The Road to Personalized Myeloma Medicine: Patient-specific Single-domain Antibodies for Anti-idiotypic Radionuclide Therapy

To this day, multiple myeloma remains an incurable cancer. For many patients, recurrence is unavoidably a result of lacking treat-ment options in the minimal residual disease stage. This is due to residual and treatment-resistant myeloma cells that can cause disease relapse. However, patient-specific membrane-expressed paraproteins could hold the key to target these residual cells responsible for disease recurrence. Here, we describe the therapeutic potential of radiolabeled, anti-idiotypic camelid single-domain antibody fragments (sdAbs) as tumor-restrictive vehicles against a membrane-bound paraprotein in the syngeneic mouse 5T33 myeloma model and analogously assess the feasibility of sdAb-based personalized medicine for patients with multiple myeloma. Llamas were immunized using extracts containing paraprotein from either murine or human sera, and selective sdAbs were retrieved using competitive phage display selections of immune libraries. An anti-5T33 idiotype sdAb was selected for targeted radionuclide therapy with the b--particle emitter 177Lu and the a-particle emitter 225Ac. sdAb-based radionuclide therapy in syn-geneic mice with a low 5T33 myeloma lesion load significantly delayed tumor progression. In five of seven patients with newly diagnosed myeloma, membrane expression of the paraprotein was confirmed. Starting from serum-isolated paraprotein, for two of three selected patients anti-idiotype sdAbs were successfully generated.

Automated summary

Multiple myeloma is an incurable cancer, and the lack of effective treatment options has led to disease recurrence. However, patient-specific membrane-expressed paraproteins could hold the key to targeting residual cells responsible for disease recurrence. In this study, radiolabeled anti-idiotypic camelid single-domain antibody fragments (sdAbs) were used as tumor-restrictive vehicles and showed potential for personalized medicine in multiple myeloma patients.