A Humanized Monoclonal Antibody Potentiates Killing by Antibiotics of Diverse Biofilm-Forming Respiratory Tract Pathogens

2022 ◽  
Author(s):  
Nikola Kurbatfinski ◽  
Steven D. Goodman ◽  
Lauren O. Bakaletz
Keyword(s):  
Monoclonal Antibody ◽  
Respiratory Tract ◽  
Dependent Manner ◽  
Structural Element ◽  
Bacterial Diseases ◽  
Humanized Monoclonal Antibody ◽  
Highly Sensitive ◽  
Physiologic State ◽  
Phenotypic State ◽  
New Strategies

New strategies to treat diseases wherein biofilms contribute significantly to pathogenesis are needed as biofilm-resident bacteria are highly recalcitrant to antibiotics due to physical biofilm architecture and a canonically quiescent metabolism, among many additional attributes. We, and others, have shown that when biofilms are dispersed or disrupted, bacteria released from biofilm residence are in a distinct physiologic state that, in part, renders these bacteria highly sensitive to killing by specific antibiotics. We sought to demonstrate the breadth of ability of a recently humanized monoclonal antibody against an essential biofilm structural element (DNABII protein) to disrupt biofilms formed by respiratory tract pathogens and potentiate antibiotic-mediated killing of bacteria released from biofilm residence. Biofilms formed by six respiratory tract pathogens were significantly disrupted by the humanized monoclonal antibody in a dose- and time-dependent manner, as corroborated by CLSM imaging. Bacteria newly released from the biofilms of 3 of 6 species were significantly more sensitive than their planktonic counterparts to killing by 2 of 3 antibiotics currently used clinically and were now also equally as sensitive to killing by the 3 rd antibiotic. The remaining 3 pathogens were significantly more susceptible to killing by all 3 antibiotics. A humanized monoclonal antibody directed against protective epitopes of a DNABII protein effectively released six diverse respiratory tract pathogens from biofilm residence in a phenotypic state that was now as, or significantly more, sensitive to killing by three antibiotics currently indicated for use clinically. These data support this targeted, combinatorial, species-agnostic therapy to mitigate chronic bacterial diseases.

scholarly journals Defining Limits of Treatment with Humanized Neutralizing Monoclonal Antibody for West Nile Virus Neurological Infection in a Hamster Model

2007 ◽  
Vol 51 (7) ◽  
pp. 2396-2402 ◽  
Author(s):  
John D. Morrey ◽  
Venkatraman Siddharthan ◽  
Aaron L. Olsen ◽  
Hong Wang ◽  
Justin G. Julander ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
West Nile Virus ◽  
Time Window ◽  
Dependent Manner ◽  
Convection Enhanced Delivery ◽  
West Nile ◽  
Hamster Model ◽  
Humanized Monoclonal Antibody ◽  
Neutralizing Monoclonal Antibody ◽  
The Central Nervous System

ABSTRACT A potent anti-West Nile virus (anti-WNV)-neutralizing humanized monoclonal antibody, hE16, was previously shown to improve the survival of WNV-infected hamsters when it was administered intraperitoneally (i.p.), even after the virus had infected neurons in the brain. In this study, we evaluated the therapeutic limit of hE16 for the treatment of WNV infection in hamsters by comparing single-dose peripheral (i.p.) therapy with direct administration into the pons through a convection-enhanced delivery (CED) system. At day 5 after infection, treatments with hE16 by the peripheral and the CED routes were equally effective at reducing morbidity and mortality. In contrast, at day 6 only the treatment by the CED route protected the hamsters from lethal infection. These experiments suggest that hE16 can directly control WNV infection in the central nervous system. In support of this, hE16 administered i.p. was detected in a time-dependent manner in the serum, cerebrospinal fluid (CSF), cerebral cortex, brain stem, and spinal cord in CSF. A linear relationship between the hE16 dose and the concentration in serum was observed, and maximal therapeutic activity occurred at doses of 0.32 mg/kg of body weight or higher, which produced serum hE16 concentrations of 1.3 μg/ml or higher. Overall, these data suggest that in hamsters hE16 can ameliorate neurological disease after significant viral replication has occurred, although there is a time window that limits therapeutic efficacy.

