Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG.

Nicolas Fischer, Greg Elson, Giovanni Magistrelli, Elie Dheilly, Nicolas Fouque, Amélie Laurendon, Franck Gueneau, Ulla Ravn, Jean-François Depoisier, Valery Moine, Sylvain Raimondi, Pauline Malinge, Laura Di Grazia, François Rousseau, Yves Poitevin, Sébastien Calloud, Pierre-Alexis Cayatte, Mathias Alcoz, Guillemette Pontini, Séverine Fagète, Lucile Broyer, Marie Corbier, Delphine Schrag, Gérard Didelot, Nicolas Bosson, Nessie Costes, Laura Cons, Vanessa Buatois, Zoe Johnson, Walter Ferlin, Krzysztof Masternak, Marie Kosco-Vilbois

Index: Nat. Commun. 6 , 6113, (2015)

Full Text: HTML

Abstract

Bispecific antibodies enable unique therapeutic approaches but it remains a challenge to produce them at the industrial scale, and the modifications introduced to achieve bispecificity often have an impact on stability and risk of immunogenicity. Here we describe a fully human bispecific IgG devoid of any modification, which can be produced at the industrial scale, using a platform process. This format, referred to as a κλ-body, is assembled by co-expressing one heavy chain and two different light chains, one κ and one λ. Using ten different targets, we demonstrate that light chains can play a dominant role in mediating specificity and high affinity. The κλ-bodies support multiple modes of action, and their stability and pharmacokinetic properties are indistinguishable from therapeutic antibodies. Thus, the κλ-body represents a unique, fully human format that exploits light-chain variable domains for antigen binding and light-chain constant domains for robust downstream processing, to realize the potential of bispecific antibodies.