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Updated: Mar 26, 2026
Synthesis and Bioconjugation of Thiol-Reactive Reagents for the Creation of Site-Selectively Modified Immunoconjugates
Published on: March 6, 2019
Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates
Emma Aneheim1, Anna Gustafsson1, Per Albertsson2
1Department of Radiation Physics, Gothenburg University , Gula Stråket 2B, 41345 Gothenburg, Sweden.
Abstract:
Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 μm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies.
Insights
Targeted alpha therapy using astatine-211 shows promise for treating cancer metastasis. A new method improves antibody conjugation, enhancing stability and effectiveness for targeted cancer cell destruction.
Area of Science:
- Oncology
- Radiochemistry
- Immunology
Background:
- Metastasis presents a significant challenge in cancer treatment.
- Targeted alpha therapy (TAT) offers a precise approach for microtumor and single-cell eradication due to alpha particles' short range.
- Astatine-211 is a promising radionuclide for TAT, typically conjugated to antibodies.
Purpose of the Study:
- To develop and evaluate a novel disulfide-based conjugation method for astatine-211 labeling of monoclonal antibodies.
- To enhance the immunoreactivity and stability of antibody conjugates for improved targeted alpha therapy.
Main Methods:
- A new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), was used for disulfide-based conjugation.
- Chemical stability of the MSB-conjugate was assessed in vitro.
- Immunoconjugates were radiolabeled with astatine-211.
- In vivo distribution studies were performed in tumor-bearing mice, comparing MSB conjugates with other tin-based conjugates.
Main Results:
- The MSB conjugation method demonstrated high radiochemical yield and specific activity after astatination.
- The MSB-conjugate exhibited excellent chemical stability and a long shelf life prior to radiolabeling.
- In vivo studies confirmed the MSB conjugation method as a viable option for astatine labeling.
Conclusions:
- Disulfide-based conjugation using MSB offers a stable and efficient method for preparing astatine-211 immunoconjugates.
- This approach holds potential for advancing targeted alpha therapy in oncology.
- The MSB method is suitable for labeling various monoclonal antibodies for cancer treatment.
