Abstract Details

Title Binding Characteristics of PRX012 Surrogate Demonstrate Potent Engagement of Toxic Amyloid Beta Protofibrils and Robust Clearance of Pyroglutamate-modified Amyloid Beta

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P7 - Poster Session 7 (11:45 AM-12:45 PM)

Poster/Presentation
Number 9-003

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.

Authors/Disclosures
Brian Campbell (Prothena Biosciences Inc) PRESENTER	Dr. Campbell has received personal compensation for serving as an employee of Prothena Biosciences. Dr. Campbell has received personal compensation in the range of $0-$499 for serving as a Consultant for Mindimmune Therapeutics. Dr. Campbell has stock in Prothena Biosciences. Dr. Campbell has stock in MindImmune Therapeutics.
Gang Zhang (Prothena Biosciences)	No disclosure on file
Joshua Salmans (Prothena Biosciences)	No disclosure on file
Abderrahman Elmaarouf (AstraZeneca)	No disclosure on file
Stephen Tam	No disclosure on file
Amir Porat (Prothena Biosciences)	No disclosure on file
Michael Skov (Prothena Biosciences)	No disclosure on file
Philip Dolan (Prothena Biosciences)	No disclosure on file
Gene Kinney (Prothena)	No disclosure on file
Wagner Zago (Prothena Biosciences)	Wagner Zago has received personal compensation for serving as an employee of Prothena Biosciences. Wagner Zago has stock in Prothena Biosciences. Wagner Zago has received intellectual property interests from a discovery or technology relating to health care.

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