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

Building on clinical case reports of the abscopal effect, there has been considerable interest in the synergistic effects of radiation and immunotherapies for the treatment of cancer. Here, the first radiolabeled antibody-recruiting small molecule that can chelate a variety of cytotoxic radionuclide...

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Bibliographic Details
Published in:Molecular pharmaceutics 2021-07, Vol.18 (7), p.2647-2656
Main Authors: Rathmann, Stephanie M, Genady, Afaf R, Janzen, Nancy, Anipindi, Varun, Czorny, Shannon, Rullo, Anthony F, Sadeghi, Saman, Valliant, John F
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - pharmacokinetics
Calcium - metabolism
Dinitrobenzenes - chemistry
Female
Lutetium - chemistry
Mice
Mice, Inbred BALB C
Phagocytosis
Radiopharmaceuticals - chemistry
Small Molecule Libraries - chemistry
Tissue Distribution
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Summary:Building on clinical case reports of the abscopal effect, there has been considerable interest in the synergistic effects of radiation and immunotherapies for the treatment of cancer. Here, the first radiolabeled antibody-recruiting small molecule that can chelate a variety of cytotoxic radionuclides is described. The platform consists of a tunable antibody-binding domain against a serum antibody of interest (e.g., dinitrophenyl hapten) to recruit endogenous antibodies that activate effector cell function, a chelate capable of binding diagnostic and therapeutic radiometals, and a tetrazine for bioorthogonal coupling with trans-cyclooctene-modified targeting vectors. The dinitrophenyl-tetrazine ligand was shown to both affect dose-dependent antibody recruitment and immune cell function (phagocytosis) in vitro, and the bisphosphonate 177Lu-complex was shown to accumulate at sites of calcium accretion in vivo, which was achieved using both active and pretargeting strategies.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.1c00187