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Project
Optimized anti-Neuropilin-1 Nanobody formats as cancer therapy (FWOSB119)
Immunotherapy has meant a breakthrough in the treatment of some
cancers. However, the majority of patients remain unresponsive and
multiple cancer types are refractory to immunotherapy. Hence, novel
approaches are needed to bridge the gap in response rates.
Neuropilin-1 (NRP1) is often overexpressed within tumors and
correlates with a worse prognosis, likely due to its immune
suppressive capacity. Indeed, the NRP1/Semaphorin3a (Sema3a)
interaction is crucial for the attraction of macrophages to hypoxic
tumor areas, where these cells acquire an immune suppressive
phenotype. In addition, the NRP1/Sema4a interaction boosts the
immune suppressive capacity of regulatory T cells (Treg), and drives
CD8+ T cells towards exhaustion. Hence, blocking the NRP1/Sema
interaction is likely to increase anti-tumor immunity.
We previously generated an cross-reactive anti-mouse/humanNRP1
Nanobody (Nb) that interferes with the NRP1/Sema3a interaction.
Here, we will format this Nb into multivalent and lifetime-extended
constructs that are suitable for in vivo therapy and we will assess its
impact on tumor progression and metastasis in various tumor
models. Moreover, trispecific constructs will be generated, joining
anti-NRP1 to Nbs that target macrophages, Treg or CD8+ T cells.
Finally, the most promising formats will be combined with immune
checkpoint blockade. Overall, this project will yield a novel off-theshelf biological that may improve the outcome of cancer
immunotherapy.
cancers. However, the majority of patients remain unresponsive and
multiple cancer types are refractory to immunotherapy. Hence, novel
approaches are needed to bridge the gap in response rates.
Neuropilin-1 (NRP1) is often overexpressed within tumors and
correlates with a worse prognosis, likely due to its immune
suppressive capacity. Indeed, the NRP1/Semaphorin3a (Sema3a)
interaction is crucial for the attraction of macrophages to hypoxic
tumor areas, where these cells acquire an immune suppressive
phenotype. In addition, the NRP1/Sema4a interaction boosts the
immune suppressive capacity of regulatory T cells (Treg), and drives
CD8+ T cells towards exhaustion. Hence, blocking the NRP1/Sema
interaction is likely to increase anti-tumor immunity.
We previously generated an cross-reactive anti-mouse/humanNRP1
Nanobody (Nb) that interferes with the NRP1/Sema3a interaction.
Here, we will format this Nb into multivalent and lifetime-extended
constructs that are suitable for in vivo therapy and we will assess its
impact on tumor progression and metastasis in various tumor
models. Moreover, trispecific constructs will be generated, joining
anti-NRP1 to Nbs that target macrophages, Treg or CD8+ T cells.
Finally, the most promising formats will be combined with immune
checkpoint blockade. Overall, this project will yield a novel off-theshelf biological that may improve the outcome of cancer
immunotherapy.
Date:1 Nov 2021 → Today
Keywords:Optimization of cancer immunotherapy, Reducing immune suppression in the tumor microenvironment, Anti-Neuropilin-1 multivalent and lifetime-extended nanobodies as cancer therapy
Disciplines:Applied immunology, Cancer biology, Cancer therapy