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A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo
The authors targeted DLL3 with an antibody conjugated to a cytotoxic drug, which proved to be much more effective than standard chemotherapy for treating patient-derived tumor xenografts and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.
Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity.
A novel sequence-selective pyrrolobenzodiazepine (PBD) dimer 5 (SJG-136) has been developed that comprises two C2-exo-methylene-substituted DC-81 (3) subunits tethered through their C8 positions via an inert propanedioxy linker that is a highly efficient minor groove interstrand DNA cross-linking agent that is 440-fold more potent than melphalan.
SJG-136 (NSC 694501), a Novel Rationally Designed DNA Minor Groove Interstrand Cross-Linking Agent with Potent and Broad Spectrum Antitumor Activity
Compare and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJg-136 does not fit within the clusters of any known agents, suggesting that SJG -136 possesses a distinct mechanism of action.
Antibody–drug conjugates – a perfect synergy
- J. Adair, P. Howard, J. Hartley, David G. Williams, K. Chester
- Biology, ChemistryExpert opinion on biological therapy
- 14 August 2012
This review summarises progress with development of this new class of drugs, Antibody–drug conjugates (ADCs), and describes separately the antibody and drug elements of ADCs and then examines the technology and consequences of linkage.
ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies.
In vivo, single doses of ADCT-402 resulted in highly potent, dose-dependent antitumor activity in several subcutaneous and disseminated human tumor models with marked superiority to comparator ADCs delivering tubulin inhibitors.
Preclinical assessment of an antibody–PBD conjugate that targets BCMA on multiple myeloma and myeloma progenitor cells
In vivo murine-matured human CD3(+ ) cells as a preclinical model for T cell-based immunotherapies and a nonhuman primate transplantation model to evaluate hematopoietic stem cell gene editing strategies for betahemoglobinopathies.
Improved Inhibition of Tumor Growth by Diabody-Drug Conjugates via Half-Life Extension.
The results suggest that the mechanism of half-life extension is an important consideration for designing cytotoxic antitumor agents.
Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload.
- A. Tiberghien, Jean-Noel Levy, P. Howard
- Chemistry, BiologyACS medicinal chemistry letters
- 8 June 2016
Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload and has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.
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.
Synthesis of Sequence-Selective C8-Linked Pyrrolo[2,1-c][1,4]benzodiazepine DNA Interstrand Cross-Linking Agents.
- D. Thurston, D. S. Bose, L. Hurley
- Chemistry, BiologyThe Journal of organic chemistry
- 15 November 1996
In order to construct the key A-ring fragments (9a-d), a versatile convergent approach has been developed to join two units of vanillic acid with alpha,omega-dihaloalkanes of varying length to provide the required bis(4-carboxy-2-methoxyphenoxy)alkanes while avoiding the formation of mixtures of monoalkylated and bisalkylation products.