The occurrence of bona fide antibodies devoid of light chains in Camelidae was one of the major discoveries within our department. These so-called heavy-chain antibodies (HCAbs) bind antigens solely with one single variable domain, referred to as VHH. Methods were developed to clone the VHH repertoire of an immunized dromedary (or llama) in phage display vectors, and to select the antigen-specific VHHs from these “immune” VHH libraries.
Our current research activities on camelid HCAbs and VHHs aims at three goals: (i) to increase the fundamental knowledge of VHH characteristics and HCAb ontogeny, (ii) to broaden the efficacy of VHHs and extend their applications in medical or biotechnological fields where the unique VHH properties offer a clear advantage over other antibody formats, and (iii) to develop new VHH selection strategies that are amenable to a high throughput mode. The objective here is to arrive at a rapid identification of small molecular probes to be employed in biosensors, functional genomics, structural genomics and proteomics. Obviously, the appearance of HCAbs requires the acquisition of multiple events to allow their generation and maturation into functional molecules. The dromedary germline genes (V, D and J) and constant immunoglobulin genes used to generate HCAbs were cloned. Analysis of these genes forms the cornerstone for understanding the HCAb ontogeny in camelids, and might eventually lead to the generation of a Xeno-mouse producing camel HCAbs. The antigen-specific VHHs we retrieved already have excellent biophysical properties (antigen affinity, specificity, solubility, stability, small size, recognition of epitopes that are less immunogenic for conventional antibodies). We obtained the crystal structure of many VHHs in complex with their antigen, and this forms the basis for further engineering of the VHHs to develop more versatile small molecular units. These small units are used as building blocks for more complex constructs, which are being tested as probe in biosensors, for tumor targeting, etc.
- A case of convergence: why did a simple alternative to canonical antibodies arise in sharks and camels? (PLoS Biol, 9, e1001120, 2011)
- Modulation of protein properties in living cells using nanobodies. (Nat Struct Mol Biol, 17, 133-8, 2010)
- Single-domain antibodies as building blocks for novel therapeutics. (Curr Opin Pharmacol, 8, 600-8, 2008)
- A versatile nanotrap for biochemical and functional studies with fluorescent fusion proteins. (Mol Cell Proteomics, 7, 282-9, 2008)
- Experimental therapy of African trypanosomiasis with a nanobody-conjugated human trypanolytic factor. (Nat Med, 12, 580-4, 2006)