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Novel antibody delivery technology boosts immunotherapy against glioblastoma in mice

Journal
Nature Biomedical Engineering
Reuters Health - 21/10/2021 - A delivery technology based on glucosylated polymers conjugated onto antibodies enhanced the accumulation and safety of checkpoint blockade therapy in a mouse model of glioblastoma.

"Immune checkpoint blockade antibodies have been notoriously ineffective against glioblastoma in the clinic," Dr. Kazunori Kataoka and Dr. Horacio Cabral of the University of Tokyo told Reuters Health by email. "One of the major reasons for such poor antitumor effects is the limited access of antibodies into tumor tissues."

"We focused on developing a disruptive delivery technology capable of selectively enhancing the accumulation of antibodies in tumors," they explained. It does this "by conjugating glucosylated polymers that promote extravasation into tumors, based on the high glucose uptake of cancer tissues."

"We estimate that a formulation based on an antibody used in the clinic modified with our glucosylated polymers could be translated into human studies in 4-5 years without much risk of failure," they said. "Since our technology takes advantage of the glucose uptake of tumors for selectively increasing the accumulation of antibodies, we envision FDG-PET imaging as an effective approach to identify tumors that are prone for targeting by our system."

As reported in Nature Biomedical Engineering, in experiments in mice with orthotopic glioblastoma tumors, the team used avelumab, which has been shown to be immunologically active in both humans and animals, as the immune checkpoint inhibitor (ICI).

ICIs engineered with properly configured glucose molecules recognized glucose transporter 1 (GLUT1) in the glioblastoma vasculature, resulting in about 20-fold greater accumulation compared to the native antibody.

Further, the amount of ICI accumulated specifically in the brain tumor site was 33 times greater than that in normal brain tissue, indicating high brain tumor selectivity.

A single dose of avelumab given at 15% of the standard dose (1.5 mg/kg given once vs. 10 mg/kg given multiple times) achieved a 60% response rate. In responding mice, treatment reinvigorated antitumor immune responses, induced immunological memory that protected the animals against rechallenge with tumor cells, and suppressed autoimmune responses - and thereby, immune-related adverse events - in the animals' healthy tissues.

Further investigation showed that the number of natural killer and CD8+ cells increased, along with effective repolarization of M2-like macrophages to M1-like macrophages (an antitumor state). Regulatory T cells and bone marrow-derived immunosuppressive cells declined, and effector memory T cells were found in the spleen of responding mice whose tumors disappeared within 60 days.

Drs. Kataoka and Cabral said, "We are now evaluating the delivery of ICIs to other tumors, such as melanoma. Moreover, other antibodies and antibody drug conjugates are being modified with our glucosylated polymers for improving tumor targeting, as well as reducing side effects."

Dr. Yazmin Odia, Chief of Neuro-Oncology at Miami Cancer Institute, part of Baptist Health South Florida, commented in an email to Reuters Health. "The authors present a truly novel and potentially highly useful tool for better targeting immunotherapy for historically refractory cancers like glioblastoma, while limiting the unwanted effects of uncontrolled immune reactions in normal brain and body organs."

"Their engineered Gluc-S-aPD-L1 construct serves as homing beacon that targets the glucose transporter-1 (GLUT1) that is not only common in brain blood vessels but necessary for transporting glucose, an essential fuel used to energize glioblastoma," she said. "Simultaneously, (it) also senses the unique environment of glioblastoma, thus shielding the nearby normal brain tissue from the negative effects of intensified immune response."

"Our cautious optimism awaits the human trials that will better clarify the benefit and utility of their Gluc-S-aPD-L1 construct," Dr. Odia concluded.

Dr. Fabio Iwamoto, Deputy Director, Division of Neuro-Oncology at Columbia University Irving Medical Center in New York City, commented in an email to Reuters Health, "This is a promising approach, as antibodies, being such large molecules, often do not reach therapeutic levels in the central nervous system. The platform using a commercially available PDL-1 inhibitor is promising and could potentially be used for many different antibodies."

"The main concern is if more CNS toxicity will happen with this approach," he added. "CNS immune adverse events tend to be very rare but very serious with immune checkpoint blockers and the question is if this approach will increase such CNS side effects."

SOURCE: https://go.nature.com/30OqayW Nature Biomedical Engineering, online October 11, 2021.

By Marilynn Larkin



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