity of murine IL-12 in murine adenocarcinoma and sarcoma models using both systemic and peritumoral administration. Antitumor effects were consistently demonstrated both in models of microdisease, in which IL-12 treatment was initiated soon after tumor inoculation (1 to 5 days), and in animals bearing large established tumors (7 to 14 days). Treatment with IL-12 markedly prolonged survival and, in most cases, caused complete tumor regression. Significant reduction in pulmonary metastases after systemic treatment was observed when treatment was delayed for 10 days after tumor inoculation. Increases in serum IFN-gamma, TNF-alpha, and nitrogen oxides were demonstrated, exceeding those observed with IL-2 treatment. Systemic administration of anti-IFN-gamma Abs before IL-12 treatment nearly completely abrogated the antitumor effect in experiments using subcutaneous tumors or pulmonary metastases. Depletion of the individual T cell subsets CD4 and CD8 by systemic administration of mAbs diminished the effectiveness of IL-12 when administered in combination. An infiltrate composed primarily of CD8+ + cells was demonstrated by using immunohistochemical analysis of tumors after IL-12 treatment. Minimal apparent toxicity was demonstrated at effective doses (0.1 to 1.0 microgram/day) of IL-12. These results indicate that IL-12 is an effective and minimally toxic antitumor agent in murine tumor models and leads to an immune-mediated rejection involving, at least in part, IFN-gamma, CD4+, and CD8+ cells. Human clinical trials of IL-12 for the treatment of malignancy are supported by these studies.

View PDF Chat

Soluble expression of recombinant proteins in the cytoplasm of Escherichia coli

2005-01-04

Hans Peter Sørensen , Kim Kusk Mortensen

Abstract Pure, soluble and functional proteins are of high demand in modern biotechnology. Natural protein sources rarely meet the requirements for quantity, ease of isolation or price and hence recombinant … Abstract Pure, soluble and functional proteins are of high demand in modern biotechnology. Natural protein sources rarely meet the requirements for quantity, ease of isolation or price and hence recombinant technology is often the method of choice. Recombinant cell factories are constantly employed for the production of protein preparations bound for downstream purification and processing. Eschericia coli is a frequently used host, since it facilitates protein expression by its relative simplicity, its inexpensive and fast high density cultivation, the well known genetics and the large number of compatible molecular tools available. In spite of all these qualities, expression of recombinant proteins with E. coli as the host often results in insoluble and/or nonfunctional proteins. Here we review new approaches to overcome these obstacles by strategies that focus on either controlled expression of target protein in an unmodified form or by applying modifications using expressivity and solubility tags.

View PDF Chat

Bacterial toxins: a table of lethal amounts

1982-03-01

D. Michael Gill

View PDF Chat

X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death

1996-05-01

Steven W. Muchmore , Michael Sattler , Heng Liang +7 more

View PDF Chat

A Receptor for the Selective Uptake and Degradation of Proteins by Lysosomes

1996-07-26

Ana María Cuervo , J. Fred Dice

Multiple pathways of protein degradation operate within cells. A selective protein import pathway exists for the uptake and degradation of particular cytosolic proteins by lysosomes. Here, the lysosomal membrane glycoprotein … Multiple pathways of protein degradation operate within cells. A selective protein import pathway exists for the uptake and degradation of particular cytosolic proteins by lysosomes. Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays. Overexpression of human LGP96 in Chinese hamster ovary cells increased the activity of the selective lysosomal proteolytic pathway in vivo and in vitro.

Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity

1990-05-01

Hilton H. Mollenhauer , D. James Morré , Loyd D. Rowe

View PDF Chat

Molecular chaperones and protein folding in plants

1996-10-01

Rebecca S. Boston , Paul V. Viitanen , Elizabeth Vierling

GAL4-VP16 is an unusually potent transcriptional activator

1988-10-01

Ivan Sadowski , Jun Ma , Steven J. Triezenberg +1 more

Lectins as Plant Defense Proteins

1995-10-01

Willy J. Peumans , Els J. M. Van Damme

tively agglutinate erythrocytes of a particular human blood group (from the Latin verb legere, which means "to select"). tively agglutinate erythrocytes of a particular human blood group (from the Latin verb legere, which means "to select").

View PDF Chat

Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways

1994-08-01

Bente Lowin , Michael Hahne , Chantal Mattmann +1 more

Engineering Chemical Reactivity on Cell Surfaces Through Oligosaccharide Biosynthesis

1997-05-16

Lara K. Mahal , Kevin J. Yarema , Carolyn R. Bertozzi

Cell surface oligosaccharides can be engineered to display unusual functional groups for the selective chemical remodeling of cell surfaces. An unnatural derivative of N-acetyl-mannosamine, which has a ketone group, was … Cell surface oligosaccharides can be engineered to display unusual functional groups for the selective chemical remodeling of cell surfaces. An unnatural derivative of N-acetyl-mannosamine, which has a ketone group, was converted to the corresponding sialic acid and incorporated into cell surface oligosaccharides metabolically, resulting in the cell surface display of ketone groups. The ketone group on the cell surface can then be covalently ligated under physiological conditions with molecules carrying a complementary reactive functional group such as the hydrazide. Cell surface reactions of this kind should prove useful in the introduction of new recognition epitopes, such as peptides, oligosaccharides, or small organic molecules, onto cell surfaces and in the subsequent modulation of cell-cell or cell-small molecule binding events. The versatility of this technology was demonstrated by an example of selective drug delivery. Cells were decorated with biotin through selective conjugation to ketone groups, and selectively killed in the presence of a ricin A chain-avidin conjugate.

View PDF Chat

Beitrag zur kollektiven Behandlung pharmakologischer Reihenversuche

1931-07-01

G. Kärber

A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes

1986-10-01

Louis M. Staudt , Harinder Singh , Ranjan Sen +3 more

Bcl-xL forms an ion channel in synthetic lipid membranes

1997-01-01

Andy J. Minn , Patricio Vélez , Sharon L. Schendel +5 more

Protein a from Staphylococcus aureus. Its isolation by affinity chromatography and its use as an immunosorbent for isolation of immunoglobulins

1972-11-15

Hans Hjelm , Katarina Hjelm , John Sjöquist

View PDF Chat

The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death

1994-03-01

Craig A. Smith , Terry Farrah , Raymond G. Goodwin

One molecule of diphtheria toxin fragment a introduced into a cell can kill the cell

1978-09-01

Masaru Yamaizumi , Eisuke Mekada , Tsuyoshi Uchida +1 more

NAD-dependent inhibition of protein synthesis by Pseudomonas aeruginosa toxin,.

1975-06-01

Barbara H. Iglewski , David Kabat

Pseudomonas aeruginosa toxin (PA toxin) inhibits protein synthesis in a reticulocyte cell-free system. The inhibition requires NAD and results in a block at an elongation step of polypeptide assembly. PA … Pseudomonas aeruginosa toxin (PA toxin) inhibits protein synthesis in a reticulocyte cell-free system. The inhibition requires NAD and results in a block at an elongation step of polypeptide assembly. PA toxin was found to act like diphtheria toxin fragment A. Both toxins catalyze the transfer of radioactivity from nicotinamide(U-14-C)adenine dinucleotide ((14-C)NAD) into covalent linkage with the 100,000 dalton elongation (EF-2) protein. Furthermore, in the presence of a limiting amount of EF-2, excess toxin, and (14-C)NAD, the two toxins were non-additive in the amount of label transferred to EF-3. Unlike free fragment A of diphtheria toxin, the enzymatic activity of PA toxin is heat labile and neutralizable with antibody to PA toxin but not with antibody to fragment A. Although PA and diphtheria toxins have different cellular specificities and molecular properties and produce different clinical symptoms, their intracellular mechanisms of action appear to be identical.

