In 2013, the editorial board of Science proclaimed cancer immunotherapy, in particular immune checkpoint therapy, as breakthrough of the year. Ever since, checkpoint inhibitors, such as monoclonal antibodies (mAbs) blocking programmed death-1 (PD-1) and its ligand PD-L1, are exploding in popularity. This is evidenced by the increasing amount of clinical trials testing mAbs, such as nivolumab and pembrolizumab, which antagonize PD-1, and atezolizumab, avelumab and durvalumab, which antagonize PD-L1. Although immune checkpoint blockade has already proven its merit, there are still several aspects that require further attention in order to fully capitalize on the potential of checkpoint blockade. One of these is to develop theranostics, antigen-binding moieties that enable (1) predicting which patients will or will not benefit from the treatment, (2) monitoring of patients during treatment and (3) more efficient treatment through improved tumor penetration and inhibition of PD-1/PD-L1
interactions. In this regard, we proposed to study single domain antibodies (sdAbs), the smallest fragment from Camelid antibodies, as novel checkpoint theranostics, because the single-domain nature of sdAbs offers many advantages over conventional mAbs. We developed and fully characterized sdAbs that target human PD-L1, resulting in the selection of a high affinity lead sdAb, referred to as K2. This sdAb has the unique trait that it shows low kidney retention and can be used as a theranostic. Using xenograft models and human PD-L1 engineered tumor cells, we showed that the 99m-Technetium labeled sdAb K2 could be used for noninvasive molecular imaging. Moreover, using several in-house established in vitro assays, we showed that sdAb K2 could be used to inhibit the binding of human PD-L1 to PD-1, and as such potentiate stimulation of antigen-specific T-cell responses. To further prove the potential of sdAb K2 as a novel theranostic with advantageous properties, we are
currently performing imaging studies using 68-Gallium or 18-Fluorine as radiolabels, because these are more relevant for clinical translation. Moreover, we aim to study whether we can detect human PD-L1 in a physiological relevant situation, i.e. upregulated on tumor cells in response to interferon-gamma (IFN-y) producing T cells, and if so whether the images are predictive for subsequent immune checkpoint therapy with either avelumab or sdAb K2. These experiments are the subject of the current project proposal, and are of utmost importance to support clinical translation ofsdAb K2.
Short titleNICHE
Effective start/end date1/01/1930/06/19

    Flemish discipline codes

  • Applied immunology
  • Medical imaging and therapy not elsewhere classified

ID: 39436215