Porcine von Willebrand Factor Binding to Human Platelet GPIb Induces Transmembrane Calcium Influx

1996 ◽  
Vol 75 (04) ◽  
pp. 655-660 ◽  
Author(s):  
Mario Mazzucato ◽  
Luigi De Marco ◽  
Paola Pradella ◽  
Adriana Masotti ◽  
Francesco I Pareti
Keyword(s):  
Monoclonal Antibody ◽  
Shear Stress ◽  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Human Platelet ◽  
Platelet Glycoprotein ◽  
Dependent Manner ◽  
Transmembrane Flux ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryPorcine von Willebrand factor (P-vWF) binds to human platelet glycoprotein (GP) lb and, upon stirring (1500 rpm/min) at 37° C, induces, in a dose-dependent manner, a transmembrane flux of Ca2+ ions and platelet aggregation with an increase in their intracellular concentration. The inhibition of P-vWF binding to GP lb, obtained with anti GP lb monoclonal antibody (LJ-Ib1), inhibits the increase of intracellular Ca2+ concentration ([Ca2+]i) and platelet aggregation. This effect is not observed with LJ-Ib10, an anti GP lb monoclonal antibody which does not inhibit the vWF binding to GP lb. An anti GP Ilb-IIIa monoclonal antibody (LJ-CP8) shown to inhibit the binding of both vWF and fibrinogen to the GP IIb-IIIa complex, had only a slight effect on the [Ca2+]i rise elicited by the addition of P-vWF. No inhibition was also observed with a different anti GP IIb-IIIa monoclonal antibody (LJ-P5), shown to block the binding of vWF and not that of fibrinogen to the GP IIb-IIIa complex. PGE1, apyrase and indomethacin show a minimal effect on [Ca2+]i rise, while EGTA completely blocks it. The GP lb occupancy by recombinant vWF fragment rvWF445-733 completely inhibits the increase of [Ca2+]i and large aggregates formation. Our results suggest that, in analogy to what is seen with human vWF under high shear stress, the binding of P-vWF to platelet GP lb, at low shear stress and through the formation of aggregates of an appropriate size, induces a transmembrane flux of Ca2+, independently from platelet cyclooxy-genase metabolism, perhaps through a receptor dependent calcium channel. The increase in [Ca2+]i may act as an intracellular message and cause the activation of the GP IIb-IIIa complex.

Nanobiotics: Challenging the anti-microbial perspective - The game changer?

2017 ◽  
Vol 6 (10) ◽  
pp. 5518 ◽  
Author(s):  
Deepak Narang ◽  
Jeevan Singh Tityal ◽  
Amit Jain ◽  
Reena Kulshreshtra ◽  
Fatima Khan
Keyword(s):  
Bacterial Resistance ◽  
Public Health Problem ◽  
Drug Resistant ◽  
European Science Foundation ◽  
Resistance Development ◽  
Bacterial Diseases ◽  
European Science ◽  
Tremendous Impact ◽  
New Strategies ◽  
Game Changer

Antibiotics are the most important medical inventions in human history and are the invaluable weapons to fight against various infectious diseases. Multi drug resistant microorganisms are becoming a serious issue and increasingly public health problem in present day scenario. Antibiotics are becoming less useful due to increasing bacterial resistance. Development of new and more powerful antibiotics leading to drastic pathogens response by developing resistance to the point where the most powerful drugs in our arsenal are no longer effective against them. New strategies for the management of bacterial diseases are urgently needed and nanomaterials can be a very promising approach. Nanobiotics uses nano-sized tools for the successful management bacterial diseases and to gain increased understanding of the complex underlying patho-physiology of disease. (European Science Foundation. Forward Look Nanomedicine: An EMRC Consensus Opinion 2005. Available online: http://www.esf.org (accessed on 15 July 2017). The application of nanotechnologies to medicine, or nanomedicine, which has already demonstrated its tremendous impact on the pharmaceutical and biotechnology industries, is rapidly becoming a major driving force behind ongoing changes in the antimicrobial field. Present review providing important insights on nanobiotics, and their preparation, mechanism of action, as well as perspectives on the opportunities and challenges in nanobiotics.

scholarly journals Mechanisms contributing to ado-trastuzumab emtansine (T-DM1)-induced toxicities: a gateway to better understanding ADC-associated toxicities

2021 ◽  
Author(s):  
Yukinori Endo ◽  
Nishant Mohan ◽  
Milos Dokmanovic ◽  
Wen Jin Wu
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Metastatic Breast ◽  
Invasive Disease ◽  
Dependent Manner ◽  
Trastuzumab Emtansine ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Humanized Monoclonal Antibody ◽  
Significant Efficacy