View PDF Chat

IN VITRO METHOD FOR TESTING THE TOXIN‐PRODUCING CAPACITY OF DIPHTHERIA BACTERIA

1948-03-01

Örjan Ouchterlony

Ricin Poisoning

2005-11-08

Jennifer Audi , Martin Belson , Manish M. Patel +2 more

concern about ricin, a potent biologic toxin, as a possible terrorist weapon has necessitated a comprehensive review of this poison. 1The Centers for Disease Control and Prevention (CDC) categorizes ricin … concern about ricin, a potent biologic toxin, as a possible terrorist weapon has necessitated a comprehensive review of this poison. 1The Centers for Disease Control and Prevention (CDC) categorizes ricin as a Category B agent (second-highest priority), as it is moderately easy to disseminate, resulting in low mortality but moderate to high morbidity, and requires specific enhancement of the CDC's diagnostic and disease surveillance capacity. 2 Such agents are not routinely encountered, so heightened awareness in the health care community and a strong public health infrastructure are necessary for detection and response.We therefore have summarized the literature on ricin poisoning and provided recommendations for clinicians and public health professionals dealing with a ricin attack against a civilian population. EVIDENCE ACQUISITIONUsing PubMed, we searched MEDLINE and OLDMEDLINE databases from January 1950 to August 2005 using the keywords ricin, ricinus communis, ricinine, plant toxins, castor beans, castor dust, and castor oil.Keywords were used alone and with the modifiers toxicity, poisoning

The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophage

1983-10-01

Barry N. Kreiswirth , Sven Löfdahl , M J Betley +4 more

Analysis of membrane and surface protein sequences with the hydrophobic moment plot

1984-10-01

David Eisenberg , Erich M. Schwarz , M C Komaromy +1 more

Mechanism of cholera toxin action: Covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system

1978-06-01

Dan Cassel , Thomas Pfeuffer

Treatment of pigeon erythrocyte membranes with cholera toxin and NAD + enhanced the GTP stimulation and suppressed the F - activation of the adenylate cylase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. … Treatment of pigeon erythrocyte membranes with cholera toxin and NAD + enhanced the GTP stimulation and suppressed the F - activation of the adenylate cylase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1]. In the presence of NAD + labeled with 32 P in the AMP moiety the toxin catalyzed the covalent incorporation of radioactivity into membrane proteins with molecular weights ( M r s) of 200,000, 86,000, and 42,000. Extraction of toxin-treated membranes with Lubrol PX followed by affinity chromatography on a GTP-Sepharose column resulted in a 200-fold purification of the 42,000- M r labeled protein and in its complete separation from the other labeled proteins. The fraction containing the purified GTP-binding component from toxin-treated membranes conferred an enhanced GTP-stimulated activity on adenylate cyclase solubilized from nontreated membranes. Likewise, the addition of GTP-binding fraction from nontreated membranes to an enzyme solubilized from toxin-treated membranes restored F - stimulation of the adenylate cyclase. The toxin-induced modification of adenylate cyclase and the incorporation of radioactivity into the 42,000- M r protein were partially reversed upon incubation with toxin and nicotinamide at pH 6.1. The results indicate that cholera toxin affects the adenylate cyclase system by catalyzing an ADP-ribosylation of the 42,000- M r component bearing the guanyl nucleotide regulatory site.

View PDF Chat

The crystal structure of diphtheria toxin

1992-05-01

Seunghyon Choe , Melanie J. Bennett , Gary Fujii +4 more

Experimental Transmission of a Kuru-like Syndrome to Chimpanzees

1966-02-01

D. C. Gajdusek , Clarence J. Gibbs , Michael P. Alpers

A functional interleukin 12 receptor complex is composed of two β-type cytokine receptor subunits

1996-11-26

David H. Presky , Hong Yang , Lisa J. Minetti +5 more

We have identified a cDNA from a human phytohemagglutinin-activated lymphoblast library encoding a protein that binds 125I-labeled human interleukin 12 (125I-huIL-12) with a Kd of about 5 nM when expressed … We have identified a cDNA from a human phytohemagglutinin-activated lymphoblast library encoding a protein that binds 125I-labeled human interleukin 12 (125I-huIL-12) with a Kd of about 5 nM when expressed in COS-7 cells. When coexpressed in COS-7 cells with the previously identified IL-12 beta receptor (IL-12R beta) protein, two classes of 125I-huIL-12 binding sites were measured with Kds of about 55 pM and 8 nM, corresponding to the high- and low-affinity binding sites seen on phytohemagglutinin-activated lymphoblasts. This newly identified huIL-12R subunit is a member of the cytokine receptor superfamily, with closest resemblance to the beta-type cytokine receptor gp130 and the receptors for leukemia inhibitory factor and granulocyte colony-stimulating factor. Consequently, we have reclassified the previously identified IL-12R beta subunit as huIL-12R beta 1 and designated the newly identified subunit as huIL-12R beta 2. huIL-12R beta 2 is an 862-amino acid type I transmembrane protein with a 595-amino-acid-long extracellular domain and a cytoplasmic tail of 216 amino acids that contains three tyrosine residues. A cDNA encoding the mouse homolog of the huIL12R beta 2 protein has also been isolated. Human and mouse IL-12R beta 2 proteins show a 68% amino acid sequence identity. When expressed in COS-7 cells, huIL-12R beta 2 exists as a disulfide-linked oligomer with an apparent monomeric molecular weight of 130 kDa. Coexpression of the two identified IL-12R subunits in Ba/F3 cells conferred IL-12 responsiveness, and clones of these cotransfected Ba/F3 cells that grew continuously in the presence of IL-12 were isolated and designated LJM-1 cells. LJM-1 cells exhibited dose-dependent proliferation in response to huIL-12, with an ED50 of about 1 pM huIL-12. Interestingly, Ba/F3 cells transfected with IL-12R beta 2 alone proliferated in response to huIL-12 with an ED50 of about 50 pM, although a role for endogenous mouse IL-12R beta 1 in IL-12 signal transduction in these transfectants cannot be ruled out. These results demonstrate that the functional high-affinity IL-12R is composed of at least two beta-type cytokine receptor subunits, each independently exhibiting a low affinity for IL-12.

View PDF Chat

Induction by Antigen of Intrathymic Apoptosis of CD4 + CD8 + TCR lo Thymocytes in Vivo

1990-12-21

Kenneth M. Murphy , Amy B. Heimberger , Dennis Y. Loh

In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic … In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4 + CD8 + TCR lo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.

Vβ-Specific Stimulation of Human T Cells by Staphylococcal Toxins

1989-05-19

J W Kappler , Brian L. Kotzin , Lynne R. Herron +7 more

The staphylococcal toxins are responsible for a number of diseases in man and other animals. Many of them have also long been known to be powerful T cell stimulants. They … The staphylococcal toxins are responsible for a number of diseases in man and other animals. Many of them have also long been known to be powerful T cell stimulants. They do not, however, stimulate all T cells. On the contrary, each toxin reacts with human T cells bearing particular Vβ sequences as part of their receptors for major histocompatibility complex protein-associated antigen. The specificity of these toxins for Vβs puts them in the recently described class of superantigens and may account for the differential sensitivity of different individuals to the toxic effects of these proteins.

Ribosome-inactivating proteins from plants

1993-12-01

Luigi Barbieri , Maria Giulia Battelli , Fiorenzo Stirpe

lnterleukin-13 is a new human lymphokine regulating inflammatory and immune responses

1993-03-01

A Minty , Pascale Chalon , Jean‐Marie Derocq +7 more

Group Epitope Mapping by Saturation Transfer Difference NMR To Identify Segments of a Ligand in Direct Contact with a Protein Receptor

2001-06-01

Moriz Mayer , Bernd Meyer

A protocol based on saturation transfer difference (STD) NMR spectra was developed to characterize the binding interactions at an atom level, termed group epitope mapping (GEM). As an example we … A protocol based on saturation transfer difference (STD) NMR spectra was developed to characterize the binding interactions at an atom level, termed group epitope mapping (GEM). As an example we chose the well-studied system of galactose binding to the 120-kDa lectin Ricinus communis agglutinin I (RCA120). As ligands we used methyl β-d-galactoside and a biantennary decasaccharide. Analysis of the saturation transfer effects of methyl β-d-galactoside showed that the H2, H3, and H4 protons are saturated to the highest degree, giving evidence of their close proximity to protons of the RCA120 lectin. The direct interaction of the lectin with this region of the galactose is in excellent agreement with results obtained from the analysis of the binding specificities of many chemically modified galactose derivatives (Bhattacharyya, L.; Brewer, C. F. Eur. J. Biochem. 1988, 176, 207−212). This new NMR technique can identify the binding epitope of even complex ligands very quickly, which is a great improvement over time-consuming chemical modifications. Efficient GEM benefits from a relatively high off rate of the ligand and a large excess of the ligand over the receptor. Even for a ligand like the biantennary decasaccharide with micromolar binding affinity, the binding epitopes could easily be mapped to the terminal β-d-Gal-(1−4)-β-d-GlcNAc (β-d-GlcNAc = N-acetyl-d-glucosamine) residues located at the nonreducing end of the two carbohydrate chains. The binding contribution of the terminal galactose residue is stronger than those of the penultimate GlcNAc residues. We could show that the GlcNAc residues bind "edge-on" with the region from H2 to H4, making contact with the protein. Analysis of STD NMR experiments performed under competitive conditions proved that the two saccharides studied bind at the same receptor site, thereby ruling out unspecific binding.

