A Versatile Platform for the Development of Radiolabeled Antibody-Recruiting Small Molecules

Area of Science:

• Oncology
• Radiochemistry
• Immunotherapy

Background:

• Clinical interest in the abscopal effect highlights the potential synergy between radiation and immunotherapy for cancer treatment.
• Existing strategies often lack the ability to precisely target and deliver cytotoxic payloads while recruiting the immune system.

Purpose of the Study:

• To describe the first radiolabeled antibody-recruiting small molecule platform capable of chelating various cytotoxic radionuclides.
• To evaluate the in vitro and in vivo performance of this novel platform for cancer therapy.

Main Methods:

• Development of a platform featuring a tunable antibody-binding domain, a radiometal chelate, and a tetrazine for bioorthogonal coupling.
• In vitro assessment of dinitrophenyl-tetrazine ligand for dose-dependent antibody recruitment and immune cell phagocytosis.
• In vivo evaluation of a bisphosphonate ¹⁷⁷Lu-complex accumulation at calcium accretion sites using active and pretargeting strategies.

Main Results:

• The dinitrophenyl-tetrazine ligand demonstrated effective dose-dependent antibody recruitment and immune cell function modulation in vitro.
• The ¹⁷⁷Lu-complex showed accumulation at sites of calcium accretion in vivo, confirming its targeting capability.
• Both active and pretargeting strategies were successfully employed to achieve targeted radionuclide delivery.

Conclusions:

• The described radiolabeled antibody-recruiting small molecule platform offers a versatile approach for combining targeted radionuclide therapy with immune activation.
• This platform holds promise for enhancing cancer treatment by leveraging the synergistic effects of radiation and immunotherapy.
• Further development could lead to novel therapeutic strategies for various cancers.