Tumor-specific surface marker-independent targeting of tumors through nanotechnology and bioorthogonal glycochemistry

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Abstract

Biological targeting is crucial for effective cancer treatment with reduced toxicity but is limited by the availability of tumor surface markers. To overcome this, we developed a nanoparticle-based, Tumor-specific suRfACE maRker-independent (TRACER) targeting approach. Utilizing the unique biodistribution properties of nanoparticles, we encapsulated Ac4ManNAz to selectively label tumors with azide reactive groups. Surprisingly, while NP-delivered Ac4ManNAz was cleared by the liver, it did not label macrophages, potentially reducing off-target effects. To exploit this tumor-specific labeling, we functionalized anti-4-1BB antibodies with dibenzocyclooctyne (DBCO) to target azide-labeled tumor cells and activate the immune response. In syngeneic B16F10 melanoma and orthotopic 4T1 breast cancer models, TRACER enhanced anti-4-1BB’s therapeutic efficacy, increasing median survival time. Immunofluorescence analyses revealed increased tumor infiltration of CD8+ T and NK cells with TRACER. Importantly, TRACER reduced hepatotoxicity associated with anti-4-1BB, resulting in normal serum ALT and AST levels and decreased CD8+ T cell infiltration in the liver. Quantitative analysis confirmed a 4.5-fold higher tumor-to-liver ratio of anti-4-1BB accumulation with TRACER compared to conventional anti-4-1BB antibodies. Our work provides a promising approach for developing targeted cancer therapies that circumvent limitations imposed by the paucity of tumor-specific markers, potentially improving efficacy and reducing off-target effects to overcome liver toxicity associated with anti-4-1BB.

Authors

Hyesun Hyun, Bo Sun, Mostafa Yazdimamaghani, Albert Wielgus, Yue Wang, Stephanie Ann Montgomery, Tian Zhang, Jianjun Cheng, Jonathan S. Serody, Andrew Z. Wang