Probody therapeutic design of 89Zr-CX-072 promotes accumulation in PD-L1 expressing tumors compared to normal murine lymphoid tissueGiesen, D., Broer, L. N., Lub-de Hooge, M. N., Popova, I., Howng, B., Nguyen, M., Vasiljeva, O., de Vries, E. G. E. & Pool, M., 17-Jan-2020, In : Clinical Cancer Research. 26, 15, p. 3999-4009 11 p.
Research output: Contribution to journal › Article › Academic › peer-review
PURPOSE: Probody™ therapeutic CX-072 is a protease-activatable antibody that is cross-reactive with murine and human programmed death-ligand 1 (PD-L1). CX-072 can be activated in vivo by proteases present in the tumor microenvironment, thereby potentially reducing peripheral, anti-PD-L1-mediated toxicities. To study its targeting of PD-L1-expressing tissues, we radiolabeled CX-072 with the positron emission tomography (PET) isotope zirconium-89 (89Zr).
EXPERIMENTAL DESIGN: 89Zr-labeled CX-072, non-specific Probody control molecule (PbCtrl) and CX-072 parental antibody (CX-075) were injected in BALB/c nude mice bearing human MDA-MB-231 tumors or C57BL/6J mice bearing syngeneic MC38 tumors. Mice underwent serial PET imaging 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo biodistribution. Intratumoral 89Zr-CX-072 distribution was studied by autoradiography on tumor tissue sections, which were subsequently stained for PD-L1 by immunohistochemistry. Activated CX-072 species in tissue lysates were detected by Western capillary electrophoresis.
RESULTS: PET imaging revealed 89Zr-CX-072 accumulation in MDA-MB-231 tumors with 2.1-fold higher tumor-to-blood ratios at 6 days pi compared to 89Zr-PbCtrl. Tumor tissue autoradiography showed high 89Zr-CX-072 uptake in high PD-L1-expressing regions. Activated CX-072 species were detected in these tumors, with 5.3-fold lower levels found in the spleen. Furthermore, 89Zr-CX-072 uptake by lymphoid tissues of immune-competent mice bearing MC38 tumors was low compared to 89Zr-CX-075, which lacks the Probody design.
CONCLUSIONS: 89Zr-CX-072 accumulates specifically in PD-L1-expressing tumors with limited uptake in murine peripheral lymphoid tissues. Our data may enable clinical evaluation of 89Zr-CX-072 whole-body distribution as a tool to support CX-072 drug development (NCT03013491).
|Number of pages||11|
|Journal||Clinical Cancer Research|
|Publication status||E-pub ahead of print - 17-Jan-2020|