Evaluating 225Ac and 177Lu Radioimmunoconjugates against Antibody–Drug Conjugates for Small-Cell Lung Cancer

• DOI: 10.1021/acs.molpharmaceut.0c00703
• Publication Date: 2020-10-12T19:12:33Z
• Authors: Andrew L. Lakes; Dahlia D. An; Stacey S. Gauny; Camille Ansoborlo; Benjamin H. Liang; Julian A. Rees; Kristen D. McKnight; Holger Karsunky; Rebecca J. Abergel
• Keywords: Conjugate

Interest in the use of 225Ac for targeted alpha therapies has increased dramatically over past few years, resulting a multitude new isotope production and translational research efforts. However, radioimmunoconjugate (RIC) is still its infancy, with most prior experience hematologic malignancies only one reported preclinical solid tumor study using RICs. In an effort to compare RICs other current antibody conjugates, variety are tested against intractable small-cell lung cancer (SCLC). We directly compare, vitro vivo, two promising candidates each α or β- category, 177Lu, versus pyrrolobenzodiazepine (PBD) nonradioactive benchmarks. The monoclonal constructs either delta like 3 protein (DLL3), recently discovered SCLC target, CD46 as positive control. An immunocompromised maximum tolerated dose assay performed on NOD SCID mice, along efficacy proof-of-concept studies vivo. overview conjugation techniques required create serum-stable characterize cell killing conjugated nonspecific antibodies (huIgG1) native site-specific thiol loci antigen DLL3-expressing nonexpressing lines. Using patient-derived xenografts onto growth was controlled throughout weeks before appeared, comparison PBD conjugate controls. mice showed lengthened survival compared 177Lu RICs, dimers full suppression nine out ten mice. exploration antibody-antigen systems necessary direct efforts toward candidates. anti-DLL3-RIC system appears be not effective anti-DLL3-PBD counterpart therapy matched portrays challenges both well specialized utility treatment.