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Published on: January 29, 2019
CD46-Targeted Theranostics for PET and 225Ac-Radiopharmaceutical Therapy of Multiple Myeloma
Anju Wadhwa1, Sinan Wang1,2, Bonell Patiño-Escobar3,4
1Department of Radiology and Biomedical Imaging, University of California, San Francisco, California.
Purpose:
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.
Experimental Design:
In vitro saturation binding 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.
Results:
[89Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (Kd = 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.
Conclusions:
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.
Insights
This study validates CD46 as a theranostic target for multiple myeloma. The PET probe [89Zr]Zr-DFO-YS5 successfully images tumors, and the therapeutic agent [225Ac]Ac-DOTA-YS5 effectively inhibits multiple myeloma growth in preclinical models.
Area of Science:
- Oncology
- Nuclear Medicine
- Immunotherapy
Background:
- Multiple myeloma is a plasma cell malignancy with limited therapeutic and imaging options.
- CD46 is identified as a potential therapeutic target due to its overexpression in multiple myeloma.
- Previous research established the antibody YS5 targeting CD46 and developed related imaging and therapeutic agents.
Purpose of the Study:
- To validate [89Zr]Zr-DFO-YS5 for immunoPET imaging of multiple myeloma.
- To validate [225Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma.
- To assess the potential of CD46 as a theranostic target for multiple myeloma.
Main Methods:
- In vitro binding assays using CD46-expressing multiple myeloma cell lines.
- ImmunoPET/CT imaging in mice bearing multiple myeloma xenografts using [89Zr]Zr-DFO-YS5.
- Radioligand therapy studies in mice with systemic multiple myeloma xenografts using [225Ac]Ac-DOTA-YS5, including dose escalation and fractionated dosing.
- Tumor burden assessment via bioluminescence imaging (BLI), and monitoring of body weight and survival for toxicity and efficacy.
Main Results:
- [89Zr]Zr-DFO-YS5 showed high affinity for CD46-expressing cells (Kd = 16.3 nmol/L) and significant CD46 expression was confirmed in human multiple myeloma samples.
- [89Zr]Zr-DFO-YS5 PET/CT accurately detected multiple myeloma lesions in various models with minimal uptake in controls, including CD46 knockout mice.
- Treatment with [225Ac]Ac-DOTA-YS5 resulted in significant tumor volume reduction and improved survival in preclinical models of multiple myeloma.
Conclusions:
- The CD46-targeted probe [89Zr]Zr-DFO-YS5 is effective for imaging CD46-expressing multiple myeloma xenografts.
- [225Ac]Ac-DOTA-YS5 demonstrates efficacy in inhibiting multiple myeloma growth.
- CD46 represents a promising theranostic target for multiple myeloma with potential for clinical translation.
