Nanobodies as versatile tools: A focus on targeted tumor therapy, tumor imaging and diagnostics

Monoclonal antibodies and vaccines have widely been studied for the immunotherapy of cancer, though their large size appears to limit their functionality in solid tumors, in large part due to unique properties of tumor microenvironment. Smaller formats of antibodies have been developed to throw such restrictions. These small format antibodies include antigen binding fragments, single-chain variable fragments, single variable domain of camelid antibody (so-called nanobody (Nb) or VHH). Since their serendipitous discovery, nanobodies have been studies at length in the fields of research, diagnostics and therapy. These antigen binding fragments, originating from camelid heavy-chain antibodies, possess unusual hallmarks in terms of (small) size, stability, solubility and specificity, hence allowing cost-effective production and sometimes out performing monoclonal antibodies. In addition, these small camelid heavy-chain antibodies are highly adaptable tools for cancer research as they enable specific modulation of targets, enzymatic and non-enzymatic proteins alike. Molecular imaging studies benefit from the rapid, homogeneous tumor accumulation of nanobodies and their fast blood clearance, permitting previously unattainable fast tumor visualization. Moreover, they are endowed with considerable therapeutic potential as inhibitors of receptor-ligand pairs and deliverers of drugs or drug-loaded nanoparticles towards tumors. In this review, we shed light on the current status of nanobodies in diagnosis and imaging of tumor and exploiting nanobodies revert immunosuppressive events, modulation of immune checkpoints, and as deliverers of drugs for targeted tumor therapy.