A highly selective TCR-mimic antibody reveals unexpected mechanisms of HBV peptide-MHC recognition and previously unknown target biology
Year: 2025
Type: article
Abstract: Curative therapies for chronic hepatitis B virus infection (CHB) are needed, and T-cell redirection is a promising approach, with peptide-MHC complexes (pMHC) being attractive targets. HBV core18–27 peptide (C18, 10-mer) presented by HLA-A*02:01 (C18-MHC) has two major variants (C18-V or C18-I, differing in the C-terminal residue), both of which are known to be targeted by CD8+ T cells in HBV-infected individuals. Through an extensive screening campaign, we identified a highly selective anti-C18-MHC antibody clone MUR35. A MUR35-based T-cell engager (TCE) potently killed HBV-infected hepatocytes but had no activity on uninfected hepatocytes, on other HBV-negative cell types or on host peptides with sequence similarity to C18. Crystal structures of MUR35 bound to both C18-I- and C18-V-MHC revealed a unique binding mode with contacts mediated exclusively by the light chain complementarity-determining regions (CDRs), suggesting that high specificity is achievable without a typical T-cell receptor-like binding mode involving both heavy and light chain CDRs. Although MUR35 exhibits similar binding affinity and structural contacts with C18-V and C18-I, TCE killing was only detected on hepatocytes producing C18-V. To better understand the cause of this discrepancy, we conducted a quantitative proteomics study in an HBV-infected humanized mouse model and found that C18-V was expressed at approximately 300 copies/cell, while C18-I expression was below the limit of detection. Unexpectedly, the proteomics studies revealed that previously unreported 9-mers missing the N-terminal phenylalanine of C18-I and -V were expressed at an average of 508 and 142 copies/cell, respectively, and therefore could be alternative targets for HBV pan genotypic coverage. Our data suggest unexpectedly large differences in antigen presentation efficiency between highly conservative amino acid substitutions in C18 peptide and reveal potentially novel HBV targets for future studies.
Source: mAbs
Authors: Shahzada Khan, Jeremy Lum, Heather Stephenson, Pawan Bir Kohli, David Mortenson, Dhivya Ramakrishnan, Magdeleine Hung, Sheng Ding, Elbert Seto, Sabrina Lu, Randy Yen, Debi Jin, Brian Lee, Sheila Clancy, Nicole Schirle Oakdale, Nikolai Novikov, Don Kang, Ruidong Li, David Pan, Rutwij Dave, Eric Lansdon, Simon P Fletcher, Abhishek V. Garg, Nathan Thomsen, Scott Balsitis
Institution: Gilead Sciences (United States)
Language: English
Topic: Hepatitis B Virus Studies
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,575
Awards: G102163711, G1286236842, G1313983767, G1664757510, G1767990418, G2287611682, G2539837713, G262962599, G2638771445, G3075337988, G3083819904, G3266578508, G334911014, G3353598662, G382641700, G409777406, G4501827968, G498139845, G5607048534, G6206027980, Pilatus 6m, G6652958823, G6848031779, G6918803902, G8229677252, G8546385581, G9000263589, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), G969889393
OpenAlex ID: W4414475345