Noninvasive imaging and inhibition of human programmed death ligand 1 (PD-L1) using nanobody K2 to improve cancer immunotherapy

Description

Immune checkpoint blocking monoclonal antibodies targeting programmed cell death 1 (PD-1) or its ligand programmed death ligand 1 (PD-L1) have transformed the oncology treatment landscape. PD-1/PD-L1 targeting has improved the prognosis of subsets of cancer patients, yet a significant number of patients across different cancer types do not benefit from this immunotherapy. Moreover, the necessity to administer high antibody doses is associated with a high cost and withholds an increased risk of adverse events. To optimize benefits and minimize risks from PD-1/PD-L1 blockade, it is key to develop innovative agents, theranostics that can be used for patient selection/monitoring and for efficient PD-1/PD-L1 blockade. Nanobodies are small antigen-binding proteins that efficiently penetrate tumors and cell-cell interfaces to bind their antigen with high affinity. Unbound nanobodies are rapidly cleared from blood through renal excretion. Therefore, nanobodies represent promising agents for cancer imaging and therapy. We generated K2, a human PD-L1 specific nanobody, and provided evidence of its theranostic potential. Traits of K2 are (1) high affinity and PD-L1 blocking capacity; (2) competitor for avelumab (Merck KGaA and Pfizer); (3) high signal-to-noise ratio in SPECT/CT and PET/CT imaging of PD-L1 positive tumors using technetium-99 metastable (99mTc)- or gallium-68 (68Ga)-labeled K2 respectively; (4) low kidney retention, which is unique as typically nanobodies show high retention in the proximal tubuli; (5) ability to enhance de novo activation of antigen-specific T cells in the setting of cancer vaccination where antibodies fail; and (6) ability to enhance T-cell functionality when interacting with tumor cells. These data advocate the application of K2 in tumor immunotherapy and diagnosis.

Periode	25 okt 2021 → 26 okt 2021
Evenementstitel	f-TALES meeting Leuven: Opportunities and Challenges in Cancer Immunotherapy
Evenementstype	Conference
Locatie	Leuven, Belgium
Mate van erkenning	National