PDBsum entry 6pxr

Immune system

PDB id: 6pxr

Contents

Protein chains

218 a.a.

212 a.a.

Ligands

ALA-GLY-THR-TYR-GLY-LEU-GLY-ASP

Waters ×394

PDB id:

6pxr

Name:

Immune system

Title:

Anti-tau biib092 fab with tau peptide

Structure:

Gosuranemab fab, light chain. Chain: l. Engineered: yes. Gosuranemab fab, heavy chain. Chain: h. Engineered: yes. Microtubule-associated protein tau. Chain: a. Fragment: unp residues 15-22.

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Homo sapiens. Human. Organism_taxid: 9606. Gene: mapt, maptl, mtbt1, tau.

Resolution:

1.56Å R-factor: 0.230 R-free: 0.268

Authors:

J.W.Arndt,C.Quan

Key ref:

R.Sopko et al. (2020). Characterization of tau binding by gosuranemab. Neurobiol Dis, 146, 105120. PubMed id: 32991997 DOI: 10.1016/j.nbd.2020.105120

Date:

26-Jul-19 Release date: 29-Jul-20

Protein chain

A2NHM3  (A2NHM3_MOUSE) -  If kappa light chain (Fragment) from Mus musculus

Seq: 219 a.a.

Struc: 218 a.a.*

Protein chain

No UniProt id for this chain

Struc: 212 a.a.

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

DOI no: 10.1016/j.nbd.2020.105120

Neurobiol Dis 146:105120 (2020)

PubMed id: 32991997

Characterization of tau binding by gosuranemab.

R.Sopko, O.Golonzhka, J.Arndt, C.Quan, J.Czerkowicz, A.Cameron, B.Smith, Y.Murugesan, G.Gibbons, S.J.Kim, J.Q.Trojanowski, V.M.Y.Lee, K.R.Brunden, D.L.Graham, P.H.Weinreb, H.Hering.

ABSTRACT

Deposition of tau aggregates in the brain is a pathological hallmark of several neurodegenerative diseases, termed tauopathies, such as Alzheimer's disease (AD), corticobasal degeneration, and progressive supranuclear palsy (PSP). As transcellular spread of pathological tau aggregates has been implicated in disease progression, immunotherapy is being considered as a treatment for tauopathies. Here we report a detailed biochemical and biophysical characterization of the tau-binding properties of gosuranemab, a humanized monoclonal antibody directed against N-terminal tau that is currently being investigated as a treatment for AD. Binding experiments showed that gosuranemab exhibited high affinity for tau monomer, tau fibrils, and insoluble tau from different tauopathies. Epitope mapping studies conducted using X-ray crystallography and mutagenesis showed that gosuranemab bound to human tau residues 15-22. Immunodepletion of pathological human brain homogenates and transgenic mouse interstitial fluid (ISF) with gosuranemab resulted in reduced tau aggregation in tau biosensor cells. Preincubation of seed-competent AD-tau with gosuranemab significantly inhibited tau aggregation in mouse primary cortical neurons. Gosuranemab also significantly reduced unbound N-terminal tau in cerebrospinal fluid (CSF) from individuals with PSP and AD, and in ISF and CSF of treated transgenic mice. These results are consistent with the >90% target engagement observed in the CSF of some clinical trial dosing cohorts and support the evaluation of gosuranemab as a potential treatment for AD.