作者: Smith, Adam E. ; Werfel, Thomas ; Hulugalla, Kenneth ; Iammarino, Paige ; Shofolawe-Bakare, Oluwaseyi ; Toragall, Veeresh B. ; Mayatt, Railey ; Bentley, John P.

Conventional inhibitors of immune checkpoints such as antiprogrammed death-1 and its ligand (anti-PD-1/PD-L1) and anticytotoxic T lymphocyte-associated protein 4 (anti-CTLA4) have revolutionized therapeutic approaches to cancer, establishing immunotherapy as the standard of care for many cancers.A significant number of cancers, however, remain refractory to the inhibition of these immune checkpoints, leading to the search for alternative immune checkpoints that are more relevant to those diseases.Tumor-associated macrophage (TAM)-mediated efferocytosis is an increasingly appreciated immune checkpoint with a profound impact on the phenotype of the tumor microenvironment (TME).TAMs perform their efferocytic function through the receptor MerTK, and MerTK activity correlates with tumor progression.To combat efferocytosis in the TME, we developed poly[[2-(diisopropylamino)ethyl methacrylate]-b-poly(methacrylamidomannose)] nanoparticles (PMAM NPs) capable of encapsulating and preferentially delivering UNC2025 (a MerTK inhibitor) to TAMs.The NPs had suitable physicochem. properties, such as a size of 130 nm and a neutral surface charge.The PMAM NPs encapsulated hydrophobic cargo and released them in a pH-dependent manner, showing suitability for cytosolic delivery.Moreover, the PMAM NPs showed 12-fold greater macrophage internalization than traditional PEGMA NPs.Macrophage internalization was shown to be dependent on the mannose receptor CD206, as the blockade of CD206 led to a significant decrease in PMAM NP internalization.Furthermore, PMAM NPs had a lower internalization than PEGMA NPs in 4T1 cancer cells that do not express CD206, further confirming macrophage selectivity.In vivo biodistribution studies showed that the PMAM NPs were capable of internalization by TAMs in the TME.Lastly, UNC2025-PMAM NPs significantly reduced tumor volume compared to free UNC2025, showing greater therapeutic efficacy in a model of triple-neg. breast cancer.These glycopolymer-based, efferocytosis-blocking NPs have promise both as a class of standalone cancer immunotherapy and as an adjuvant to improve response rates to checkpoint immunotherapy.

2024-11-14·JOURNAL OF MEDICINAL CHEMISTRY

Preliminary Study of Radionuclide-Labeled MerTK-Targeting PET Imaging Agents for the Diagnosis of Melanoma

Article

作者: Wang, Changjiang ; Yang, Yunyi ; Wang, Xiaodong ; Li, Zibo ; Yang, Liping ; Zhao, Weiling ; Wan, Qiang ; Wang, Li ; Liu, Hao ; Liu, Guangfu ; Chen, Yue ; Yin, Liping ; Sun, Qinghong

MerTK PET imaging holds potential as a promising approach for assessing tumor aggressiveness and monitoring treatment response. In this study, we synthesized a series of ¹⁸F- and ⁶⁸Ga-labeled tracers derived from MerTK inhibitors for detection of MerTK expression. Among the synthesized agents, the dimeric compounds [⁶⁸Ga]10 and [⁶⁸Ga]12 demonstrated good in vivo and in vitro stability, high affinities to the MerTK receptor, and good MerTK-targeting specificity. Notably, [⁶⁸Ga]10 exhibited a tumor uptake of 2.6 ± 0.2%ID/g at 1 h p. i. in B16F10 tumor-bearing mice, nearly tripling the uptake of its monomeric counterpart [⁶⁸Ga]3. A similar enhancement was observed with [⁶⁸Ga]12 compared to its monomeric analog [⁶⁸Ga]6. Additionally, [¹⁸F]14 achieved a tumor uptake of 7.6 ± 0.5%ID/g at 2 h p. i., outperforming the previously reported [¹⁸F]15. Biodistribution analysis further validated the results, highlighting their potential for clinical investigation.

2024-10-07·ONCOGENE

Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours

Article

作者: Sofela, Agbolahan A. ; Hanemann, C. Oliver ; Maze, Emmanuel A. ; Maze, Emmanuel A ; Lockley, Alex ; Sofela, Agbolahan A ; Kurian, Kathreena M ; van de Weijer, Laurien L. ; Dave, Foram ; Kurian, Kathreena M. ; Hilton, David A ; Hanemann, C Oliver ; Adams, Claire L ; Hook, Laura ; Ammoun, Sylwia ; Henderson, Summer ; Adams, Claire L. ; Herrera, Kevin ; Hilton, David A. ; van de Weijer, Laurien L ; Ercolano, Emanuela

Meningioma and schwannoma are common tumours of the nervous system. They occur sporadically or as part of the hereditary NF2-related schwannomatosis syndrome. There is an unmet need for new effective drug treatments for both tumour types. In this paper, we demonstrate overexpression/activation of TAM (TYRO3/AXL/MERTK) receptors (TAMs) and overexpression/release of ligand GAS6 in patient-derived meningioma tumour cells and tissue. For the first time, we reveal the formation of MERTK/TYRO3 heterocomplexes in meningioma and schwannoma tissue. We demonstrate the dependence of AXL and TYRO3 expression on MERTK in both tumour types, as well as interdependency of MERTK and AXL expression in meningioma. We show that MERTK and AXL contribute to increased proliferation and survival of meningioma and schwannoma cells, which we inhibited in vitro using the MERTK/FLT3 inhibitor UNC2025 and the AXL inhibitor BGB324. UNC2025 was effective in both tumour types with superior efficacy over BGB324. Finally, we found that TAMs are expressed by tumour-associated macrophages in meningioma and schwannoma tumours and that UNC2025 strongly depleted macrophages in both tumour types.

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