TREM2
Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor expressed in most innate immune cells, including microglia in the central nervous system. TREM2 plays a crucial role in maintaining microglial function, particularly in phagocytosis (engulfing and clearing debris), survival, and activation. Dysfunctional TREM2 has been strongly linked to the development of the Alzheimer's disease (AD), making it an important target in neurodegenerative drug discovery.
TREM2 in pharma and biotech pipelines
Currently, no TREM2-targeting drugs have been approved. However, several promising candidates are in clinical development, including a small-molecule TREM2 agonist (VG3927) by Vigil Neuroscience, recently acquired by Sanofi, and VHB937 , a monoclonal antibody from Novartis.
Researchers at Genentech have used TREM2 as a model target to evaluate an advanced antibody affinity optimization method known as parallel lineage repertoire mining based on convergent immune responses. This approach enables rational affinity optimization by systematically exploring antibody variants within the immune repertoire while preserving key functional properties essential for therapeutic use. Given the challenge of delivering antibodies across the blood-brain barrier, it is especially important for TREM2-targeting biologics discovery. Enhancing affinity supports the drug’s therapeutic efficiency and lowers dosing, ensures drug safety and optimizes costs.
Key findings and structural insights
Using the parallel lineage repertoire mining approach, scientists successfully created a high-affinity, functionally potent, and specific anti-TREM2 antibody - Para.09. Remarkably, it outperforms its predecessor, 3.10C2, while maintaining therapeutic relevance, even though it comes from a different antibody lineage. To enable further characterization, both antibodies were humanized, and the X-ray structures in complex with the TREM2 peptide (residues 148-165) were determined. Below you will find key structural insights for increased Para.09 affinity.
Structural comparison of hu3.10C2-TREM2 and huPara.09-TREM2 complexes revealed that, although the overall binding mode is conserved, three key amino acid differences in the CDR H3 region of the heavy chain explain the increased binding affinity of huPara.09. These include:
The presence of Asp 106h instead of Gly adds a new direct interaction with the backbone amide of TREM2 residue I159, which stabilizes the antibody-antigen complex.
I107h Introduction in huPara.09 causes conformational changes in the CDR H3 loop. It pushes Leu-115h outward, reshaping the hydrophobic pocket. This new pocket better accommodates TREM2 H154, and is more flexible, meaning it can bind either His or Ala at that position.
E116h in huPara.09 instead of Asp extends the side chain to form a hydrogen bond with TREM2 S160. It also compensates for the longer and outward-shifted CDR H3 loop in huPara.09.
These structural insights highlight the value of advanced affinity optimization techniques and their potential in developing new therapies, in this case against Alzheimer’s disease. Given the challenge of delivering therapeutic antibodies across the blood-brain barrier, achieving high-affinity binding is critical to ensure therapeutic efficacy. Enhanced affinity also enables lower dosing, which contributes to improved safety profiles and greater cost-effectiveness.
Reference
Hsiao YC, Wallweber HA, Alberstein RG, Lin Z, Du C, Etxeberria A, Aung T, Shang Y, Seshasayee D, Seeger F, Watkins AM, Hansen DV, Bohlen CJ, Hsu PL, Hötzel I. Rapid affinity optimization of an anti-TREM2 clinical lead antibody by cross-lineage immune repertoire mining. Nat Commun. 2024 Sep 27;15(1):8382. doi: 10.1038/s41467-024-52442-y. PMID: 39333507; PMCID: PMC11437124.