Yu et al. examined the impact of affinity on the activity of immunomodulatory antibodies, and showed that lower affinities delivered greater agonism through increased FcγR-independent receptor clustering. A low-affinity anti-CD40 monoclonal antibody exhibited stronger agonistic activity and more effective antitumor activity in vivo compared with the high-affinity parent antibody. More potent agonism mediated by lower affinity could also be recapitulated for a human anti-CD40 antibody. Lowering the affinity converted an inert therapeutic anti-4-1BB antibody (utomilumab) and an antagonistic therapeutic anti-PD-1 antibody (nivolumab) into agonists.
Contributed by Shishir Pant
ABSTRACT: Antibody responses during infection and vaccination typically undergo affinity maturation to achieve high-affinity binding for efficient neutralization of pathogens(1,2). Similarly, high affinity is routinely the goal for therapeutic antibody generation. However, in contrast to naturally occurring or direct-targeting therapeutic antibodies, immunomodulatory antibodies, which are designed to modulate receptor signalling, have not been widely examined for their affinity-function relationship. Here we examine three separate immunologically important receptors spanning two receptor superfamilies: CD40, 4-1BB and PD-1. We show that low rather than high affinity delivers greater activity through increased clustering. This approach delivered higher immune cell activation, in vivo T_cell expansion and antitumour activity in the case of CD40. Moreover, an inert anti-4-1BB monoclonal antibody was transformed into an agonist. Low-affinity variants of the clinically important antagonistic anti-PD-1 monoclonal antibody nivolumab also mediated more potent signalling and affected T_cell activation. These findings reveal a new paradigm for augmenting agonism across diverse receptor families and shed light on the mechanism of antibody-mediated receptor signalling. Such affinity engineering offers a rational, efficient and highly tuneable solution to deliver antibody-mediated receptor activity across a range of potencies suitable for translation to the treatment of human disease.