IL-13 signaling through the IL-13α2 receptor is involved in induction of TGF-β1 production and fibrosis

2005-12-04

Stefan Fichtner‐Feigl , Warren Strober , Koji Kawakami +2 more

Identification and Characterization of an Exotoxin from Staphylococcus aureus Associated with Toxic-Shock Syndrome

1981-04-01

Patrick M. Schlievert , Kathryn N. Shands , Bruce B. Dan +2 more

Journal Article Identification and Characterization of an Exotoxin from Staphylococcus aureus Associated with Toxic-Shock Syndrome Get access Patrick M. Schlievert, Patrick M. Schlievert Department of Microbiology and Immunology, School of … Journal Article Identification and Characterization of an Exotoxin from Staphylococcus aureus Associated with Toxic-Shock Syndrome Get access Patrick M. Schlievert, Patrick M. Schlievert Department of Microbiology and Immunology, School of Medicine, University of California, Los Angeles, CaliforniaCenters for Disease Control, Atlanta, Georgia Please address requests for reprints to Dr. Patrick M. Schlievert at his present address: Department of Microbiology, University of Minnesota Medical School, 1060 Mayo Memorial Building, Box 196, Minneapolis, Minnesota 55455. Search for other works by this author on: Oxford Academic PubMed Google Scholar Kathryn N. Shands, Kathryn N. Shands Department of Microbiology and Immunology, School of Medicine, University of California, Los Angeles, CaliforniaCenters for Disease Control, Atlanta, Georgia Search for other works by this author on: Oxford Academic PubMed Google Scholar Bruce B. Dan, Bruce B. Dan Department of Microbiology and Immunology, School of Medicine, University of California, Los Angeles, CaliforniaCenters for Disease Control, Atlanta, Georgia Search for other works by this author on: Oxford Academic PubMed Google Scholar George P. Schmid, George P. Schmid Department of Microbiology and Immunology, School of Medicine, University of California, Los Angeles, CaliforniaCenters for Disease Control, Atlanta, Georgia Search for other works by this author on: Oxford Academic PubMed Google Scholar Russell D. Nishimura Russell D. Nishimura Department of Microbiology and Immunology, School of Medicine, University of California, Los Angeles, CaliforniaCenters for Disease Control, Atlanta, Georgia Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 143, Issue 4, April 1981, Pages 509–516, https://doi.org/10.1093/infdis/143.4.509 Published: 01 April 1981 Article history Received: 21 January 1981 Revision received: 06 March 1981 Published: 01 April 1981

Interleukin-1, Interleukin-1 Receptors and Interleukin-1 Receptor Antagonist

1998-01-01

Charles A. Dinarello

IL-1 (IL-1α or IL-1β) is the prototypic “multifunctional” cytokine. Unlike the lymphocyte and colony stimulating growth factors, IL-1 affects nearly every cell type, and often in concert with other cytokines … IL-1 (IL-1α or IL-1β) is the prototypic “multifunctional” cytokine. Unlike the lymphocyte and colony stimulating growth factors, IL-1 affects nearly every cell type, and often in concert with other cytokines or small mediator molecules. Although some lymphocyte and colony stimulating growth factors may be therapeutically useful, IL-1 is a highly inflammatory cytokine and the margin between clinical benefit and unacceptable toxicity in humans is exceedingly narrow. In contrast, agents that reduce the production and/or activity of IL-1 are likely to have an impact on clinical medicine. In support of this concept, there is growing evidence that the production and activity of IL-1, particularly IL-1β, are tightly regulated events as if nature has placed specific “road blocks” to reduce the response to IL-1 during disease. In addition to controlling gene expression, synthesis and secretion, this regulation extends to surface receptors, soluble receptors and a receptor antagonist. Investigators have studied how production of the different members of the IL-1 family is controlled, the various biological activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family and the complexity of intracellular signaling. Mice deficient in IL-1β, IL-1β converting enzyme (ICE) and IL-1R type I have also been studied. Humans have been injected with IL-1 (either IL-1α or IL-1β) for enhancing bone marrow recovery and for cancer treatment. The IL-1 specific receptor antagonist (IL-IRa) has also been tested in clinical trials.

Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: Implications for TNF receptor activation

1993-05-01

David W. Banner , A. D’Arcy , Wolfgang Janes +5 more

Starch Gel Electrophoresis in a Discontinuous System of Buffers

1957-12-01

M. D. Poulik

ADP-ribosylation of membrane proteins catalyzed by cholera toxin: basis of the activation of adenylate cyclase.

1978-07-01

D. Michael Gill , Roberta Meren

In the presence of ATP and a cytosolic factor, cholera toxin fragment A1 catalyzes the transfer of ADP-ribose from NAD to a number of soluble and membrane-bound proteins of the … In the presence of ATP and a cytosolic factor, cholera toxin fragment A1 catalyzes the transfer of ADP-ribose from NAD to a number of soluble and membrane-bound proteins of the pigeon erythrocyte. Evidence is presented that suggests that the most readily modified membrane protein (Mr 42,000) is the adenylate cyclase-associated GTP-binding protein. Its modification by toxin is stimulated by guanine nucleotides. Adenylate cyclase activity increases in parallel with the addition of ADP-ribose to this protein and decreases in parallel with the subsequent reversal of ADP-ribosylation by toxin and nicotinamide. The protein is only accessible to toxin A subunits if the erythrocytes are lysed. When adenylate cyclase activity reaches a maximum, the number of ADP-ribose residues bound to this protein (about 1500 per cell) is similar to the reported number of beta-adrenergic receptors.

View PDF Chat

How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum.

1994-03-01

Ari Helenius

View PDF Chat

RESPIRATORY SYNCYTIAL VIRUS DISEASE IN INFANTS DESPITE PRIOR ADMINISTRATION OF ANTIGENIC INACTIVATED VACCINE12

1969-04-01

Hyun Wha Kim , Jose G. Canchola , Carl D. Brandt +4 more

Antitumor and antimetastatic activity of interleukin 12 against murine tumors.

1993-10-01

Michael J. Brunda , Leopoldo Luistro , Rajeev R. Warrier +5 more

It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic … It has recently been demonstrated that in vivo administration of murine interleukin 12 (IL-12) to mice results in augmentation of cytotoxic natural killer (NK)/lymphocyte-activated killer cell activity, enhancement of cytolytic T cell generation, and induction of interferon gamma secretion. In this study, the in vivo activity of murine IL-12 against a number of murine tumors has been evaluated. Experimental pulmonary metastases or subcutaneous growth of the B16F10 melanoma were markedly reduced in mice treated intraperitoneally with IL-12, resulting in an increase in survival time. The therapeutic effectiveness of IL-12 was dose dependent and treatment of subcutaneous tumors could be initiated up to 14 d after injection of tumor cells. Likewise, established experimental hepatic metastases and established subcutaneous M5076 reticulum cell sarcoma and Renca renal cell adenocarcinoma tumors were effectively treated by IL-12 at doses which resulted in no gross toxicity. Local peritumoral injection of IL-12 into established subcutaneous Renca tumors resulted in regression and complete disappearance of these tumors. IL-12 was as effective in NK cell-deficient beige mice or in mice depleted of NK cell activity by treatment with antiasialo GM1, suggesting that NK cells are not the primary cell type mediating the antitumor effects of this cytokine. However, the efficacy of IL-12 was greatly reduced in nude mice suggesting the involvement of T cells. Furthermore, depletion of CD8+ but not CD4+ T cells significantly reduced the efficacy of IL-12. These results demonstrate that IL-12 has potent in vivo antitumor and antimetastatic effects against murine tumors and demonstrate as well the critical role of CD8+ T cells in mediating the antitumor effects against subcutaneous tumors.

View PDF Chat

Plant Lectins: A Composite of Several Distinct Families of Structurally and Evolutionary Related Proteins with Diverse Biological Roles

1998-11-01

Els J. M. Van Damme , Willy J. Peumans , Annick Barre +1 more

Many plants contain carbohydrate-binding proteins that are commonly designated as lectins, agglutinins, or hemagglutinins. Due to the obvious differences in molecular structure, biochemical properties, and carbohydrate-binding specificity, plant lectins are … Many plants contain carbohydrate-binding proteins that are commonly designated as lectins, agglutinins, or hemagglutinins. Due to the obvious differences in molecular structure, biochemical properties, and carbohydrate-binding specificity, plant lectins are usually considered a complex and heterogeneous group of proteins. Recent advances in the structural analysis of lectins and molecular cloning of lectin genes enable subdividision of plant lectins in a limited number of subgroups of structurally and evolutionary related proteins. Four major lectin families, namely, the legume lectins, the chitin-binding lectins composed of hevein domains, the type 2 ribosome-inactivating proteins, and the monocot mannose-binding lectins comprise the majority of all currently known plant lectins. In addition to these four large families the jacalin-related lectins, the amaranthin family, and the Cucurbitaceae phloem lectins are now recognized as separate subgroups. Each of the above-mentioned lectin families is discussed in detail. The description of the individual lectin families includes (1) a brief historical note, (2) an overview of the occurrence, molecular structure, and primary structure of the lectins, (3) a detailed discussion of the structure of the gene(s) and the biosynthesis and posttranslational processing of the primary translation products, (4) a summary of carbohydrate-binding specificity, (5) if relevant a note on the occurrence of lectin-related proteins, (6) a description of the three-dimensional structure of the lectins and the protomers, (7) a detailed discussion of the molecular evolution, and (8) a critical assessment of the physiological role of each group of lectins. Lectins that cannot be classified into one of the seven groups are discussed separately. General conclusions about the structure, evolution, and function of plant lectins are summarized in the concluding remarks.

A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration

2005-05-20

Thorsten Buch , Frank L. Heppner , Christine Tertilt +5 more

Structure, Function, and Genetics of Ribosomes

1986-01-01

Britta Denise Hardesty , Gisela Kramer

Diphtheria Toxin

1977-06-01

A. M. Pappenheimer

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth … The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More

Drug targeting

2000-10-01

Vladimir P. Torchilin

A review of herbal therapeutics for the prevention and management of poxvirus infections

2025-06-25

Faiz Ahmad , Anu Sachdeva , Bikash Kumar Sah +3 more | Archives of Microbiology

Rabies virus utilizes neuropilin 2 as an endocytic receptor to trigger TGFBR1-mediated actin polymerization

2025-06-25

Ziruo Sun , Jinqiu Wang , Zhiyuan Wen +7 more | Journal of Virology

ABSTRACT Rabies virus (RABV), belonging to the rhabdovirus, is a typical large virus that enters cells via clathrin-mediated endocytosis (CME). RABV-containing pits are only partially clathrin-coated and require local actin … ABSTRACT Rabies virus (RABV), belonging to the rhabdovirus, is a typical large virus that enters cells via clathrin-mediated endocytosis (CME). RABV-containing pits are only partially clathrin-coated and require local actin polymerization for efficient internalization. This unconventional entry process suggests that a specific receptor may be required to initiate actin polymerization during RABV entry. Here, we found that RABV uses the cell membrane protein neuropilin 2 (NRP2) to initiate F-actin polymerization. NRP2 is required for RABV infection and directly interacts with RABV glycoprotein. An antibody against the ectodomain of NRP2 and the soluble ectodomain of NRP2 blocked RABV infection in cells. Expression of human NRP2 in non-susceptible DU145 cells enabled RABV infection. We further found that NRP2 interacted with transforming growth factor-β receptor I (TGFBR1), triggering TGFBR1/2-Cdc42-mediated F-actin polymerization. Vesicular stomatitis virus, another prototypical rhabdovirus, also uses a similar mechanism to enter cells. Our findings demonstrate that NRP2 is a novel receptor for RABV entry by transducing the signal of viral binding across the plasma membrane to initiate actin polymerization. NRP2 may represent one of the long-sought molecules that facilitate large pathogen cell entry via CME. IMPORTANCE Rabies virus (RABV) enters cells via clathrin-mediated endocytosis (CME), but RABV-containing pits are only partially clathrin-coated, requiring actin polymerization for efficient entry. However, how the virus triggers the actin polymerization remains unclear. Here, we found that the cell membrane protein neuropilin 2 (NRP2) is required for RABV infection and directly interacts with RABV glycoprotein. An antibody against the ectodomain of NRP2 and the soluble ectodomain of NRP2 blocked RABV infection in cells. Expression of human NRP2 in non-susceptible DU145 cells enabled RABV infection. We further found that NRP2 interacted with transforming growth factor-β receptor I (TGFBR1), triggering TGFBR1/2-Cdc42-mediated F-actin polymerization. Vesicular stomatitis virus, another prototypical rhabdovirus, also uses a similar mechanism to enter cells. Our findings demonstrate that NRP2 is a novel receptor for RABV entry by initiating actin polymerization and may represent one of the long-sought molecules that facilitate large pathogen cell entry via CME.

Plant-Based Chaperones as Potential Therapeutic Options for Neurodegenerative Diseases

2025-06-24

Temidayo Olamide Adigun , Mutiu A. Alabi , Raliat A. Aladodo +6 more | CRC Press eBooks

Genetic mutations enhance the production of Exotoxin A by Pseudomonas aeruginosa for use as a potential anticancer therapeutic agent

2025-06-23

Ibtesam S. Almami | Experimental and Therapeutic Medicine

Microbial proteins have emerged as promising anticancer agents for various cancer types. Pseudomonas aeruginosa derived-Exotoxin A is a potent virulence factor that specifically binds to the α2-macroglobulin cell receptor. It … Microbial proteins have emerged as promising anticancer agents for various cancer types. Pseudomonas aeruginosa derived-Exotoxin A is a potent virulence factor that specifically binds to the α2-macroglobulin cell receptor. It exhibits strong cytotoxicity and potential advantages over conventional cancer treatments due to its ability to penetrate cancer cell membranes and inhibit protein synthesis. In the present study, 20 P. aeruginosa isolates collected from microbiological laboratories between October 2023 and January 2024 were characterized. The isolates were identified using classical biochemical tests, confirmed using an automated identification system, and classified into six groups based on SDS-PAGE protein banding patterns. The gene encoding Exotoxin A was amplified in one isolate from each group using PCR, yielding a 367-bp amplicon. To enhance the production of Exotoxin A, random mutations were introduced to the selected isolates using UV irradiation. Exotoxin A was then purified using column chromatography followed by dialysis, resulting in a product with a molecular mass of ~66 kDa as determined by SDS-PAGE. The cytotoxic effects of crude and purified Exotoxin A were assessed against the MCF-7 breast cancer cell line. MTT assay results revealed that the half-maximal inhibitory concentration (IC50) of purified Exotoxin A from a wild-type isolate was 4.9 µg/ml, whereas the corresponding mutant exhibited an IC50 of 3.6 µg/ml, indicating a 1.4-fold increase in cytotoxic activity. The findings of the present study highlight the potential of microbial-derived proteins in cancer therapy. However, further evaluation of these proteins is necessary to explore their therapeutic applicability.

Fluorescence Spectroscopy Reveals Resveratrol Binding to a Hydrophobic Pocket in Leishmania amazonensis Sir2-Related Protein 1 (LaSir2RP1)

2025-06-22

Melissa Regina Fessel , Ana Paula Ribeiro Povinelli , Veronica S. Fontes +2 more | The Protein Journal

Chimeric diphtheria toxin–<scp>CCL8</scp> cytotoxic peptide for breast cancer management

2025-06-22

Bernardo Chavez , Asieh Naderi , Kim‐Tuyen Huynh‐Dam +3 more | PubMed

Deregulation of chemokine CCL8 expression is common in various malignancies and other pathologies and plays a causative role in disease progression. However, despite CCL8's acknowledged role in pathology, inhibition of … Deregulation of chemokine CCL8 expression is common in various malignancies and other pathologies and plays a causative role in disease progression. However, despite CCL8's acknowledged role in pathology, inhibition of its activity does not represent a strategy of choice for cancer management. This is because its function overlaps with that of the other structurally related chemokines, and its activity is mediated by more than one receptor. To overcome this limitation, we hypothesized that ablation of CCL8 cellular targets, as opposed to disruption of CCL8 activity, may be more advantageous. Therefore, we developed DTCCL8, a chimeric cytotoxic peptide that delivers diphtheria toxin into cells expressing CCL8 receptors which are overexpressed in both the cells of tumor microenvironment and the cancer cells. The specificity of this peptide was confirmed in vitro by testing the cytotoxic activity of breast cancer cells overexpressing CCR5, a major CCL8 receptor, and by a neutralizing anti‐CCL8 antibody we developed. In vivo , DTCCL8 transiently reduced lymphocytes in blood, and its anticancer activity was confirmed in mouse breast cancers triggered by the polyoma middle T oncogene. These findings suggest that DTCCL8 can be used as a prototype for the development of a novel class of breast cancer therapeutics, targeting chemokine targets instead of inhibiting their activity. These cytotoxic peptides may also be useful for managing cancers and other immune system‐associated pathologies.

