9PWN

Crystal structure of Fabs 7411 in complex with TREM2 peptide

Summary for 9PWN

• Entry DOI: 10.2210/pdb9pwn/pdb
• Descriptor: 7411 Fab Heavy Chain, 7411 Fab Light Chain, TREM-2 stalk peptide, ... (8 entities in total)
• Functional Keywords: fab, antibody, complex, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 49897.12

Authors

Arndt, J.W.,Chao, Q.,Cooke, H.A.,Almeida, A.D.S. (deposition date: 2025-08-04, release date: 2025-09-10)

Primary citation

da Silva Almeida, A.,Geddie, M.L.,Bhate, A.,Quan, C.,Arndt, J.W.,Jiao, Y.,Santoro, J.C.,Noiman, L.,Vijayakumar, R.,Sanchez-Salazar, J.,Datta, A.,Antognetti, G.,Hartana, C.A.,Wang, X.F.,Smith, B.A.,Bartlett, D.,Duncan, D.,Liu, C.C.,Otero Gutierrez, K.,Cameron, T.O.,Koirala, S.,Cooke, H.A.
Building a potent TREM2 agonistic, biparatopic, common light chain antibody.
Mabs, 17:2546554-2546554, 2025

PubMed Abstract: Triggering Receptor Expressed on Myeloid cells 2 (TREM2) plays an important role in microglial function and has been genetically linked to Alzheimer's disease. Activation of TREM2 signaling may contribute to protection against neurotoxic effects of amyloid. Numerous TREM2 activating antibodies have been shown to modulate downstream microglial functions to different degrees, with mixed results in preclinical models and in the clinic. We sought to generate an effectorless agonistic antibody that acted solely through TREM2 engagement with sufficient potency to activate TREM2 in the brain. Our approach focused on building a multivalent biparatopic TREM2 antibody that could mimic the higher order clustering induced by native polyanionic ligands of TREM2. We describe our screening strategy and findings that led to the discovery of a potential therapeutic molecule composed of antibodies selected for optimal affinity, binding epitopes, and geometry. The most productive antibody pair was selected from a common light chain yeast-display library, which required multiple rounds of affinity maturation. Lead antibody candidates were converted into asymmetric tetravalent bispecifics via controlled Fab-arm exchange and subsequently screened in signaling assays. The most productive antibody pair was reengineered into a symmetric tetravalent format, increasing potency and simplifying development. This molecule exhibited higher efficacy and potency in signaling assays than other antibody formats tested and elicited TREM2-mediated chemokine responses in vivo. Our results demonstrate a biparatopic strategy for producing a high potency TREM2 agonistic antibody with low effector function that can modulate TREM2 signaling in vitro and brain pharmacodynamic responses in vivo.

PubMed: 40803893
DOI: 10.1080/19420862.2025.2546554

Experimental method

X-RAY DIFFRACTION (1.8 Å)