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SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML.
Mechanistic studies indicate that the cytotoxic effects of SGN-CD33A involve DNA damage with ensuing cell cycle arrest and apoptotic cell death, and suggest that S GN-CD 33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.
Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index
This work shows that accelerated clearance arises from ADC hydrophobicity, which can be modulated through drug-linker design, and exemplifies this using hydrophilic auristatin drug linkers and PEGylated ADCs that yield uniform, high-DAR ADCs with superior in vivo performance.
Development of orally active inhibitors of protein and cellular fucosylation
- N. Okeley, S. Alley, P. Senter
- Biology, ChemistryProceedings of the National Academy of Sciences
- 14 March 2013
Oral 2-fluorofucose treatment afforded complete protection from tumor engraftment in a syngeneic tumor vaccine model, inhibited neutrophil extravasation, and delayed the outgrowth of tumor xenografts in immune-deficient mice.
The Green Tea Polyphenol EGCG Potentiates the Antiproliferative Activity of c-Met and Epidermal Growth Factor Receptor Inhibitors in Non–small Cell Lung Cancer Cells
EGG is a potent inhibitor of cell proliferation, independent of EGFR inhibition, in several NSCLC cell lines, including those resistant to both EGFR kinase inhibitors and those overexpressing c-Met, and might be a useful agent to study as an adjunct to other anticancer agents.
Formaldehyde in human cancer cells: detection by preconcentration-chemical ionization mass spectrometry.
Correlation of natural formaldehyde level with doxorubicin cytotoxicity is a function of the expression of enzymes that neutralize oxidative stress and the drug efflux pump, P-170 glycoprotein.
Optimization of a PEGylated Glucuronide-Monomethylauristatin E Linker for Antibody–Drug Conjugates
This work optimized the drug-linker by minimizing the size of the PEG side chain and incorporating a self-stabilizing maleimide to prevent payload de-conjugation in vivo, enabling highly potent, homogeneous DAR 8 conjugates and is under consideration for future ADC programs.
A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology.
In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines, demonstrating that PBDs can be effectively used for antibody-targeted therapy.
Metabolic engineering of monoclonal antibody carbohydrates for antibody-drug conjugation.
A library of fucose analogues was evaluated and a thiolated analogue, 6-thiofucose, which was incorporated into the antibody carbohydrate with good efficiency and could be used for conjugation using maleimide chemistry to produce antibody-drug conjugates with pronounced cytotoxic activities and improved homogeneity compared to drug attachment through hinge disulfides.
Design, synthesis, and biological evaluation of antibody-drug conjugates comprised of potent camptothecin analogues.
ADCs bearing the potent camptothecin analogue, 7-butyl-9-amino-10,11-methylenedioxy-camptothein, were highly potent and immunologically specific on a panel of cancer cell lines in vitro, and efficacious at well-tolerated doses in a renal cell carcinoma xenograft model.
Mass spectrometric measurement of formaldehyde generated in breast cancer cells upon treatment with anthracycline antitumor drugs.
- S. Kato, P. Burke, D. Fenick, D. Taatjes, V. Bierbaum, T. Koch
- Chemistry, BiologyChemical research in toxicology
- 5 May 2000
The results support a mechanism for drug cytotoxicity which involves drug induction of metabolic processes leading to formaldehyde production followed by drug utilization of formaldehyde to virtually cross-link DNA.