Применение специфического иммуноглобулина в комплексной терапии пациентов с COVID-19

2025-06-20

Т.А. Игитян , O. Burgasova , Д. А. Огаркова | Клиническая инфектология и паразитология

Введение. Нейтрализующие антитела эффективно ингибируют размножение виру сов и снижают тяжесть заболевания. С появлением новых штаммов COVID-19 многие препараты моноклональных антител потеряли перекрестную нейтрализующую активность. КОВИД-глобулин – высокоочищенный препарат специфического … Введение. Нейтрализующие антитела эффективно ингибируют размножение виру сов и снижают тяжесть заболевания. С появлением новых штаммов COVID-19 многие препараты моноклональных антител потеряли перекрестную нейтрализующую активность. КОВИД-глобулин – высокоочищенный препарат специфического иммуноглобулина G против SARS-CoV-2 для в/в введения, рассматривается в качестве эффективного средства в терапии COVID-19. Цель. Совершенствование комплексной терапии пациентов с COVID-19 с применением КОВИД-глобулина на основании анализа клинической эффективности и безопасности препарата. Материалы и методы. Проведено ретроспективное открытое рандомизированное одноцентровое исследование в период с 01.01.2022 по 31.01.2023. Под наблюдением находились 117 стационарных пациентов с COVID-19. Пациентам основной группы (n=57) КОВИД-глобулин вводили в/в капельно в дозировке 1 мл/кг массы тела на 1–18-й дни болезни. В динамике проводили наблюдение и анализ клинических и лабораторно-инструментальных показателей у пациентов. Статистический анализ проводили с помощью программы IBM SPSS Statistics ver. 26 (IBM, США). Результаты. Анализ основных параметров в динамике показал нарастание SpO2 до 96%, снижение ЧДД до 20 уд/мин (р<0,001). В группе пациентов, не получивших КОВИД-глобулин, была выявлена достоверно более выраженная степень поражения легких (КТ) в динамике заболевания: при выписке у пациентов, получивших КОВИД-глобулин, КТ-0 определялось у 70,4% пациентов, тогда как у пациентов, не получивших КОВИД-глобулин, КТ-0 было выявлено у 10,5% пациентов. У пациентов, получивших КОВИД-глобулин, было отмечено снижение уровня СРБ в динамике – 32 мг/л [10–91,75] при поступлении и 19 мг/л [13,5–42,25] при выписке. Не было отмечено явной положительной клинико-лабораторной динамики при однократном введении препарата спустя 7 дней от начала болезни. Заключение. Полученные результаты проведенного исследования демонстрируют эффективность и безопасность раннего (до 7-го дня болезни) применения КОВИД-глобулина в дозировке 1 мл/кг массы тела в комплексной терапии пациентов с COVID-19. Introduction. Neutralizing antibodies effectively inhibit viral replication and reduce the severity of the disease. With the emergence of new COVID-19 strains, many monoclonal antibody preparations have lost cross-neutralizing activity. COVID-globulin is a highly purified preparation of specific immunoglobulin G against SARS-CoV-2 for intravenous administration, considered as an effective agent in the treatment of COVID-19 [1]. Purpose. Improve the combination therapy of patients with COVID-19 using COVID-globulin based on an analysis of the clinical efficacy and safety of the drug. Materials and methods. A retrospective, open, randomized, single-center study was conducted from 01.01.2022 to 01.31.2023. 117 inpatients with COVID-19 were observed. Patients of the main group (n=57) were administered COVID-globulin intravenously by drip at a dosage of 1 ml/kg of body weight on days 1–18 of the disease. Clinical, laboratory and instrumental parameters of patients were observed and analyzed dynamically. Statistical analysis was performed using IBM SPSS Statistics ver. 26 (IBM; USA). Results. Analysis of the main parameters over time showed: an increase in SpO2 to 96%, a decrease in respiration rate to 20 bpm (p<0.001). In the group of patients who did not receive COVID globulin, a significantly more pronounced degree of lung damage (CT) was revealed in the dynamics of the disease: upon discharge, in patients who received COVID globulin, CT-0 was determined in 70.4% of patients, while in patients who received COVID globulin, CT-0 was detected in 10.5% of patients. In patients who received COVID globulin, a decrease in the level of CRP was noted in dynamics after the administration of 32 mg/l [10–91.75] upon admission and 19 mg/l [13.5–42.25] upon discharge in patients who received COVID globulin (p<0.001). No obvious positive clinical and laboratory dynamics were observed with a single administration of the drug 7 days after the onset of the disease. Conclusions. The results of the study demonstrate the effectiveness and safety of early (before the 7th day of illness) use in patients who received COVID-globulin at a dosage of 1 ml/kg of body weight in the complex therapy of patients with COVID-19.

Targeting Cadherins with Colicins: Molecular Docking and Dynamics Reveal Disruptive Potential in Cancer Metastasis

2025-06-20

Poornima Baskar Vimala , Leela Kagithakara Vajravelu , Rahul Harikumar Lathakumari +3 more | Computational Biology and Chemistry

In vivo Evaluation of the Acaricidal Efficacy of Polyherbal Aqueous Formulation against Rhipicephalus microplus Infested Cattle Calves

2025-06-19

Yogita Yadav , Nidhi S. Choudhary , H. K. Mehta +5 more | Deleted Journal

Comparative Efficacy of Ribosome-Inactivating Protein-Containing Immunotoxins in 2D and 3D Models of Sarcoma

2025-06-18

Giulia Calafato , Massimo Bortolotti , Letizia Polito +1 more | Toxins

Sarcomas are very complex and clinically challenging mesenchymal tumors. Although the standard therapeutic approach has improved the 5-year survival rate, many patients experience local relapses and/or distant metastases. To improve … Sarcomas are very complex and clinically challenging mesenchymal tumors. Although the standard therapeutic approach has improved the 5-year survival rate, many patients experience local relapses and/or distant metastases. To improve patient outcome, new strategies need to be investigated. Immunotoxins (ITs) based on rRNA N-glycosylases (also named ribosome-inactivating proteins, RIPs) are promising tools for cancer therapy because, by combining rRNA-glycosylase's high cytotoxicity with carrier selectivity, they can specifically eliminate target neoplastic cells. In the last few years, 3D models have been extensively used in cancer research, particularly for target-specific drug screening. This study aimed to evaluate the possibility of utilizing ribosome-inactivating protein (RIP)-containing ITs to selectively target TfR1-, EGFR1- and Her2-expressing sarcoma adherent cells (ACs), spheroids (SSs) and organoids (ORs). To compare Its' efficacy and ability to induce apoptosis, we performed dose-response viability and caspase 3/7 activation assays on rhabdomyosarcoma and osteosarcoma ACs, SSs and ORs treated with Tf-IT, αEGFR1-IT and αHer2-IT. Our results indicate that, compared to the corresponding unconjugated RIPs, all ITs showed increased cytotoxicity in sarcoma ACs. Despite the increased complexity characterizing 3D models, the higher IC50 differences between ITs and unconjugated RIPs were obtained in ORs, which appeared more resistant to the nonspecific killing of the RIPs than either the ACs or SSs, thus augmenting the therapeutic window between unconjugated and conjugated RIPs. IT induced a more delayed apoptosis in 3D compared to 2D models. Our results provide essential outcomes for the potential use of these RIP-based ITs as a therapeutic strategy to treat sarcoma.

