Antibody-Based Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The duocarmycins are members of a series of related natural products first isolated from Streptomyces bacteria in 1988 (see Chapter 5). They work by interacting in the minor groove of DNA and alkylating adenine bases at their N3 position which disrupts the DNA helix and leads to tumor cell death. Synthetic analogs of the duocarmycins (known as “cyclopropylpyrroloindoles”) include adozelesin, bizelesin, and carzelesin (Figure 7.18), and these have all been evaluated (by the then, Upjohn Company as potential stand-alone anticancer agents). In particular, the work of Professors Dale Boger (Scripps, San Diego, USA) and Laurence Hurley (University of Arizona, USA) has contributed to a better understanding of the pharmacophore and mechanism of action of these agents. Structures of examples of duocarmycin-type compounds that bind in the minor groove of DNA. Adozelesin and carzelesin form mono-alkylated adducts by establishing a covalent bond between a carbon atom of their cyclopropane moiety (a pro-cyclopropane in the case of carzelesin) and the N3-position of an adenine base. However, bizelesin contains two alkylating units, and so forms interstrand cross-links between two adenine bases within the DNA minor groove which tend to be more lethal to cells.
Novel immunotherapeutic approaches for hepatocellular carcinoma treatment
Published in Expert Review of Clinical Pharmacology, 2019
Davide Busato, Monica Mossenta, Lorena Baboci, Federica Di Cintio, Giuseppe Toffoli, Michele Dal Bo
Another possible approach to target drugs to tumor cells is to obtain an antibody-drug conjugate by binding the drug element through a linker to a monoclonal antibody representing the target unit [168,169]. Only four antibody-drug conjugates reached the FDA and EMA approval [168–171]. In the HCC context, several antibody-drug conjugates have been tested. Sacituzumab govitecan (IMMU-132) is made by the conjugation of the antibody hRS7, able to recognize the trophoblast cell surface antigen (Trop-2), with the irinotecan active component (SN-38) [172]. It is under phase I and II clinical evaluation to test its safety and toxicity in previously treated patients with advanced epithelial cancer, among them HCC (NCT01631552). Novel antibody-drug conjugates were made to treat HCC taking advantage of GPC3-positivity of tumor cells. Using hYP7 anti-GPC3 antibody, two antibody-drug conjugates were constructed, hYP7-DC with duocarmycin and hYP7-PC with pyrrolobenzodiazepine dimer as payloads. Both were tested against three HCC cell lines (HepG2, Hep3B2, and Huh7) and results highlighted a superior cytotoxicity of hYP7-PC over hYP7-DC without off-target effects. In addition, a synergistic effect was found using gemcitabine in combination with hYP7-DC both in-vitro and in-vivo [170].
Mesothelin-targeted CAR-T cell therapy for solid tumors
Published in Expert Opinion on Biological Therapy, 2021
Astero Klampatsa, Vivian Dimou, Steven M. Albelda
Other important ADCs include [58];, a humanized anti-MSLN antibody conjugated to the anti-mitotic agent monomethyl auristatin E (MMAE) which has been administered to pancreatic and ovarian cancer patients in a Phase I clinical trial [9,64], BMS-986,148 conjugated to the alkylating agent duocarmycin (MED2460) which has been tested in a clinical trial for patients with mesothelioma, NSCLC, ovarian, pancreatic and gastric cancer [56], and BAY2287411, a thorium-227 labeled antibody-chelator conjugate that is being tested in a Phase I clinical trial for patient with PDAC, serous ovarian cancer, and epithelioid mesothelioma (NCT03507452).
Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches
Published in Expert Review of Anticancer Therapy, 2022
Teodora Alexa-Stratulat, Mariana Pavel-Tanasa, Vlad-Andrei Cianga, Sabina Antoniu
On the other hand galactoconjugate form of navitoclax which in a recent study was demonstrated to have an improved senolytic index compared to the non-conjugated compound (ie specificity for senescent cells) thus protecting non-senescent cells. The conjugate was also found to be less toxic for platelets [121]. Furthermore when applied in combination with cisplatin in A549 lung cancer cells navitoclax galactoconjugate was found to increase the cytotoxicity of cisplatin [121]. Other similar approaches were tested for 5 fluorouracil or for duocarmycin [121].
Related Knowledge Centers
- Adenine
- Alkylation
- Biological Activity
- Pharmacophore
- Streptomyces
- Natural Product
- Nucleic Acid Double Helix
- Mechanism of Action
- Adozelesin
- Antibody–Drug Conjugate