Nanobody-based depletion of protumoral tumor-associated macrophages as novel cancer therapy
Evangelia Bolli1,2, Matthias D'Huyvetter3, Nick Devoogdt3, Tony Lahoutte3, Kiavash Movahedi1,2, Jo A. Van Ginderachter1,2,
1Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; 2Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium; 3In vivo Cellular and Molecular Imaging Laboratory, VUB, Brussels, Belgium
Tumors are considered as organoid structures, which contain not only cancer cells but also non-transformed types of cells, the stromal cells. A bidirectional interplay exists between transformed and non-transformed cells, which results in tumor progression and metastasis. Tumor-associated macrophages (TAMs) are one of the dominant cell types present in murine and human tumors. Clinical and experimental studies have delineated the highly pro-tumorigenic role of TAMs through a variety of mechanisms: they induce immunosuppression, angiogenesis, tumor growth, metastasis and facilitate resistance to currently used therapies such as chemotherapy, immune checkpoint and anti-angiogenic therapy and tumor relapse. For this reason, the depletion of pro-tumorigenic TAMs forms an attractive perspective in the treatment of cancer as a novel immunotherapy. TAM depletion in combination with currently used therapies is also of high importance as it could prevent therapy-induced resistance.
We and others have previously shown that the Macrophage Mannose Receptor (MMR, CD206) is highly expressed on the surface of pro-tumorigenic TAMs, rendering it an important molecule for targeted TAM depletion. Hence, we intend to deplete the pro-tumorigenic MMRhigh TAMs by using anti-MMR Nanobody (Nb)-conjugates, whereby Nbs are the antigen-recognition domains of camelid heavy chain-only antibodies. For this purpose, we have generated both anti-mouse and cross-reactive anti-human/mouse MMR Nbs and have selected the lead compounds, cross-reactive Nb3.49 and anti-mouse Nb1, based on their optimal in vivo pharmacokinetic properties. [99mTc]-labeled Nb1 exhibits high tumor penetrance, upon blocking of extra-tumoral binding sites with an excess of unlabeled bivalent Nb1, as visualized via SPECT/microCT imaging. The same behavior has been observed in the case of [18F]-labeled Nb3.49 via PET imaging. We have currently conjugated the lead anti-MMR Nb1 to the therapeutic radionuclide 177Lu for radioimmunotherapy. Co-administration of therapeutic radiolabeled anti-MMR Nb1 with an excess of unlabeled bivalent anti-MMR Nb1 to breast tumor-bearing mice, leaded to remarkable retardation of tumor growth compared to non-treated animals. Combination of the therapeutic radiolabeled anti-MMR Nb1 with currently used immunotherapies, such as a-PD1 immune checkpoint therapy and standard-of-care treatments, such as chemotherapy, is of great interest.
The present work is granted by Flanders Institute of Innovation and Technology (VLAIO).