Immunotoxin: A New Generation Agent for Cancer Treatment

2025-06-18

Subha R. Das , Dibyendu Giri , Tamanna Roy +5 more | BENTHAM SCIENCE PUBLISHERS eBooks

According to WHO/ Pan American Health Organization, 10 million global cancer deaths have been estimated in 2023. The International Agency for Research on Cancer (IARC) declares that over the ensuing … According to WHO/ Pan American Health Organization, 10 million global cancer deaths have been estimated in 2023. The International Agency for Research on Cancer (IARC) declares that over the ensuing two decades, the burden of cancer will augment by about 60%. For several years, the main treatment modalities for cancer were entailing chemotherapy, radiotherapy, and surgery. Conventional chemotherapies were not tumor-tissue specific and presented a large toll of toxicities for normal cells. But in the last two decades, the idea of targeted therapy, where drug or protein molecules are delivered to specific cells, is a captivating approach to treating malignancy. Immunotoxins comprising a toxin together with an antibody or growth factor hinder the growth and progression of cancer by disrupting specific genes that employ tumor growth and development. With further advances, it is expected that immunotoxins will exhibit a brilliant role and will bring a new era in the treatment of malignancy.

Tricin selectively combats KRAS-mutant non-small cell lung cancer by inhibiting the PDGF-BB-induced SRC/MAPK/AP-1/PD-L1 signaling pathway and potentiating the antitumor effect of an anti-PD-1 antibody

2025-06-17

Jiaxin Li , Shiyu Tan , Li-Qi Li +7 more | Frontiers in Pharmacology

Background KRAS is a commonly mutated gene that is present in approximately 30% of NSCLC patients. Currently, the identification of effective therapies for KRAS-mutant NSCLC is difficult for reasons of … Background KRAS is a commonly mutated gene that is present in approximately 30% of NSCLC patients. Currently, the identification of effective therapies for KRAS-mutant NSCLC is difficult for reasons of the structural and biochemical characteristics of the KRAS protein. Our previous study has revealed that tricin was a bioactive component having selective effects on KRAS G12C -mutant NSCLC cell lines. Thus, our aim in this project was to explore the mechanism by which tricin inhibited the progression of KRAS-mutant NSCLC much more deeply. Methods First of all, we detected the acute toxicity of an intraperitoneal injection of tricin in mice according to the improved up-and-down procedure. Next, we integrated network pharmacology, molecular docking with transcriptomics analysis and biological methods to probe the underlying mechanisms of tricin in the treatment of patients with KRAS-mutant NSCLC. Furthermore, we explored the pharmaceutical effects of combination therapy with tricin and an anti-PD-1 inhibitor. Finally, we detected and analyzed the data from clinical samples to prepare for the clinical translation of tricin. Results Intraperitoneal injection of tricin resulted in low acute toxicity. In vitro , tricin inhibited the migration, proliferation and colony formation of KRAS G12C -mutant NSCLC cells in a dose-dependent manner. Mechanistically, tricin inhibited KRAS G12C -mutant NSCLC cell growth primarily by suppressing the PDGF-BB-induced SRC/MAPK/AP-1/PD-L1 signaling pathway. SRC was identified as a potentially crucial target. In vivo , combined treatment with tricin and an anti-PD-1 antibody markedly suppressed the growth of tumors. The combination treatment had nearly no toxicity to the organs of the mice. In terms of immune regulation, tricin increased the numbers of CD8 + T lymphocytes and the levels of the functional cytokines TNFα, IFNγ, and Granzyme B. Tricin also increased the numbers of B lymphocytes and disrupted the PD-1/PD-L1 pathway. These results indicated that tricin could compensate for the deficiency of immunotherapy and enhance the antitumor activity of immunotherapy. Moreover, the detection of clinical samples indicated that the rate of SRC positivity was higher in elderly patients with KRAS mutations at the early stage. A positive correlation between the expression of SRC and PD-L1 was observed in tumor tissues. Conclusion We believe that tricin is a safe and promising agent for the treatment of patients with KRAS-mutated NSCLC. Our study provides an experimental basis for improving the clinical application of traditional Chinese medicine.

Immunopathogenetic features of lyme disease

2025-06-15

Mykola Dmytrovych Chemych , Vladyslav Svitailo , Oksana Mykolaivna Chemych +3 more | Likarska sprava

The aim: to study the immunological features of Lyme disease and the pathophysiological mechanisms that lead to multiple organ damage. Materials and methods: articles and studies published in the PubMed … The aim: to study the immunological features of Lyme disease and the pathophysiological mechanisms that lead to multiple organ damage. Materials and methods: articles and studies published in the PubMed database, the Public Health Center of the Ministry of Health of Ukraine, Karger, Onlinelibrary, CDC, and Ecdc. Particular attention is paid to studies on the immunological characteristics and pathophysiological mechanisms of Lyme disease. Articles published between 2013 and 2024 were analyzed using systematic literature review methods and comparative analysis of clinical results to ensure the relevance and accuracy of the conclusions. Conclusions: In the process of diagnosing Lyme disease, clinicians may currently encounter a wide range of manifestations, leading to both underdiagnosis and overdiagnosis of this disease. The incidence of this disease in Ukraine and worldwide fluctuates, showing periods of increase and decrease, while the overall trend is upward. The development of chronic forms of Lyme disease is a complex process involving many links in cellular and humoral immunity. The balance of cytokines, including IL-1β, IL-2, IL-6, IL-8, IL-10, IL-15, IL-17, and IFN-γ, is crucial in the development of Lyme arthritis, chronic atrophic acrodermatitis, and neuroborreliosis, and IL-17 levels can be used as a diagnostic marker for some chronic forms of this disease.

Potencial antitumoral de exotoxinas bacterianas

2025-06-14

Francisco Rômulo Estevam Da Silva , Joaquim Abreu de Sousa , Luís Costa +1 more | Revista Intertox de Toxicologia Risco Ambiental e Sociedade

As exotoxinas bacterianas têm ganhado destaque na pesquisa oncológica por apresentarem propriedades capazes de interferir diretamente na viabilidade de células tumorais. Inicialmente reconhecidas por seu papel patogênico, essas proteínas passaram … As exotoxinas bacterianas têm ganhado destaque na pesquisa oncológica por apresentarem propriedades capazes de interferir diretamente na viabilidade de células tumorais. Inicialmente reconhecidas por seu papel patogênico, essas proteínas passaram a ser exploradas como potenciais agentes terapêuticos, especialmente por mecanismos como a inibição da síntese proteica, a indução de apoptose e a modulação de vias imunes no microambiente tumoral. O presente estudo foi desenvolvido por meio de uma revisão de literatura, com consulta às bases de dados MEDLINE, LILACS, EMBASE e SCOPUS, a fim de reunir e analisar evidências sobre os mecanismos de ação e a eficácia terapêutica das toxinas em questão no tratamento de neoplasias malignas. Os estudos selecionados demonstraram que exotoxinas, como aquelas derivadas de Pseudomonas aeruginosa, Bacillus anthracis e Shigella dysenteriae, vêm sendo reestruturadas por meio de engenharia molecular para aumentar sua seletividade por células tumorais, minimizando danos aos tecidos saudáveis. Ensaios in vitro e in vivo indicam eficácia citotóxica significativa em diferentes modelos tumorais, como mama, pâncreas, bexiga, região colorretal e sistema nervoso central. A imunogenicidade, a estabilidade estrutural e a heterogeneidade tumoral constituem obstáculos à sua aplicação clínica em larga escala. Frente a essas limitações, estratégias como a conjugação com ligantes tumorais, a encapsulação em nanopartículas e o uso de sistemas de liberação controlada são propostas favoráveis para aprimorar sua eficácia e segurança. Conclui-se que as exotoxinas bacterianas representam uma alternativa promissora na terapêutica oncológica, especialmente no contexto da medicina personalizada, sendo necessária a continuidade de pesquisas e ensaios in vivo para sua validação clínica.

