A Small Discovery with a Big Impact
Fifteen years after mAbs were unlocked, Raymond Hamers-Casterman and his colleagues made another groundbreaking discovery. They found that animals from the Camelidae family, such as camels, llamas, and alpacas, produce a unique class of small antibodies in addition to conventional immunoglobulins. These camelid heavy chain-only antibodies are lacking the CH1 domains typically needed for light chain pairing. The full-length (VHH-hinge-Fc) protein found in camelid serum is termed a heavy-chain only antibody, or hcAb. The VH domain from these hcAb are VHH.3 Once researchers isolated the VHH domains, they found that these single-domain antibodies had better solubility and stability than conventional full-length monoclonal antibodies.4,5 It was also discovered that VHH naturally possess longer complementarity determining region 3 (CDR3) loops that enable improved access to hard-to-reach epitopes.6,7 VHH are able to mature toward longer CDR3 lengths because they are unconstrained by the paired VL present in a mAb.
VHH have since been harnessed extensively for a variety of research and clinical applications, largely due to their small size, high affinity and stability, low immunogenicity, enhanced solubility, and good tissue penetration. In 2019, the FDA approved its first VHH therapeutic, with four more approvals following suit. Today, VHH antibody-based therapeutics are being evaluated in 22 clinical trials worldwide.8
Successful diagnostic and therapeutic antibody engineering depends on discovering antibodies with high affinity and specificity for the target and low off-target toxicity. Advances in antibody engineering approaches allow the finetuning of qualities like affinity, size, and valency to optimize biodistribution and pharmacokinetics for specific applications. And, as technology continues to advance, new frontiers in personalized medicine will emerge, offering endless possibilities for those willing to explore.