Evaluation of an in vivo pre-targeting approach for targeted radionuclide therapy of cancer using clickable anti-B7-H3 single domain antibodies.

Targeted radionuclide therapy (TRNT) is an attractive therapeutic
approach as it can specifically deliver lethal radiation doses both to
the primary tumour site as well as disseminated disease, while
sparing non-target organs. TRNT using full-sized antibodies as
vectors remains challenging in solid tumours due to their long
circulation time. Single-domain antibody fragments (sdAbs) are
vectors with appropriate characteristics for TRNT, however their
kidney retention limits the radioactive dose that can be given to treat
without inducing renal toxicity. In an attempt to avoid this limitation, I
will deploy a modified pre-targeting strategy on sdAbs against B7-H3,
an immune checkpoint protein that is found overexpressed in many
human cancers. Pre-targeting was initially designed to limit
haematological exposure to radiation in the case of radiolabelled
mAbs. In this project I aim to use the pre-targeting strategy to reduce
renal exposure to radiation thereby optimizing the therapeutic index
of sdAb-based TRNT.
For this purpose, sdAbs will be functionalized to allow recognition by
a fast-clearing radiolabeled hapten. I will investigate the benefit of
site-specific functionalization over the conventional random approach
using a completely new enzyme-based ligation strategy. At the end, I
aim to obtain a sdAb-based radiopharmaceutical for TRNT with
optimal therapeutic index achieved by an innovative pre-targeting
strategy, and effective in B7-H3 overexpressing cancer.