The Development of a Sensitive and Selective Method for the Quantitative Detection of Ricin via ICP-MS Combined with Metal Element Chelated Tag and Modified Nanoparticles

2025-06-12

Long Yan , Kexuan Li , Ji-Na Wu +3 more | International Journal of Molecular Sciences

As a type II ribosome-inactivating protein (RIP-II) toxin, Ricin has garnered widespread recognition due to its inherent qualities as an easily prepared and highly stable substance, posing serious implications as … As a type II ribosome-inactivating protein (RIP-II) toxin, Ricin has garnered widespread recognition due to its inherent qualities as an easily prepared and highly stable substance, posing serious implications as a potential chemical and biological terrorist threat. For the detection of ricin, traditional immunoassay technologies, including methods like peptide cleavage combined with liquid chromatography mass spectrometry (LC-MS) or the more commonly used enzyme-linked immunosorbent assay (ELISA), have offered reliable results. However, these techniques are unfortunately limited by the requirement of a complex sample pretreatment process, which can be time-consuming and labor-intensive. In an effort to overcome these limitations, a highly sensitive and selective method was introduced via metal element labeling combined with inductively coupled plasma mass spectrometry (ICP-MS) in this research. The method centered on designing and synthesizing a europium-labeled compound (DOTA-NHS-Eu) that specifically targets the amino groups (-NH2) on ricin. The compound, coupled with the application of specific magnetic beads, achieved the specific enrichment and subsequent quantitative detection of ricin by ICP-MS, which is based on the amount of europium element present. The established method demonstrated high specificity for ricin recognition, with a signal response to bovine serum protein that was found to be less than 10% of that for ricin. Furthermore, the calibration curve created for the method (y = 81.543x + 674.02 (R2 > 0.99)) for quantifying ricin in a concentration range of 1.0–100 μg/mL demonstrated good linearity. The method was further evidenced by the limit of detection and quantitation results of 0.1 and 1.89 μg/mL, respectively. Collectively, these findings suggested that the research has offered a highly sensitive and selective method for ricin detection, which was not only easy to operate but also provided efficient results. The scheme showed great potential for the verification of chemical weapons and the destruction of toxic chemicals, therefore representing a significant advancement in the field of biomolecular detection and analysis.

Uncovering the Anti-Herpetic Activity of Anionic Peptides Derived From the Cytoplasmic Domain of Nectin-1

2025-06-01

Rakesh Ravishankar Rahangdale , Sumit Birangal , Gautham G. Shenoy +3 more | Bioinformatics and Biology Insights

Nectin-1/herpes simplex virus glycoprotein D (HSV gD) interaction is crucial to drive herpes simplex virus (HSV) entry. Polyanions are known to show great potential as antivirals. Thus, we explored a … Nectin-1/herpes simplex virus glycoprotein D (HSV gD) interaction is crucial to drive herpes simplex virus (HSV) entry. Polyanions are known to show great potential as antivirals. Thus, we explored a peptide-based biotherapeutic approach and, for the first time, evaluated an anionic peptide derived from nectin-1 designed to bind HSV gD. Peptides enriched in acidic and basic residues were selected and computationally modeled using PEP-FOLD3, PROCHECK, ClusPro 2.0, and Desmond. Their antiviral efficacy was tested through virucidal, cell pretreatment, attachment inhibition, entry inhibition, and cytopathic effect (CPE) inhibition assays using a 10 TCID50 (Tissue Culture Infectious Dose 50%) viral dose. Among 4 designed peptides, C1 and C2 showed strong binding to HSV-1 and HSV-2 gD in molecular dynamic (MD) simulations. Peptide C1 exhibited significant virucidal activity (HSV-1: 64.92%, HSV-2: 67.16%), attachment inhibition (HSV-1: 62.03%, HSV-2: 59.38%), and host cell-entry inhibition (HSV-1: 71.37%, HSV-2: 76.28%) at 250 µg/mL concentration. Combination treatment with peptides C1 and C2 at a final concentration of 250 µg/mL (125 µg/mL each) exhibited an additive effect against HSV-1 (68.57%) and HSV-2 (73.37%) infections when tested by CPE inhibition assay. This highlights the potential of HSV gD-targeted anionic peptides for future anti-HSV therapeutics.

Mechanisms and synergistic effects of the active components of Xanthocerais lignum in inhibiting rheumatoid arthritis through the modulation of the biological behavior of synovial cells

2025-06-01

Hao Qian , Bai Cui-lan , Xin Jia +3 more | Journal of Ethnopharmacology

Analyses of Spatiotemporal Variation of Antioxidative Activity in Common Mistletoe (Viscum Album l.) Accompanied by Antibacterial Activity of Green Synthesized Silver Nanoparticles

2025-06-01

Lidija Kalinić , Martina Šrajer Gajdošik , Valentina Pavić +5 more | ChemistrySelect

Abstract Common mistletoe ( Viscum album L.) is a semi‐parasitic plant that grows on various woody species and is known for its anti‐inflammatory, antibacterial, and antitumor properties. It is used … Abstract Common mistletoe ( Viscum album L.) is a semi‐parasitic plant that grows on various woody species and is known for its anti‐inflammatory, antibacterial, and antitumor properties. It is used in the treatment of various diseases and conditions. The antioxidant properties of mistletoe depend on the type of the host, region, and sampling time. In this study, we investigated the impact of location and sampling time on the content of bioactive compounds content and antioxidative activity in a freshly harvested mistletoe leaves, twigs, and commercial tea mixtures. Additionally, we present a suitable green synthesis procedure for silver nanoparticles (AgNPs) using mistletoe extract, followed by antimicrobial activity analyses. Samples harvested in October exhibited significantly higher content of bioactive compounds compared to those collected in February. Fresh samples and commercial tea mixtures showed no significant difference in measured parameters, except for the samples in Istria, Petrijevci, and Aljmaš. AgNPs were successfully synthesized using mistletoe methanolic extract with a UV–vis absorption peak at 439 nm. The crystallite diameter of the AgNPs, as determined by PXRD averaged 21 nm. The AgNPs synthesized using mistletoe methanolic extract demonstrated potent antimicrobial activity against the human pathogens Escherichia coli (E. coli) , Pseudomonas aeruginosa (P. aeruginosa), Bacillus subtilis (B. subtilis) , and Staphylococcus aureus (S. aureus) .

Phytochemical analysis, molecular docking, in vitro cytotoxicity, enzyme inhibition and antioxidant activity of Viscum album subsp. austriacum in Turkey

2025-06-01

Yakup Kadri TEKEL , Mehmet Hakkı Alma , Yunus Başar +5 more | Biocatalysis and Agricultural Biotechnology

Recent advances of trichosanthin and its role in diseases

2025-06-01

Bin He , Hang‐Ping Yao , Xiaoqian Zhang | Fitoterapia

Methanol Leaf Extract of Ricinus communis L. Mitigates Dichlorvos-Induced Cardiac Injury via Anti-Inflammatory, Antioxidant, and Anti-Apoptotic Mechanisms in Wistar Rats

2025-05-31

Waidi Adeoye Saka , Funmilayo M. Moronkeji , Funmilayo M. Akano +3 more | Tropical Journal of Natural Product Research

SIRNA: ITS TRANSLATIONFROM RESEARCH TO THERAPEUTIC APPLICATIONS

2025-05-31

Prerana Prakash , M G Hariprasad | International Journal of Advanced Research

Small interfering RNA (siRNA) is a short, double-stranded RNA molecule that has emerged as a pivotal tool for gene silencing through the RNA interference (RNAi) pathway. It is a powerful … Small interfering RNA (siRNA) is a short, double-stranded RNA molecule that has emerged as a pivotal tool for gene silencing through the RNA interference (RNAi) pathway. It is a powerful post-transcriptional gene-silencing molecule central to RNA interference (RNAi) mechanisms1. Typically 21â€“25 nucleotides in length, it guides the RNA-induced silencing complex (RISC) to a target messenger RNA (mRNA), enabling sequence-specific degradation and effectively silencing gene expression2. This process is highly specific and forms the foundation for siRNAâ€™s role in research and therapeutic interventions3. By guiding the RNA-induced silencing complex (RISC) to target mRNA, siRNA enables post-transcriptional gene regulation with unparalleled precision. This targeted action holds immense promise in treating genetic, infectious, and degenerative diseases4. Therapeutically, siRNA offers unique advantages over traditional treatments, including the ability to target undruggable proteins, rapid development timelines, and reduced systemic toxicity. These advantages have catalyzed interest in siRNA for precision medicine and rare genetic disorders5

3,4-Dihydroxybenzoic acid methyl ester from Vespa velutina auraria Smith against rheumatoid arthritis via modulating the apoptosis and inflammation through NF-κB pathway

2025-05-31

Yi-Hao Che , Chao-He Liu , Xiu-Qin Pang +4 more | Inflammopharmacology

Insecticidal potential of seeds of Datura metel L., Abrus precatorius L., and Diploknema butyracea (Roxb.) H.J. Lam

