Radiolabeled Antibodies for Cancer Imaging and Therapy

Abstract

Radioimmunoconjugates consist of a monoclonal antibody (mAb) linked to a radionuclide. Radioimmunoconjugates as theranostics tools have been in development with success, particularly in hematological malignancies, leading to approval by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin's lymphoma. Radioimmunotherapy (RIT) allows for reduced toxicity compared to conventional radiation therapy and enhances the efficacy of mAbs. In addition, using radiolabeled mAbs with imaging methods provides critical information on the pharmacokinetics and pharmacodynamics of therapeutic agents with direct relevance to the optimization of the dose and dosing schedule, real-time antigen quantitation, antigen heterogeneity, and dynamic antigen changes. All of these parameters are critical in predicting treatment responses and identifying patients who are most likely to benefit from treatment. Historically, RITs have been less effective in solid tumors; however, several strategies are being investigated to improve their therapeutic index, including targeting patients with minimal disease burden; using pre-targeting strategies, newer radionuclides, and improved labeling techniques; and using combined modalities and locoregional application. This review provides an overview of the radiolabeled intact antibodies currently in clinical use and those in development.

Keywords: radioimmunotherapy; radioisotopes; radiolabeled monoclonal antibodies; theranostics.

Figure 1

¹¹¹In-ABT-806 (ABT-806i) biodistribution and SPECT/CT images of patient with high-grade glioma on (A) day 1, (B) day 2, and (C) day 3, demonstrating that rapid uptake of ABT-806i in known glioblastoma (arrow) is identified as early as day 2 and increases over time. (D) SPECT/MR images showing high uptake of ABT-806i in glioblastoma (arrow) in a posterior fossa lesion. Visualization of ABT-806i uptake in the anterior venous sinus is due to blood-pool activity. Reprinted with permission: Gan, H.K., et al. A Phase 1 and Biodistribution Study of ABT-806i, an ¹¹¹In-Radiolabeled Conjugate of the Tumor-Specific Anti-EGFR Antibody ABT-806. J Nucl Med, 2021. 62 (6): p. 787–794 [20].

Figure 2

⁸⁹Zr-girentuximab in renal cancer patient. Left panel: top row, axial PET imaging at 168 h post administration (h p.a).; middle row, contrast enhanced CT; bottom row, fused PET/CT imaging showing (from left to right) ⁸⁹Zr-girentuximab uptake in the adrenal gland (red arrow), left kidney (red arrowhead), and mediastinal lymph node (red arrow). Right panel: the maximum intensity projection (MIP) whole-body PET image at 168 h p.a. Reprinted with permission from Merkx, R.I.J.; Lobeek, D.; Konijnenberg, M.; et al. Phase I study to assess safety, biodistribution, and radiation dosimetry for ⁸⁹Zr-girentuximab in patients with renal cell carcinoma. Eur J Nucl Med Mol Imaging, 2021. 48, 3277–3285 [43].

Figure 3

Left to right: ¹⁷⁷Lu-J591 anterior and posterior whole-body images 7 days after ¹⁷⁷Lu-J591 administration, and Technetium 99m-methyl diphosphonate (^99mTc-MDP) bone scan anterior and posterior whole-body images, showing ¹⁷⁷Lu-J591 targeting of extensive bone and soft-tissue metastases. Reprinted with permission from: Tagawa S.T, et al. Phase 1/2 Study of Fractionated Dose Lutetium-177–Labeled Anti–Prostate-Specific Membrane Antigen Monoclonal Antibody J591 (¹⁷⁷Lu-J591) for Metastatic Castration-Resistant Prostate Cancer. Cancer, 2019 Aug 1; 125 (15): 2561–2569 [97].