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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Unlike methylating agents that add a relatively small methyl group to bases in the major groove of DNA, alkylating agents covalently attach bulkier molecular fragments, usually in the minor groove. The only commercialized example of an alkylating agent at the time of writing is trabectedin (YondelisTM), which adds a bulky group of over 760 Da to guanines in the DNA minor groove. This causes significant distortion of the helix and invokes DNA repair. Although still at the experimental stage, the pyrrolobenzodiazepine (PBD) monomer and dimer families of agents are also mentioned in this section and in Section 5.3.10 (Sequence-Selective Cross-Linking Agents) because they lead to covalent attachment of bulky molecular fragments of approximately 300 Da and 600 Da, respectively, by alkylating or cross-linking in the DNA minor groove. Agents of this type are being developed as cytotoxic payloads for Antibody-Drug Conjugates (ADCs), and are further described in Chapter 7.
Harnessing the power of foot-and-mouth-disease virus for targeting integrin alpha-v beta-6 for the therapy of cancer
Published in Expert Opinion on Drug Discovery, 2021
Pancreatic ductal adenocarcinoma (PDAC) has a 5 year survival rate of less than 5% [28], with current treatment options limited and relative failure to improve mortality rates over the last 50 years [29]. Reports show αvβ6 is overexpressed in most PDAC tissues [30,31], but is absent or weak in normal pancreatic cells, making αvβ6 a promising therapeutic target. A20FMDV2 conjugated to tesirine, a toxic DNA-binding pyrrolobenzodiazepine, was selectively delivered to αvβ6 expressing cells of PDAC xenografts in mice [32]. The results showed effective and significant suppression of growth rates of established tumors. In fact, in some experiments the A20FMDV2-drug conjugate eliminated established xenografts completely and therefore significantly extended the lifespan of the mice [32].
Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy
Published in Expert Opinion on Biological Therapy, 2021
Anthramycin was the first of the pyrrolobenzodiazepine (PBD) family of antitumour antibiotics to be discovered in the 1960s. This class of naturally occurring, and later synthetic, compounds are tricyclic systems consisting of an aromatic A-ring, a 1-4-diazepin-5-one B-ring and a pyrrolidine C-ring (Figure 1(a)). Their mechanism of action involves sequence selective binding in the minor groove of DNA and covalent binding to the exocyclic C2-amino group of guanine bases. Wholly synthetic PBD dimers, in which two PBD monomer units are joined through their C8-positions via a flexible tether, are significantly more cytotoxic due to their ability to form two covalent bonds and thereby cross-link DNA. The development of PBDs and PBD dimers as stand-alone agents has been reviewed previously [1,2].
Daratumumab-225Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
Published in OncoImmunology, 2019
Wojciech Dawicki, Kevin J.H. Allen, Rubin Jiao, Mackenzie E. Malo, Muath Helal, Mark S. Berger, Dale L. Ludwig, Ekaterina Dadachova
Therapeutic monoclonal antibodies have become critically important in the treatment and control of cancer. Despite many approved therapeutic antibodies, such as the anti-CD38 antibody daratumumab, demonstrating improvements in response rate and outcome for patients, many patients fail to respond to treatment and durable responses are infrequent. The potential reasons for such failures are complex, and some of them such as pretreatment CD38 tumor expression level; relationship of CD38-expression to survival, disease stages, molecular entities, and high-risk definitions; and alternative splicing or lack of CD38-expression as potential mechanisms of upfront resistance are discussed by Seckinger et al.16 Improvements in antibody technology may be leveraged to enhance therapeutic potency, to expand the responding population of patients, without increasing toxicity risk. Engineered antibody conjugates have shown promise, recognizing the exquisite specificity of antibodies as delivery vehicles. For example, very recently B cell maturation antigen (BCMA) was identified as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients, and IgG-based BCMA-T cell bispecific antibody (EM801) was shown to increase CD3+ T-cell/myeloma cell crosslinking, followed by CD4+/CD8+ T-cell activation, and secretion of interferon-γ, granzyme B, and perforin.17 Chemoconjugates, however, have had relatively few regulatory successes and often have narrow therapeutic windows. Increasingly, payloads with greater potency have been developed, particularly those focused on eliciting DNA damage, such as the pyrrolobenzodiazepine (PBD).18 However, with increased potency, toxicity risk may also increase.