Author Correction: Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice.

The original version of this Article omitted the following from the Acknowledgements: 'This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program under Award No. W81XWH-15-1-0692. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense'. This error has now been corrected in the PDF and HTML versions of the Article.

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice.

Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.

α- Versus ß-Emitting Radionuclides for Pretargeted Radioimmunotherapy of Carcinoembryonic Antigen-Expressing Human Colon Cancer Xenografts.

Pretargeted radioimmunotherapy (PRIT) with the ß-emitting radionuclide 177Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such as 213Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of 213Bi and 177Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213Bi-IMP288 were compared with those of 177Lu-IMP288. Tumor targeting of 213Bi-IMP288 and 177Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of 213Bi-IMP288 (6, 12, or 17 MBq) and 177Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of 177Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of 213Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g). 213Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of 213Bi-IMP288 was comparable to that of 177Lu-IMP288. Mice treated with a single dose of 213Bi-IMP288 or 177Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq 213Bi-IMP288, 12 MBq 213Bi-IMP288, and 60 MBq 177Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq 213Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: To our knowledge, this study shows for the first time that PRIT with TF2 and 213Bi-IMP288 is feasible and at least as effective as 177Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity.