Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment

Galstyan, A.; Chiechi, A.; Korman, A. J.; Sun, T.; Isreal, L. L.; Braubach, O.; Patil, R.; Shatalova, E.; Ljubimov, V. A.; Markman, J.; Grodzinski, Z.; Black, K. L.; Penichet, M. L.; Holler, E.; Ljubimov, A. V.; Ding, H.; Ljubimova, J. Y.

doi:10.1101/466508

bioRxiv · 10.1101/466508

Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment

Galstyan, A.·Chiechi, A.·Korman, A. J.·Sun, T.·Isreal, L. L.·Braubach, O.·Patil, R.·Shatalova, E.·Ljubimov, V. A.·Markman, J.·Grodzinski, Z.·Black, K. L.·Penichet, M. L.·Holler, E.·Ljubimov, A. V.·Ding, H.·Ljubimova, J. Y.

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Abstract

Treatment of brain gliomas with checkpoint inhibitor antibodies to cytotoxic T-lymphocyte-associated antigen 4 (a-CTLA-4) and programmed cell death-1 (a-PD-1) was largely unsuccessful due to their inability to cross the blood-brain barrier (BBB). We describe a new generation of nano immunoconjugates (NICs) developed on natural biopolymer scaffold, poly({beta}-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response in glioma-bearing mice. NIC treatment of mice bearing intracranial GL261 glioblastoma (GBM) resulted in an increase of CD8+ T-cells with a decrease of T regulatory cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local brain tumor immune response.

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Galstyan, A., Chiechi, A., Korman, A. J., Sun, T., Isreal, L. L., Braubach, O., Patil, R., Shatalova, E., Ljubimov, V. A., Markman, J., Grodzinski, Z., Black, K. L., Penichet, M. L., Holler, E., Ljubimov, A. V., Ding, H., Ljubimova, J. Y.. 2018-11-09. Nano immunoconjugates crossing blood-brain barrier activate local brain tumor immune system for glioma treatment. https://doi.org/10.1101/466508

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