Clinical and experimental studies delineate protumorigenic roles for immune cell subsets in particular tumorassociated macrophages or TAM. Hence, it seems plausible to target these cells and eliminate or reprogram their function, but at present the role of distinct TAM subsets in the tumor microenvironment is insufficiently understood and tools to specifically target TAM subsets in vivo are largely non-existing. Very recent evidence, from our lab and others, identified the Macrophage Mannose Receptor (MMR,CD206) as marker for strongly protumorigenic TAM. Indeed, MMR TAM were reported to contribute to diminished therapy responsiveness and tumor relapse following anti-angiogenic or vascular-disrupting therapies and chemotherapy in peclinical tumor models. Interestingly, our previous work providede the first evidence that Nanobodies (Nbs), generated against mouse MMR, efficiently penetrate solid mouse tumors and specifically recognice MMR TAM, providing a solid basis for Nb-mediated TAM targeting.
In this study, we will employ newly generated cross-reactive anti-mouse/human MMR Nbs (unpublishes data from our lab) to target MMR TAM , craeting the possibility for future clinical translation of interesting lead compound(s). Distinct anti-MMR, Nb-conjugates will be generated wih the aim to eliminate or reprogram MMR TAM, including Nbs directly coupled to cytotoxic compounds(toxin, pro-apoptotic peptides) or to innovative nanoparticles carrying characteristics will be assessed in pre-clinical mouse tumor models. Finally, we will combine anti-MMR Nb-conjugate treatment with existing therapeutic strategies (chemotherapy, anti-angiogenic therapy) to evaluate the added value of these novel compounds in a relevant therapeutic setting. The ultimate deliverable of this study should be an anti-MMR Nb-conjugate lead compound for future clinical use as tool for the elimination of tumor-supporting macrophages, resulting in a highger efficiency of combined conventional therapies