scholarly journals In vivoaffinity and target engagement in skin and blood in a first-time-in-human study of an anti-oncostatin M monoclonal antibody

2018 ◽  
Vol 84 (10) ◽  
pp. 2280-2291 ◽  
Author(s):  
Juliet Reid ◽  
Stefano Zamuner ◽  
Ken Edwards ◽  
Sally-Anne Rumley ◽  
Katherine Nevin ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Study ◽  
Oncostatin M ◽  
Target Engagement ◽  
First Time

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

2021 ◽  
Author(s):  
Raphael R. Steimbach ◽  
Corey J. Herbst-Gervasoni ◽  
Glynis Klinke ◽  
Magalie Géraldy ◽  
Gergely Tihanyi ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Target Engagement ◽  
Target Validation ◽  
Chemical Probes ◽  
Combination Cancer Therapy ◽  
Selective Chemical ◽  
First Time ◽  
Double Digit ◽  
Novel Therapeutic ◽  
Thermal Shift

We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded DKFZ-748, which has a double-digit nanomolar IC50 against HDAC10 in cells and >500-fold selectivity over the closest relative HDAC6 as well as the Class I enzymes (HDAC1, 2, 3, 8). Potency of our aza-SAHA derivatives is rationalized with HDAC10 co-crystal structures and demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a poly-amine deacetylase. Selective HDAC10 chemical probes provide a valuable pharmacological tool for target validation and will enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines. HDAC10-selective aza-SAHA derivatives are not cytotoxic, which opens the doors to novel therapeutic applications as immunomodulators or in combination cancer therapy.

scholarly journals A red-emissive antibody–AIEgen conjugate for turn-on and wash-free imaging of specific cancer cells

2017 ◽  
Vol 8 (10) ◽  
pp. 7014-7024 ◽  
Author(s):  
Xiujuan Shi ◽  
Chris Y. Y. Yu ◽  
Huifang Su ◽  
Ryan T. K. Kwok ◽  
Meijuan Jiang ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Cells ◽  
Turn On ◽  
Specific Cancer ◽  
First Time

For the first time, an AIEgen-conjugated monoclonal antibody is designed for “turn-on” and “wash-free” imaging of EGFR-overexpressed cancer cells.

UHPLC–MS/MS method to determine FP-208 in human plasma and its application to a pharmacokinetic study

Bioanalysis ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 367-378
Author(s):  
Huanhuan Wang ◽  
Teng Wang ◽  
Zhanqing Wang ◽  
Zhenjian Du ◽  
Qian Zhao ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Human Study ◽  
Pharmacokinetic Profile ◽  
Target Of Rapamycin ◽  
Precipitation Method ◽  
Molecule Inhibitor ◽  
Ionization Mode ◽  
First Time ◽  
Reliable Analytical Method

Aim: FP-208 is a novel and effective small-molecule inhibitor blocking the mammalian target of rapamycin complex-1/mammalian target of rapamycin complex-2/PI3Ka. To investigate the pharmacokinetic profile of FP-208, a rapid and reliable analytical method was needed to be established to determine FP-208 in the plasma of patients with solid tumors. Materials & methods: FP208 was separated on a charged surface hybrid (CSH) C18 column (2.1 mm × 50 mm, 1.7 μm) after the plasma samples were purified using a protein precipitation method. Detection was performed on an AB Sciex 5500 mass spectrometer in the positive electrospray ionization mode. The established method was validated according to the bioanalytical guidelines. Conclusion: For the first time, the developed and validated method was successfully applied in the first-in-human study for FP-208 in patients with solid tumors after oral administration (Number: CTR20180683).

O4-05-01: A first-in-human study of BAN2401, a novel monoclonal antibody against beta-amyloid protofibrils

2013 ◽  
Vol 9 ◽  
pp. P689-P689 ◽  
Author(s):  
Robert Lai ◽  
Veronika Logovinsky ◽  
June M. Kaplow ◽  
Kenan Gu ◽  
Yanke Yu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Study ◽  
Beta Amyloid

First-in-human study of MM-141: A novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 3068-3068 ◽  
Author(s):  
Steven J. Isakoff ◽  
Mansoor N. Saleh ◽  
Alexey Lugovskoy ◽  
Sara Manoli ◽  
Akos Gabor Czibere ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Study ◽  
Antibody Targeting

A phase I, first-in-human study of ARGX-110, a monoclonal antibody targeting CD70, a receptor involved in immune escape and tumor growth in patients with solid and hematologic malignancies.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 3023-3023 ◽  
Author(s):  
Ahmad Awada ◽  
Christian D. Rolfo ◽  
Sylvie Rottey ◽  
Laure Ysebrant de Lendonck ◽  
Wilfried A. Schroyens ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Phase I ◽  
Immune Escape ◽  
Human Study ◽  
Hematologic Malignancies ◽  
Antibody Targeting
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