An armed anti-immunoglobulin light chain nanobody protects mice against influenza A and B infections.

Liu, Xin [PCMM, Boston Children's Hospital - Harvard Medical School] (Co-premier auteur) Balligand, Thomas [UCL] (Co-premier auteur) Carpenet, Claire [PCMM, Boston Children's Hospital - Harvard Medical School] Ploegh, Hidde L [PCMM, Boston Children's Hospital - Harvard Medical School]

The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the influenza neuraminidase inhibitor zanamivir, to a nanobody that recognizes the kappa light chains of mouse immunoglobulins. This adduct was designed to achieve half-life extension of zanamivir through complex formation with the much-larger immunoglobulins in the circulation. The zanamivir moiety targets the adduct to virus-infected cells, whereas the anti-kappa component simultaneously delivers polyclonal immunoglobulins of indeterminate specificity and all isotypes. Activation of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity promoted elimination of influenza neuraminidase-positive cells. A single dose of the conjugate protected mice against influenza A or B viruses and was effective even when given several days after infection with a lethal dose of virus. In the absence of circulating immunoglobulins, we observed no in vivo protection from the adduct. The type of conjugates described here may thus find application for both anti-influenza prophylaxis and therapy.