Structural analysis of light chain-driven bispecific antibodies targeting CD47 and PD-L1.

In contrast to natural antibodies that rely mainly on the heavy chain to establish contacts with their cognate antigen, we have developed a bispecific antibody format in which the light chain (LC) drives antigen binding and specificity. To better understand epitope-paratope interactions in this context, we determined the X-ray crystallographic structures of an antigen binding fragment (Fab) in complex with human CD47 and another Fab in complex with human PD-L1. These Fabs contain a κ-LC and a λ-LC, respectively, which are paired with an identical heavy chain (HC).

Round optimization for improved discovery of native bispecific antibodies.

The assembly of bispecific antibodies (bsAb) that retain the structure of a standard IgG can be challenging as the correct pairing of the different heavy and light chains has to be ensured while unwanted side products kept to a minimum. The use of antibodies sharing a common chain facilitates assembly of such bsAb formats but requires additional efforts during the initial discovery phase. We have developed a native bsAb format called κλ body based on antibodies that, while being specific for different antigens, share the same heavy chain.

Dual display: phage selection driven by co-engagement of two targets by two different antibody fragments.

Antibody phage display technology has supported the emergence of numerous therapeutic antibodies. The development of bispecific antibodies, a promising new frontier in antibody therapy, could be facilitated by new phage display approaches that enable pairs of antibodies to be co-selected based on co-engagement of their respective targets. We describe such an approach, making use of two complementary leucine zipper domains that heterodimerize with high affinity.

Antibody Neutralization of CXCL10 Is Dependent on Binding to Free and Not Endothelial-bound Chemokine: IMPLICATIONS FOR THE DESIGN OF A NEW GENERATION OF ANTI-CHEMOKINE THERAPEUTIC ANTIBODIES.

To improve our understanding of properties that confer successful inhibition of chemokines , we analyzed anti-murine CXCL10 monoclonal antibodies (mAb) having different characteristics. 1B6 displayed potent inhibition of cell recruitment with an IC of 0.5 nm but demonstrated little efficacy in various animal models of human disease.