scholarly journals The Role of Fc Receptors on the Effectiveness of Therapeutic Monoclonal Antibodies

2021 ◽  
Vol 22 (16) ◽  
pp. 8947
Author(s):  
Patricia Gogesch ◽  
Simone Dudek ◽  
Ger van Zandbergen ◽  
Zoe Waibler ◽  
Martina Anzaghe
Keyword(s):  
Point Mutations ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Antigen Specificity ◽  
Fcγ Receptor ◽  
Clinical Safety ◽  
Safety And Efficacy ◽  
Effector Functions ◽  
Experimental Approaches ◽  
Therapeutic Monoclonal Antibodies

Since the approval of the first monoclonal antibody (mAb) in 1986, a huge effort has been made to guarantee safety and efficacy of therapeutic mAbs. As of July 2021, 118 mAbs are approved for the European market for a broad range of clinical indications. In order to ensure clinical efficacy and safety aspects, (pre-)clinical experimental approaches evaluate the respective modes of action (MoA). In addition to antigen-specificity including binding affinity and -avidity, MoA comprise Fc-mediated effector functions such as antibody dependent cellular cytotoxicity (ADCC) and the closely related antibody dependent cellular phagocytosis (ADCP). For this reason, a variety of cell-based assays have been established investigating effector functions of therapeutic mAbs with different effector/target-cell combinations and several readouts including Fcγ receptor (FcγR)-mediated lysis, fluorescence, or luminescence. Optimized FcγR-mediated effector functions regarding clinical safety and efficacy are addressed with modification strategies such as point mutations, altered glycosylation patterns, combination of different Fc subclasses (cross isotypes), and Fc-truncation of the mAb. These strategies opened the field for a next generation of therapeutic mAbs. In conclusion, it is of major importance to consider FcγR-mediated effector functions for the efficacy of therapeutic mAbs.

The role of therapeutic antibodies in drug discovery

2003 ◽  
Vol 31 (2) ◽  
pp. 433-436 ◽  
Author(s):  
L.H. Stockwin ◽  
S. Holmes
Keyword(s):  
Recombinant Antibodies ◽  
Major Effect ◽  
Human Antibody ◽  
Clinical Use ◽  
Single Chain ◽  
Effector Functions ◽  
Clinical Biomarkers ◽  
Single Chain Variable Fragments ◽  
Therapeutic Monoclonal Antibodies

The last 5 years have seen a major upturn in the fortune of therapeutic monoclonal antibodies (mAbs), with nine mAbs approved for clinical use during this period and more than 70 now in clinical trials beyond phase II. Sales are expected to reach $4 billion per annum worldwide in 2002 and $15 billion by 2010. This success can be related to the engineering of mouse mAbs into mouse/human chimaeric antibodies or humanized antibodies, which have had a major effect on immunogenicity, effector function and half-life. The issue of repeated antibody dosing at high levels with limited toxicity was essential for successful clinical applications. Emerging technologies (phage display, human antibody-engineered mice) have created a vast range of novel, antibody-based therapeutics, which specifically target clinical biomarkers of disease. Modified recombinant antibodies have been designed to be more cytotoxic (toxin delivery), to enhance effector functions (bivalent mAbs) and to be fused with enzymes for prodrug therapy and cancer treatment. Antibody fragments have also been engineered to retain specificity and have increased the penetrability of solid tumours (single-chain variable fragments). Radiolabelling of antibodies has now been shown to be effective for cancer imaging and targeting. This article focuses on developments in the design and clinical use of recombinant antibodies for cancer therapy.

scholarly journals Anti-malarial drug: the emerging role of artemisinin and its derivatives in liver disease treatment

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ye Xiong ◽  
Jianrong Huang
Keyword(s):  
Liver Diseases ◽  
Molecular Mechanisms ◽  
Disease Treatment ◽  
Clinical Safety ◽  
Safety And Efficacy ◽  
Anti Cancer ◽  
Induction Of Apoptosis

