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

Abstract

Interest in the use of 225 Ac for targeted alpha therapies has increased dramatically over the past few years, resulting in a multitude of new isotope production and translational research efforts. However, 225 Ac radioimmunoconjugate (RIC) research is still in its infancy, with most prior experience in hematologic malignancies and only one reported pre-clinical solid tumor study using 225 Ac RICs. In an effort to compare 225 Ac RICs to other current antibody-conjugates, a variety of RICs are tested against intractable small cell Lung cancer (SCLC). We directly compare, in vitro and in vivo, two promising candidates of each α or βcategory, 225 Ac and 177 Lu, vs pyrrolobenzodiazepine (PBD) non-radioactive benchmarks. The monoclonal antibody constructs are targeted to either delta like 3 protein (DLL3), a recently discovered SCLC target, or CD46 as a positive control. An immunocompromised maximum tolerated dose (MTD) assay is performed on NOD SCID mice, along with tumor efficacy proof-of-concept studies in vivo. We overview the conjugation techniques required to create serum-stable RICs, and characterize and compare in vitro cell killing with RICs conjugated to non-specific antibodies (huIgG1) with either native or site-specific thiol loci against tumor antigen DLL3-expressing and nonexpressing cell lines. Using patient derived xenografts (PDX) of SCLC onto NOD SCID mice, solid tumor growth was controlled throughout 3 weeks before growth appeared, in comparison to PBD conjugate controls. NOD SCID mice showed lengthened survival using 225 Ac compared to 177 Lu RICs, and PBD dimers showed full tumor suppression with nine out of ten mice. The exploration of RICs on a variety of antibody-antigen systems is necessary to direct efforts in cancer research towards promising candidates. However, the anti-DLL3-RIC system with 225 Ac and 177 Lu appears to be not as effective as the anti-DLL3-ADC counterpart in SCLC therapy 2 with matched antibodies, and portrays the challenges in both SCLC therapy as well as the specialized utility of RICs in cancer treatment.3 determination in radiolabeled immunoconjugates to take into account daughter nuclide generation; additional results including drug/antibody ratio determination, cell viability data, MTD comparisons, PDX tumor efficacy comparisons, and radiolabel biodistribution data.

Dll3 Regulates Notch Signaling in SCLC

“…Clinical trials using Rovalpituzumab tesirine (Rova-T), an ADC targeting DLL3, have been largely unsuccessful due to toxic side effects of this molecule (e.g., (Blackhall et al, 2021; Johnson et al, 2021; Malhotra et al, 2021)). However, other strategies are being develop to target DLL3 expressing cells (e.g., (Giffin et al, 2021; Hipp et al, 2020; Lakes et al, 2020; Tully et al, 2022)) and DLL3 remains a target of interest for the detection and the treatment of SCLC.…”

Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application

“…As the great potential of targeted cancer treatment with alpha emitters is beginning to draw worldwide attention [ 9 , 10 , 11 , 12 ], the demand for the radionuclide 225 Ac is expected to increase by several orders of magnitude. The current production via chemical separation from existing stocks of 229 Th cannot meet the projected demand [ 13 ].…”

Synthesis, Characterization, and Solid-State Structural Chemistry of Uranium(IV) Aliphatic Dicarboxylates

“…The actinides are central to areas of critical importance including radiotherapeutics, energy generation, and national security. − Despite their widely impactful applications, activities such as mining, waste storage, and nuclear weapons testing have resulted in anthropogenic releases of these radionuclides to the environment. − Alarmingly, current models have failed to accurately predict the distances and mechanisms through which these metal ions have migrated in the environment. , This suggests, in some cases, an inability to reliably predict and control the behavior of actinides in complex systems . Actinide complexation by organic carboxylates is of particular significance as carboxylate functionalities are present in systems ranging from waste management and separations chemistries to the environment. , In this respect, the identification of novel actinide-carboxylate structural units and the elucidation of the conditions under which particular phases form and are stable may provide important insight into the modeling of actinide behavior to address this critical need.…”