Binding Characteristics of PRX012 Surrogate Demonstrate Potent Engagement of Toxic Amyloid Beta Protofibrils and Robust Clearance of Pyroglutamate-modified Amyloid Beta
Brian Campbell1, Gang Zhang1, Joshua Salmans1, Abderrahman Elmaarouf1, Stephen Tam1, Amir Porat1, Michael Skov1, Philip Dolan1, Gene Kinney1, Wagner Zago1
1Prothena Biosciences Inc
Objective:

To build a more detailed understanding of the biological activity and binding interactions of PRX012, a next-generation, subcutaneously delivered anti-amyloid-beta (Aβ) monoclonal antibody (mAb) under investigation for the treatment of Alzheimer’s disease (AD).

Background:
Multiple clinical trials evaluating first-generation anti-Aβ mAbs (aducanumab, lecanemab, donanemab) show that Aβ plaque reduction closely correlates with slowing clinical decline in AD. In addition to plaque reduction, two additional mechanisms of action, neutralization of toxic Aβ protofibrils (lecanemab) and clearance of pyroglutamate-modified Aβ in plaques (donanemab), have been described. PRX012 was designed as a subcutaneous IgG1 mAb to induce robust neutralization and clearance of aggregated forms of Aβ, including protofibrils and plaques, with relative low doses/volumes due to its high binding avidity. Here, we describe nonclinical evaluations that compared head-to-head 1) the binding of a PRX012 surrogate (PRX012s) and lecanemab to Aβ protofibrils and 2) the ability of PRX012s and donanemab to induce microglial clearance of pyroglutamate-Aβ from AD brain tissue.
Design/Methods:

Antibody binding to Aβ protofibrils was characterized by surface plasmon resonance using published methods for lecanemab. Antibody-dependent phagocytosis of pyroglutamate-modified Aβ from AD plaques was evaluated ex vivo with post-mortem AD brain tissue in the presence of microglia and potentially clinically relevant antibody concentrations.

Results:

PRX012s bound to Aβ protofibrils with nearly 20-fold higher affinity/avidity when compared with lecanemab. Binding kinetics for lecanemab were consistent with previously published values. PRX012s was substantially more potent than donanemab in promoting clearance of pyroglutamate-Aβ from plaques of AD tissue ex vivo.

Conclusions:

PRX012s, an N-terminal-targeted anti-Aβ mAb, demonstrated superior binding to protofibrils and phagocytic clearance of pyroglutamate-modified Aβ when compared with lecanemab and donanemab, respectively. These data further support the ongoing clinical development of PRX012 as a potential best-in-class anti-Aβ immunotherapy that could enable a low-volume, infrequent subcutaneous injectable to reduce barriers to treatment.

10.1212/WNL.0000000000205068