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Multiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [⁸⁹Zr]Zr-DFO-YS5 for imaging and [²²⁵Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [⁸⁹Zr]Zr-DFO-YS5 for immunoPET imaging and [²²⁵Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models. In vitro saturation bindingmore » was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [⁸⁹Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [²²⁵Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity. [⁸⁹Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (K_d = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [⁸⁹Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [²²⁵Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups. Our study showed that the CD46-targeted probe [⁸⁹Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [²²⁵Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation.« less

Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody–drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [²²⁵Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. [²²⁵Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysismore » of the [²²⁵Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. Biodistribution study shows that [²²⁵Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [²²⁵Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line–derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope ²¹³Bi. [²²⁵Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen–positive and prostate-specific membrane antigen–deficient models. Overall, this preclinical study confirms that [²²⁵Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.« less

Found in biomolecules, pharmaceuticals, and agrochemicals, amide-containing molecules are ubiquitous in nature, and their derivatization represents a significant methodological goal in fluorine chemistry. Trifluoromethyl amides have emerged as important functional groups frequently found in pharmaceutical compounds. To date, there is no strategy for synthesizing N-trifluoromethyl amides from abundant organic carboxylic acid derivatives, which are ideal starting materials in amide synthesis. Here, we report the synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature. Through this strategy, isothiocyanates are desulfurized with AgF, and then the formedmore » derivative is acylated to afford N-trifluoromethyl amides, including previously inaccessible structures. This method shows broad scope, provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners, and should find application in the modification of advanced intermediates.« less