Antibody engineering for increased potency, breadth and half-life

Sievers, Stuart A.; Scharf, Louise; West, Anthony P.; Bjorkman, Pamela J.

In a different approach, features of clonally related antibodies with similar specificities can sometimes be combined into one antibody to increase breadth and/or potency. For example, a chimeric version of glycan-dependent bNAbs 10-1074 and PGT121 [14, 57] was constructed by grafting five PGT121 heavy chain residues identified as contacting a complex-type N-linked glycan into the 10-1074 heavy chain [57] . The chimera (10-1074 GM ) exhibited improved potency and neutralized some viral strains resistant to wildtype 10-1074. In the case of PG9 and PG16, members of a family of bNAbs targeting the V1V2 loop and glycans at positions Asn160 gp120 and Asn176 gp120 [14] , three PG16 LC residues that contact a complex or hybrid-type N-glycan at Asn176 gp120 were grafted onto LC PG9 to create PG9-PG16-RSH [62] . The resulting chimeric antibody had improved potency compared with PG9 [62] . In both examples, grafting residues contacting complex-type N-glycans onto a family member that favors a high-mannose N-glycan at the same Env position seemed to allow the antibody to accommodate different types of glycoforms. In another example, the neutralization potency of the MPER antibody 4E10 was improved nearly two-fold by engineering its CDRH3 to mimic lipid-binding properties observed for 10E8 [63] .