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.

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