Abstract Antibody-drug conjugates (ADCs) incorporating potent indolinobenzodiazepine (IGN) DNA alkylators as the cytotoxic payload are currently undergoing clinical evaluation. The optimized design of these payloads consists of an unsymmetrical dimer possessing both an imine and an amine effectively eliminating DNA crosslinking and demonstrating improved tolerability in mice. Here we present an alternate approach to generating DNA alkylating ADCs by linking the IGN monomer with a biaryl system which has a high DNA binding affinity to potentially enhance tolerability. These BIA ADCs were found to be highly cytotoxic in vitro and demonstrated potent antitumor activity in vivo .
Since the first approval of gemtuzumab ozogamicin (Mylotarg; Pfizer; CD33 targeted), two additional antibody–drug conjugates (ADC), brentuximab vedotin (Adcetris; Seattle Genetics, Inc.; CD30 targeted) and inotuzumab ozogamicin (Besponsa; Pfizer; CD22 targeted), have been approved for hematologic cancers and 1 ADC, trastuzumab emtansine (Kadcyla; Genentech; HER2 targeted), has been approved to treat breast cancer. Despite a clear clinical benefit being demonstrated for all 4 approved ADCs, the t...
Tumor-selective delivery of cytotoxic agents in the form of antibody–drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA–cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class o...
#1Eytan M. Stein(MSK: Memorial Sloan Kettering Cancer Center)H-Index: 33
#2Roland B. Walter(Fred Hutchinson Cancer Research Center)H-Index: 60
Last. Anthony S. Stein(City of Hope National Medical Center)H-Index: 56
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Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in ...
Antibody–drug conjugate (ADCs), which aim to target highly cytotoxic drugs specifically to cancer cells, are one of the fastest growing classes of anticancer therapeutics, with more than 50 such agents currently in clinical trials. This Review discusses lessons learned and emerging strategies in the development of ADCs, including aspects such as target selection, the development of warheads, the optimization of linkers and new conjugation chemistries, and provides an overview of agents that are ...
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective DNA minor-groove binding agents that form a covalent aminal bond between their C11-position and the C2-NH2 groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG-136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaem...
Last. David R. Spigel(Sarah Cannon Research Institute)H-Index: 85
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Summary Background Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. Methods We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged...
Purpose: An anti-HER2 antibody–drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed. Experimental Design:In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. The mechanism of action for the efficacy was also evaluated. Pharmacokinetics in cynomolgus monkeys an...
The promise of tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) has now been realized, evidenced by the approval of two ADCs, both of which incorporate highly cytotoxic tubulin-interacting agents, for cancer therapy. An ongoing challenge remains in identifying potent agents with alternative mechanisms of cell killing that can provide ADCs with high therapeutic indices and favorable tolerability. Here we describe the development of a new class of potent ...
Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent a...
The binding of nuclear factor Y (NF-Y) to inverted CCAAT boxes (ICBs) within the promoter region of DNA topoisomerase IIα results in control of cell differentiation and cell cycle progression. Thus, NF-Y inhibitory small molecules could be employed to inhibit the replication of cancer cells. A library of pyrrolobenzodiazepine (PBD) C8-conjugates consisting of one PBD unit attached to tri-heterocyclic polyamide fragments was designed and synthesized. The DNA-binding affinity and sequence selectiv...
#1Yufei Xue(CSIRO: Commonwealth Scientific and Industrial Research Organisation)
#1Yufei Xue(CSIRO: Commonwealth Scientific and Industrial Research Organisation)
Last. Nicolas H. Voelcker(CSIRO: Commonwealth Scientific and Industrial Research Organisation)H-Index: 60
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Stimulus-cleavable nanoscale drug delivery systems are receiving significant attention owing to their capability of achieving exquisite control over drug release via the exposure to specific stimuli. Central to the construction of such systems is the integration of cleavable linkers showing susceptibility to one stimulus or several stimuli with drugs, prodrugs or fluorogenic probes on the one hand, and nanocarriers on the other hand. This review summarises recent advances in stimulus-cleavable l...