Abstract In order to improve the safety of novel therapeutic drugs, better understanding of the mechanisms of action is important. Ado-trastuzumab emtansine (also known as T-DM1) is an antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody directed against HER2 (trastuzumab) and a maytansinoid-derived toxin (DM1), which are linked by a non-cleavable thioether linker. T-DM1 has been approved for the treatment of trastuzumab-resistant HER2-positive metastatic breast cancer and recently for use as an adjuvant treatment option for patients with HER2-positive early breast cancer who have residual invasive disease. While the treatment with T-DM1 results in significant efficacy in the selected patient population, nonetheless, there are also concerns with the side effects such as thrombocytopenia and hepatotoxicity. While current understanding of the mechanism of T-DM1-mediated side effects is still incomplete, there have been several reports of HER2-dependent and/or -independent mechanisms that could be associated with the T-DM1-induced adverse events. The results from our laboratory show that T-DM1 binds to cytoskeleton-associated protein 5 (CKAP5) on the cell surface of hepatocytes via its payload component (DM1). This interaction is independent of HER2 and leads to cell growth inhibition and apoptosis of hepatocytes in a T-DM1 dose dependent manner. This review highlights the importance of HER2-independent mechanism of T-DM1 to induce hepatotoxicity, which offers a new insight into a role for CKAP5 in the overall maytansinoid-based ADC (DM1 and DM4)-mediated cytotoxicity. This discovery provides a molecular basis for T-DM1-induced off-target toxicity and opens a new avenue for developing the next generation of ADCs.

scholarly journals Clearance Kinetics and External Dosimetry of 131I-Labeled Murine and Humanized Monoclonal Antibody A33 in Patients with Colon Cancer: Radiation Safety Implications

2009 ◽  
Vol 96 (5) ◽  
pp. 550-557 ◽  
Author(s):  
Lawrence T. Dauer ◽  
Daniel C. Boylan ◽  
Matthew J. Williamson ◽  
Jean St. Germain ◽  
Steven M. Larson
Keyword(s):  
Monoclonal Antibody ◽  
Colon Cancer ◽  
Radiation Safety ◽  
Humanized Monoclonal Antibody ◽  
Clearance Kinetics

scholarly journals Organic Nanocarriers for Bevacizumab Delivery: An Overview of Development, Characterization and Applications

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4127
Author(s):  
Aline de Cristo Soares Alves ◽  
Franciele Aline Bruinsmann ◽  
Silvia Stanisçuaski Guterres ◽  
Adriana Raffin Pohlmann
Keyword(s):  
Monoclonal Antibody ◽  
Physicochemical Characterization ◽  
Vascular Endothelial ◽  
Organic Nanoparticles ◽  
Humanized Monoclonal Antibody ◽  
Angiogenesis Process ◽  
Endothelial Growth Factor ◽  
Drug Pharmacokinetics

Bevacizumab (BCZ) is a recombinant humanized monoclonal antibody against the vascular endothelial growth factor, which is involved in the angiogenesis process. Pathologic angiogenesis is observed in several diseases including ophthalmic disorders and cancer. The multiple administrations of BCZ can cause adverse effects. In this way, the development of controlled release systems for BCZ delivery can promote the modification of drug pharmacokinetics and, consequently, decrease the dose, toxicity, and cost due to improved efficacy. This review highlights BCZ formulated in organic nanoparticles providing an overview of the physicochemical characterization and in vitro and in vivo biological evaluations. Moreover, the main advantages and limitations of the different approaches are discussed. Despite difficulties in working with antibodies, those nanocarriers provided advantages in BCZ protection against degradation guaranteeing bioactivity maintenance.

scholarly journals Reduction of Respiratory Syncytial Virus (RSV) in Tracheal Aspirates in Intubated Infants by Use of Humanized Monoclonal Antibody to RSV F Protein

1998 ◽  
Vol 178 (6) ◽  
pp. 1555-1561 ◽  
Author(s):  
Richard Malley ◽  
John DeVincenzo ◽  
Octavio Ramilo ◽  
Penelope H. Dennehy ◽  
H. Cody Meissner ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Respiratory Syncytial Virus ◽  
F Protein ◽  
Humanized Monoclonal Antibody ◽  
Syncytial Virus ◽  
Tracheal Aspirates
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