Use of glucose residues for polymer binding: development of immune checkpoint inhibitor (ICI) antibodies by iCONM and the University of Tokyo

Senior researcher Yuki Mochida and researcher Tao Yang at the Innovation Center of Nanomedicine (iCONM) of Kawasaki Institute of Industrial Promotion collaborated with The University of Tokyo to develop a compound comprising an ICI (anti-PD-L1 antibody) that is modified with a polymer that has a glucose residue. Such modification enabled large amounts of this inhibitor to be accumulated in malignant gliomas, a highly malignant type of brain tumor, while avoiding side effects. The researchers revealed that a single dose induced a high response rate of 60% in mice.

In experiments using "avelumab" as an anti-PD-L1 antibody anti-tumor immunity was confirmed to be induced, and recurrence was suppressed in mice whose brain tumors disappeared following drug administration. As modification with a polymer is applicable to other antibodies, extensive practical application of this type of modification is expected in the future. These findings were published in the October 11 issue of Nature Biomedical Engineering.

ICIs are antibody drugs that exhibit excellent efficacy against various cancers by inhibiting the suppression of T cells responsible for immunity to cancer cells. Six drugs, including avelumab, are currently used in clinical practice for the treatment of cancer. They work by inhibiting PD-L1 ligands on the surface of ganglion cells and PD-1 receptors on the surface of T cells. Challenges, such as the occurrence of serious adverse events, were encountered as the modified antibody acted on normal cells. In addition, the inability of antibodies to sufficiently reach the brain tumor owing to the blood-brain tumor barrier and their low efficacy served as another challenge. Despite advances in medicine over the past 50 years, malignant gliomas remain active for a median of 16 months.

The research group designed and synthesized a compound (glucose-conjugated polymer-modified avelumab) comprising a polymer and a glucose residue (PEG) with a linker to avelumab; this linker is specifically cleaved in the cancer cell environment. Avelumab has been shown to have immunostimulatory effects in human and animal therapies and so was chosen by the group for the development of a technology that combines the efficacy and safety of ICIs with brain tumor integration.

Previously, the study group found that glucose uptake was increased, and glucose transporters were overexpressed in brain tumors. To assess the mouse model of brain tumors, the no-treatment group, the avelumab (unmodified) group, and the glucose conjugated polymer-modified avelumab group were established, and the survival rate of mice in each group was compared. All mice in the no-treatment group and the avelumab group died between days 18 and 30. In contrast to this, all mice in the glucose-conjugated polymer-modified avelumab group survived for more than 90 days, 60% of which were cancer-free. A single low dose (1.5 milligrams per kilogram, standard 10 milligrams per kilogram) of the glucose-conjugated polymer-modified avelumab was found to exert a positive effect.

In mice that were cancer-free after the administration of glucose-conjugated polymer-modified avelumab, immunoreactivity, such as that mediated by CD8 + T cells and NK cells, was confirmed. Furthermore, the levels of immunosuppressive cells, such as regulatory T cells and monocyte bone marrow-derived inhibitory cells, were decreased. When cancer-free mice were re-transplanted with brain tumor cells after 84 days, in 80% of them tumors did not grow, and they were considered to have acquired anti-tumor immunity. The potential to prevent recurrence and metastatic cancer to the brain was revealed.

Four hours after administration, glucose-conjugated polymer-modified avelumab accumulated in brain tumors at a concentration 18-fold higher than that of unmodified avelumab and 33-fold higher than levels seen in normal cells. The administration of glucose-conjugated polymer-modified avelumab was also confirmed to suppress the effects on immune cells in the lung, kidney, and liver and be effective for malignant melanoma. As glucose-conjugated polymer modification can be applied to other ICIs, this strategy may be effective against various cancers in the future.