AbstractArtemisinin and its derivatives belong to a family of drugs approved for the treatment of malaria with known clinical safety and efficacy. In addition to its anti-malarial effect, artemisinin displays anti-viral, anti-inflammatory, and anti-cancer effects in vivo and in vitro. Recently, much attention has been paid to the therapeutic role of artemisinin in liver diseases. Several studies suggest that artemisinin and its derivatives can protect the liver through different mechanisms, such as those pertaining to inflammation, proliferation, invasion, metastasis, and induction of apoptosis and autophagy. In this review, we provide a comprehensive discussion of the underlying molecular mechanisms and signaling pathways of artemisinin and its derivatives in treating liver diseases. Further pharmacological research will aid in determining whether artemisinin and its derivatives may serve as promising medicines for the treatment of liver diseases in the future.

scholarly journals Site-specific N-glycan Analysis of Antibody-binding Fc γ Receptors from Primary Human Monocytes

2019 ◽  
Vol 19 (2) ◽  
pp. 362-374 ◽  
Author(s):  
Jacob T. Roberts ◽  
Kashyap R. Patel ◽  
Adam W. Barb
Keyword(s):  
Nk Cell ◽  
Glycosylation Site ◽  
Antibody Binding ◽  
Recent Analysis ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Post Translational Modification ◽  
Complex Type ◽  
Post Translational Modifications ◽  
Effector Functions ◽  
Therapeutic Monoclonal Antibodies

FcγRIIIa (CD16a) and FcγRIIa (CD32a) on monocytes are essential for proper effector functions including antibody dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Indeed, therapeutic monoclonal antibodies (mAbs) that bind FcγRs with greater affinity exhibit greater efficacy. Furthermore, post-translational modification impacts antibody binding affinity, most notably the composition of the asparagine(N)-linked glycan at N162 of CD16a. CD16a is widely recognized as the key receptor for the monocyte response, however the post-translational modifications of CD16a from endogenous monocytes are not described. Here we isolated monocytes from individual donors and characterized the composition of CD16a and CD32a N-glycans from all modified sites. The composition of CD16a N-glycans varied by glycosylation site and donor. CD16a displayed primarily complex-type biantennary N-glycans at N162, however some individuals expressed CD16a V158 with ∼20% hybrid and oligomannose types which increased affinity for IgG1 Fc according to surface plasmon resonance binding analyses. The CD16a N45-glycans contain markedly less processing than other sites with >75% hybrid and oligomannose forms. N38 and N74 of CD16a both contain highly processed complex-type N-glycans with N-acetyllactosamine repeats and complex-type biantennary N-glycans dominate at N169. The composition of CD16a N-glycans isolated from monocytes included a higher proportion of oligomannose-type N-glycans at N45 and less sialylation plus greater branch fucosylation than we observed in a recent analysis of NK cell CD16a. The additional analysis of CD32a from monocytes revealed different features than observed for CD16a including the presence of a predominantly biantennary complex-type N-glycans with two sialic acids at both sites (N64 and N145).

Coronary Intervention with the Excimer Laser: Review of the Technology and Outcome Data

2016 ◽  
Vol 11 (1) ◽  
pp. 27
Author(s):  
John Rawlins ◽  
◽  
◽  
◽  
◽  
...  
Keyword(s):  
Excimer Laser ◽  
Coronary Intervention ◽  
Outcome Data ◽  
Boston Scientific ◽  
Technical Aspects ◽  
Safety And Efficacy ◽  
Percutaneous Coronary ◽  
Short Period ◽  
Complex Lesions

Excimer laser coronary atherectomy (ELCA) is a long-established adjunctive therapy that can be applied during percutaneous coronary intervention (PCI). Technical aspects have evolved and there is an established safety and efficacy record across a number of clinical indications in contemporary interventional practice where complex lesions are routinely encountered. The role of ELCA during PCI for thrombus, non-crossable or non-expandable lesions, chronic occlusions and stent under-expansion are discussed in this review. The key advantage of ELCA over alternative atherectomy interventions is delivery on a standard 0.014-inch guidewire. Additionally, the technique can be mastered by any operator after a short period of training. The major limitation is presence of heavy calcification although when rotational atherectomy (RA) is required but cannot be applied due to inability to deliver the dedicated RotaWire™ (Boston Scientific), ELCA can create an upstream channel to permit RotaWire passage and complete the case with RA – the RASER technique.

Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

2020 ◽  
Vol 20 ◽  
Author(s):  
Bipin Singh
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

scholarly journals The Enigma of Eosinophil Degranulation

2021 ◽  
Vol 22 (13) ◽  
pp. 7091
Author(s):  
Timothée Fettrelet ◽  
Lea Gigon ◽  
Alexander Karaulov ◽  
Shida Yousefi ◽  
Hans-Uwe Simon
Keyword(s):  
Blood Cells ◽  
Inflammatory Diseases ◽  
White Blood Cells ◽  
Exact Role ◽  
Effector Cells ◽  
Effector Functions ◽  
Cytotoxic Effector ◽  
Eosinophil Degranulation

Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are traditionally known as cytotoxic effector cells but have been suggested to additionally play a role in immunomodulation and maintenance of homeostasis. The exact role of these granule-containing leukocytes in health and diseases is still a matter of debate. Degranulation is one of the key effector functions of eosinophils in response to diverse stimuli. The different degranulation patterns occurring in eosinophils (piecemeal degranulation, exocytosis and cytolysis) have been extensively studied in the last few years. However, the exact mechanism of the diverse degranulation types remains unknown and is still under investigation. In this review, we focus on recent findings and highlight the diversity of stimulation and methods used to evaluate eosinophil degranulation.

scholarly journals Tackling the challenges of nanomedicines: are we ready?

2021 ◽  
Author(s):  
John B Hertig ◽  
Vinod P Shah ◽  
Beat Flühmann ◽  
Stefan Mühlebach ◽  
Gunar Stemer ◽  
...  
Keyword(s):  
Complex Nature ◽  
Pharmaceutical Sciences ◽  
Patient Benefit ◽  
World Congress ◽  
Clinical Safety ◽  
Hospital Pharmacists ◽  
Drug Products ◽  
Regulatory Bodies ◽  
Regulatory Landscape

Abstract Purpose This review provides an overview of the proceedings of the symposium “Tackling the Challenges of Nanomedicines: Are We Ready?” organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars. Summary The evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit. Conclusion Supportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

Safety and Efficacy of Single-Dose Ketorolac for Postoperative Pain Management After Primary Palatoplasty: A Prospective Cohort Study With Historical Controls

2021 ◽  
pp. 105566562110128
Author(s):  
Jason R. Stein ◽  
Esperanza Mantilla-Rivas ◽  
Marudeen Aivaz ◽  
Md Sohel Rana ◽  
Ishwarya Shradha Mamidi ◽  
...  
Keyword(s):  
Single Dose ◽  
Postoperative Pain Management ◽  
Postoperative Hemorrhage ◽  
Bleeding Complications ◽  
Control Group ◽  
Study Group ◽  
Safety And Efficacy ◽  
Opioid Dose ◽  
Historical Controls

Objective: To analyze safety and efficacy of single-dose ketorolac after primary palatoplasty (PP). Design: Consecutive cohort of patients undergoing PP, comparing to historical controls. Setting: A large academic children’s hospital. Patients, Participants: A consecutive cohort of 111 patients undergoing PP (study n = 47) compared to historical controls (n = 64). Interventions: All patients received intraoperative acetaminophen, dexmedetomidine, and opioids while the study group received an additional single dose of ketorolac (0.5 mg/kg) at the conclusion of PP. Main Outcome Measures: Safety of ketorolac was measured by significant bleeding complications and need for supplementary oxygen. Efficacy was assessed through bleeding, Face Legs Activity Cry Consolability (FLACC) scale, and opioid dose. Results: Length of stay was similar for both groups (control group 38.5 hours [95% CI: 3.6-43.3] versus study group 37.6 hours [95% CI: 31.3-44.0], P = .84). There were no significant differences in all postoperative FLACC scales. The mean dose of opioid rescue medication measured as morphine milligram equivalents did not differ between groups ( P = .56). Significant postoperative hemorrhage was not observed. Conclusions: This is the first prospective study to evaluate the safety and efficacy of single-dose ketorolac after PP. Although lack of standardization between study and historical control groups may have precluded observation of an analgesic benefit, analysis demonstrated a single dose of ketorolac after PP is safe. Further investigations with more patients and different postoperative regimens may clarify the role of ketorolac in improving pain after PP.

Sign in / Sign up

Export Citation Format

Share Document