Nanobodies: The Future of Antibody-Based Immune Therapeutics

Targeted therapy is a fast evolving treatment strategy to reduce unwanted damage to healthy tissues, while increasing efficacy and specificity. Driven by state-of-the-art technology, this therapeutic approach is especially true of cancer. Antibodies with their remarkable specificity have revolutionized therapeutic strategies for autoimmune conditions and cancer, particularly blood-borne cancers, but have severe limitations in treating solid tumors. This is mainly due to their large molecular size, low stability, tumor-tissue penetration difficulties, and pharmacokinetic properties. The tumor microenvironment, rich in immune-suppressing molecules is also a major barrier in targeting solid tumors by antibody-based drugs. Nanobodies have recently emerged as an alternative therapeutic agent to overcome some of the drawbacks of traditional antibody treatment. Nanobodies are the VHH domains found on the heavy-chain only antibodies of camelids and are the smallest naturally available antibody fragments with excellent antigen-binding specificity and affinity, equivalent to conventional antibodies but with molecular weights as low as 15 kDa. The compact size, high stability, enhanced hydrophilicity, particularly in framework regions, excellent epitope interactions with protruding CDR3 regions, and improved tissue penetration make nanobodies the next-generation therapeutics (Nano-BioDrugs). In this review, the authors discuss the interesting properties of nanobodies and their advantages over their conventional counterparts and provide insight into how nanobodies are being utilized as agonists and antagonists, bispecific constructs, and drug and enzyme-conjugates to combat the tumor microenvironment and treat disease.