2025-05-30

Elina Maharjan , Mui‐Yun Wong , Sudeep Kumar Upadhyay +4 more | Banko Janakari

The present study aimed to assess the insecticidal efficacy of methanol extracts of the seeds of three plants: Datura metel L., Abrus precatorius L., and Diploknema butyracea (Roxb.) H.J. Lam. … The present study aimed to assess the insecticidal efficacy of methanol extracts of the seeds of three plants: Datura metel L., Abrus precatorius L., and Diploknema butyracea (Roxb.) H.J. Lam. The bioactive compounds in crude extracts were analyzed using Fourier Transform Infrared (FTIR) spectroscopy and Gas Chromatography- Mass Spectrometry (GC-MS). Insecticidal activities of different concentrations of extracts were evaluated against adults and the second instar larvae of Drosophila melanogaster by using ingestion and spraying methods. Among the three seeds, the extract of Datura metel L. at a concentration of 30 mg/mL consistently exhibited a higher mortality rate of 73.33±7.64% against adult insects while applying each method. However, all concentrations of the seed extracts exhibited lower mortality rates in larvae compared to adults of D. melanogaster. The qualitative phytochemical analysis of the seed extracts revealed the presence of detected alkaloids, phenols, flavonoids, carbohydrates, saponins, and tannins. FTIR analysis of the seeds revealed the presence of alcohols or phenols, alkanes, esters or ethers, amines, ketones, and nitro-compounds. GC-MS analysis identified a wide array of bioactive compounds. Abrus precatorius L. contained 1,2,3-benzenetriol, and 9-octadecenoic acid, methyl ester (E)-. Atropine, and scopolamine were abundantly detected in Datura metel L. Similarly, stigmasterol, 2,4,6-triaminoquinazoline, and brucine were identified in Diploknema butyracea (Roxb.) H.J. Lam. Since these GC-MS identified compounds are known for insecticidal properties, the seeds of all three plants particularly Datura metel L., can be a potential candidate for development as biopesticide against insect pests. Although field applications require further verification, our findings provide laboratory-based evidence supporting the potential of Nepalese indigenous plant-based biopesticides for reducing crop loss and enhancing food security.

Ficha de Aulostomus strigosus

2025-05-29

Alfredo Carvalho‐Filho , Fabio Di Dario , Matheus Marcos Rotundo +5 more | Datasets - Sistema SALVE - ICMBio

Novel Proteins to Neutralize Venom Toxins

2025-05-28

José Marı́a Gutiérrez | New England Journal of Medicine

Development and validation of a biology-based novel therapeutic agent targeting the LIN28/ let-7 pathway in cancer.

2025-05-28

Patrick Sipila , Yusheng Zhao , N. Susan +2 more | Journal of Clinical Oncology

3114 Background: Currently, brain tumors that are diagnosed in infants and young children carry an exceptionally high risk for treatment resistance and toxicities. The LIN28 family of RNA-binding proteins regulate … 3114 Background: Currently, brain tumors that are diagnosed in infants and young children carry an exceptionally high risk for treatment resistance and toxicities. The LIN28 family of RNA-binding proteins regulate stem cell biology and pluripotency. In addition to embryonic development, they have also been implicated in oncogenesis through interaction with the tumor suppressor micro-RNA (miRNA), let-7 . In cancer, LIN28 expression leads to let-7 loss-of-function, oncogenic activation, and tumorigenesis. Importantly, LIN28 expression has been associated with stemness and subsequent tumor aggressiveness and poor survival in early childhood brain tumors. Thus, LIN28 may offer an effective therapeutic strategy to prevent relapse by specifically targeting cancer stem cells. In this study, we describe a novel therapeutic inhibitor of LIN28 in cancer. Methods: Using an in silico approach, we designed and synthesized a panel of novel compounds predicted to bind and inhibit the critical molecular interaction between LIN28 and let-7 . Cytotoxicity was evaluated by alamar blue viability assay in a panel of LIN28-positive cancer cell lines derived from atypical teratoid rhabdoid tumor (ATRT), embryonal tumor with multilayered rosettes (ETMR), and germ cell tumor. LIN28-negative cells were used as control. LIN28 protein expression and let-7 miRNA levels were determined by immunoblot and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. Self-renewal capacity was analyzed by sphere formation assay. Mice carrying xenografts were treated to investigate LIN28 inhibition in vivo . Results: Preliminary screening of small molecule inhibitors identified a lead compound, designated THNB-3, that induces cell death at micromolar concentrations in LIN28-positive cell lines established from various tumors, without affecting LIN28-negative controls. Treatment with THNB-3 increased the level of let-7 tumor suppressor, confirming effective inhibition of LIN28. In addition to cytotoxicity, THNB-3 significantly inhibited sphere formation in brain tumor cells, reducing self-renewal and multipotency of cancer stem cells. Lastly, the anticancer activity of THNB-3 was validated in vivo against LIN28-positive xenografts and the drug also demonstrated systemic tolerability in mice. Conclusions: Our studies provide the first evidence for an effective, targeted therapeutic agent against the LIN28/ let-7 pathway for the treatment of cancer in the future. THNB-3 selectively induces cytotoxicity in LIN28-positive cancers by restoring let-7 miRNA, confirming effective target modulation. Further, LIN28 inhibition by THNB-3 may reduce self-renewal and multipotency of cancer stem cells. Together, our preclinical data supports further development of THNB-3 for the treatment of high-risk LIN28-positive tumors.

Preliminary results from a first-in-human phase 1 dose escalation trial of ADRX-0706, a next generation Nectin-4 ADC, in subjects with advanced solid tumors.

2025-05-28

Alexandra Drakaki , Justin Call , Sreenivasa R Chandana +7 more | Journal of Clinical Oncology

3018 Background: ADRX-0706 is a Nectin-4 targeting ADC designed to provide an increased therapeutic window through stable conjugation of a novel microtubule inhibitor payload (AP052) to an IgG1 monoclonal antibody … 3018 Background: ADRX-0706 is a Nectin-4 targeting ADC designed to provide an increased therapeutic window through stable conjugation of a novel microtubule inhibitor payload (AP052) to an IgG1 monoclonal antibody at a drug-to-antibody ratio of 8. Preliminary safety, anti-tumor activity, pharmacokinetic (PK) and Nectin-4 expression results are presented from the dose escalation part of the ongoing Phase 1 trial (NCT06036121). Methods: Eligible subjects with select advanced solid tumors (urothelial [UC], cervical [CC], breast [BC], head and neck [HNSCC], ovarian [OC], non-small cell lung [NSCLC], and pancreatic [PC]) were enrolled in cohorts of escalating dose levels (1-16 mg/kg, Q3W, IV) using a BOIN design with backfill. Nectin-4 expression was evaluated retrospectively. Primary and secondary endpoints included dose-limiting toxicities [DLTs], adverse events [AEs], laboratory value changes, PK, immunogenicity, and response per RECIST v1.1. Results: As of the 13Dec24 data cutoff, 53 subjects with a median age of 59 years and median of 4 (1-14) prior therapies were enrolled. One DLT (G3 stomatitis) occurred at the highest dose of 16 mg/kg. The most common treatment related AEs (TRAE ≥15%) were arthralgia (32%), fatigue (21%), rash (19%), anemia (17%), and nausea (15%). The majority of TRAEs were G1-2 in severity and manageable, including only 3 (5.7%) subjects with peripheral neuropathy and 2 (3.8%) with liver enzyme increase. The most common ≥G3 TRAE was neutropenia (11%). ADC exposure increased in a dose-proportional manner with minimal deconjugation and the ADC half-life was 15 days. There were 5 subjects who achieved objective response across different tumor types (UC, NSCLC, CC) and 9 with stable disease per RECIST among 30 response-evaluable subjects treated at doses ≥8 mg/kg (ORR 16.7%, DCR 46.7%), including 2 triple negative BC (TNBC) subjects with 27% and 29% decrease in tumor size who remain on treatment. ADRX-0706 demonstrated Nectin-4 expression-dependent anti-tumor activity with all responses observed in tumors with H-score ≥100, including a confirmed complete response (CR) in a CC subject (H-score 250). Two responses were observed after prior progression on other Nectin-4 targeting MMAE drugs and three responses remain ongoing with subjects on treatment for 9+ to 23+ weeks. Based on these data, 10 mg/kg Q3W was selected as the Phase 1b dose. Conclusions: ADRX-0706 demonstrated a preliminary safety profile differentiated from MMAE-conjugates and with manageable toxicities. The antibody-like PK profile together with minimal deconjugation supports Q3W dosing. Encouraging anti-tumor activity was observed in multiple heavily pretreated tumors with moderate-high Nectin-4 expression. Enrollment in Phase 1b cohorts of UC, CC, and TNBC is ongoing. Clinical trial information: NCT06036121 .