LLAMA-DERIVED IMMUNOGLOBULIN SINGLE VARIABLE DOMAINS TO BUILD MULTIVALENT SUPERPOTENT AND BROADENED NEUTRALIZING ANTI-VIRAL MOLECULES

HULTBERG A.; TEMPERTON N.J.; ROSSEELS V.; KOENDERS M.; GONZALEZ-PAJUELO M.; PINTO D.; SCHEPENS B.; IBAÑEZ L.I.; VANLANDSCHOOT P.; SCHILLEMANS J.; SAUNDERS M.; WEISS R.A.; SAELENS X.; MELERO J.A.; VERRIPS C.T.; VAN GUCHT S.

Brujas, Bélgica

Congreso; 14th International Negative Strand Virus Meeting 2010; 2010

For efficient prevention of viral infections, simultaneous targeting of multiple epitopes is a powerful strategy. Neutralizing Llama-derived VHHs were selected against trimeric glycoproteins of Respiratory Syncytial Virus, Rabies virus and Influenza H5N1 virus. By fusing multiple copies of identical VHH, multivalent molecules were generated with improved potency with up to 3000-fold for RSV. Both neutralization and broadness was improved greatly by building biparatopic constructs, combining VHHs with different epitope recognition.By combining a VHH neutralizing RSV subtype A, but not subtype B with a poorly neutralizing VHH with high affinity for subtype B, a biparatopic construct was made with high neutralizing potency at low nanomolar concentrations against both subtypes. Similar results were obtained with multimeric VHHs against all three viruses. These data demonstrate the potential and general applicability of VHHs for construction of highly potent anti-viral molecules to achieve best-in-class and broader neutralization capacity.