scholarly journals Development and validation of receptor occupancy pharmacodynamic assays used in the clinical development of the monoclonal antibody vedolizumab

2015 ◽  
Vol 90 (2) ◽  
pp. 168-176 ◽  
Author(s):  
Tim Wyant ◽  
Jose Estevam ◽  
Lili Yang ◽  
Maria Rosario
Keyword(s):  
Monoclonal Antibody ◽  
Receptor Occupancy ◽  
Clinical Development ◽  
Development And Validation

scholarly journals ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yuning Chen ◽  
Ya-Nan Zhang ◽  
Renhong Yan ◽  
Guifeng Wang ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Broad Spectrum ◽  
Management Strategy ◽  
Spectrum Management ◽  
Clinical Development ◽  
Severe Toxicity ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Residues

AbstractThe evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 “knock-in” mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and “alanine walk” studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and “broad-spectrum” management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.

scholarly journals 295 First-in-human Phase I trial of IBI188, an anti-CD47 targeting monoclonal antibody, in patients with advanced solid tumors and lymphomas

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A322-A322
Author(s):  
Nehal Lakhani ◽  
Marlana Orloff ◽  
Siqing Fu ◽  
Ying Liu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Solid Tumors ◽  
Dose Level ◽  
Maintenance Dose ◽  
Receptor Occupancy ◽  
Priming Dose ◽  
Dose Escalation Study ◽  
Optimal Maintenance ◽  
Grade 3

BackgroundIBI188 is a humanized IgG4 monoclonal antibody targeting CD47, an antiphagocytic (‘don’t eat me’) signal present on cancer cells. Blockage of this myeloid checkpoint, IBI188 enhances tumor cell phagocytosis and cross priming of T-cells. We conducted a first-in-human phase 1a trial to evaluate the tolerability, safety and PK/PD characteristics of IBI188. (NCT03763149).MethodsPatients with advanced/refractory solid tumors or lymphoma were enrolled in this two-part dose-escalation study: Part A for testing optimal priming doses at 0.1, 0.3, and 1 mg/kg and Part B for optimal maintenance doses at 3, 10, 20, 30 mg/kg weekly. An accelerated titration followed by traditional 3+3 design was used in this study with a 28-day dose-limiting toxicity (DLT) observation period. Primary endpoint was safety profile; secondary endpoints included PK parameters and PD markers, i.e. CD47 receptor occupancy.ResultsAs of June 18, 2020, 20 patients have been enrolled, 6 in Part A and 14 in Part B. There was no DLT reported at any dose level. The median treatment duration was 1.8 months (0.2–5.5) months. The most common treatment-related adverse events (TRAEs) were nausea (n=7), back pain (n=7), fatigue (n=6), vomiting (n=4) and blood bilirubin increased (n=4). Three patients had ≥ Grade 3 TRAEs (Grade 3 blood bilirubin increase, Grade 4 platelet count decrease and Grade 3 anemia, each in 1 patient). Three of 20 patients (15%) had anemia, an expected TRAE associated with the mechanism of IBI188. Majority of the patients (65%) had infusion related reactions (IRR). All IRRs were Grade 1–2 and able to be managed with standard IRR treatment. The clearance of IBI188 decreased with the increasing dose from 3 to 20 mg/kg and IBI188 can overcome the sink at 10 mg/kg or higher dose level. The PK analysis at 30 mg/kg is ongoing. The 10 mg/kg maintenance dose resulted in T cells receptor occupancy above 80%. After multiple administrations (≥ 3 times, including the priming dose), the RBC and T cells receptor occupancy tends to be stable and maintained around 90%. The receptor occupancy analysis at 20 mg/kg and 30 mg/kg is ongoing.ConclusionsIBI188 was well tolerated at 1 mg/kg priming dose following by the maintenance dose up to 30 mg/kg.Trial RegistrationNCT03763149

Abstract 4595: Development and validation of a novel EGF receptor-neutralizing monoclonal antibody

2016 ◽  
Author(s):  
Krystyna Zuberek Hincman ◽  
Christopher A. Manning ◽  
Michael R. Nelson ◽  
Michael Lewis ◽  
Roy Scialdone ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Egf Receptor ◽  
Neutralizing Monoclonal Antibody ◽  
Development And Validation

scholarly journals Antibody–Drug Conjugates for Cancer Therapy

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4764
Author(s):  
Umbreen Hafeez ◽  
Sagun Parakh ◽  
Hui K. Gan ◽  
Andrew M. Scott
Keyword(s):  
Monoclonal Antibody ◽  
Molecular Imaging ◽  
Cancer Therapy ◽  
Normal Tissue ◽  
Clinical Development ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Novel Drugs ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.

scholarly journals Clinical development of monoclonal antibody-based drugs in HIV and HCV diseases

BMC Medicine ◽  
2013 ◽  
Vol 11 (1) ◽  
Author(s):  
Michela Flego ◽  
Alessandro Ascione ◽  
Maurizio Cianfriglia ◽  
Stefano Vella
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Development

Development and validation of H11B2C2 monoclonal antibody-reactive hyaluronic acid binding protein: overexpression of HABP during human tumor progression

Tumor Biology ◽  
2012 ◽  
Vol 34 (1) ◽  
pp. 597-608 ◽  
Author(s):  
Rajeev K Boregowda ◽  
Hitesh N. Appaiah ◽  
Mortha Karunakumar ◽  
Shivanna Parameshwariah ◽  
Geetha Avadani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Hyaluronic Acid ◽  
Tumor Progression ◽  
Binding Protein ◽  
Human Tumor ◽  
Protein Overexpression ◽  
Acid Binding Protein ◽  
Development And Validation ◽  
Hyaluronic Acid Binding

scholarly journals Development and validation of a direct competitive monoclonal antibody-based immunoassay for the sensitive and selective analysis of the phytoregulator forchlorfenuron

2012 ◽  
Vol 403 (7) ◽  
pp. 2019-2026 ◽  
Author(s):  
Celia Suárez-Pantaleón ◽  
Francesc A. Esteve-Turrillas ◽  
Josep V. Mercader ◽  
Consuelo Agulló ◽  
Antonio Abad-Somovilla ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Development And Validation ◽  
Selective Analysis
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