Development of anti-CD38 nanobodies as theranostic agents

Researchers from the Hematology laboratory (GIGA-I3) have just published their results in the "Journal of Hematology & Oncology". This work, although ambitious at the time of its beginning 5 years ago, has been rewarded by the quality of the results obtained and the interest aroused during national and international congresses (European school of hematology, European society for molecular imaging, International myeloma society,...).

Researchers from the Hematology laboratory (GIGA-I3) have just published their results in the "Journal of Hematology & Oncology". This work, although ambitious at the time of its beginning 5 years ago, has been rewarded by the quality of the results obtained and the interest aroused during national and international congresses (European school of hematology, European society for molecular imaging, International myeloma society,...).

Antibody-based therapies targeting the CD38 enzyme are currently used as single agents as well as in combination regimens for multiple myeloma, a malignant disease of plasma cells, a population of B lymphocytes. In this study, researchers developed single-domain anti-CD38 antibodies (sdAbs) that can be used to track CD38-positive tumor cells and then used for targeted radionuclide therapy. The sdAbs are derived from camelid heavy chain antibodies and have shown to be promising theranostic agents due to their favorable pharmacological properties.

At the beginning of this project, 4 anti-CD38 nanobodies (#1053, #551, #375 & #2F8) were produced, purified and characterized (in the Protein Engineering Center). A first phase of in vitro and in vivo characterization (radio-labeling with technetium-99m) allowed to identify nanobody 2F8 for which the properties sought in the context of diagnostic tools (specific accumulation within the tumor, very good tumor/background ratio as early as 1h post-injection) or therapeutic tools (absence of competition with daratumumab currently used on the market, absence of aspecific retention within non-targeted organs, ... ) were found.

Then, the internalization of the receptor after treatment was evaluated. Indeed, internalization is observed when using the monoclonal antibody daratumumab (current therapeutic agent in the treatment of myeloma). In the case of Nb 2F8, a limited (20%) and constant internalization over time was demonstrated using a radio-labeling technique. These results were confirmed using a second method, flow cytometry (via the GIGA-Flow Cytometry platform). This low internalization opened the possibility, due to its novelty, to protect this tool by a European patent filed in 2020.

After having verified the efficacy of this antibody in vitro, it was necessary to test its behavior in vivo when conjugated to a therapeutic radioisotope (beta or alpha emitter). In this step carried out in collaboration with the VUB, lutetium was chosen on the basis of its availability, its direct labelling after coupling with a chelator (as for indium) and its emission of β-particles (targeted radioimmunotherapy) and radiation (bio-distribution).

In this first therapeutic experience, a significant tumor regression was observed. The efficacy of the anti-CD38 agent was then confirmed. During the different experiments (diagnosis and therapy), one of the rare side effects of this compound was the presence of a renal toxicity following an aspecific retention of the radio-labelled compound linked to the glomerular filtration. Some devices, such as the co-injection of gelofusine (a solution known to act on this renal retention), have been implemented during the last therapeutic experiments allowing to reduce considerably this side effect. New studies are currently underway to continue the project and further improve efficacy while reducing side effects.

Reference

Contact

Jo Caers - jo.caers@chuliege.be