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
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.