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79
NOVEL HLA-E SPECIFIC IMMTAV® MOLECULES FOR THE
TREATMENT OF HEPATITIS B
Sarah Leonard, Rachel Paterson, Luis Godinho, Dawn Howe,
Mauro Monteiro, Ruth Martinez Hague, Kate Atkin, Anshuk
Sarkar, Richard Suckling, Wilawan Bunjobpol, Daniel Kay,
Tressan Grant, Carole Perot and Andrew Knox, Immunocore
Ltd.
Background: ImmTAV molecules are bispecific fusion
proteins consisting of an affinity enhanced TCR targeting
domain and an anti-CD3 scFv effector that mediates T cell
redirection to eliminate virally infected cells IMC-I109V,
an HBV specific ImmTAV that can eliminate HBV infected
cells in vitro, is currently undergoing first in human studies
in chronic Hepatitis B Similar to all current TCR-based
therapeutics, IMC-I109V is restricted to targeting an allele
from the highly polymorphic HLA class I complex Therefore,
to overcome HLA-restriction and enable ImmTAV molecules
to reach all patient populations, we further developed our
platform to generate the first HBV-specific ImmTAV that
targets HLA-E, a universally expressed, highly conserved
MHC molecule with only two functional alleles Methods:
Bioinformatic tools, biochemical peptide binding assays
and HLA-E surface stability assays were used to identify
HBV-derived peptides that bind HLA-E. Affinity, potency
and specificity of ImmTAV molecules was tested with SPR,
and Incucyte and IFN-g ELISpot assays using HBV antigen
positive and negative cells PBMCs obtained from healthy
donors were used as effectors in both experimental set ups
Results: Using a range of HLA-E binding assays, we have
shown for the first time that peptides derived from HBsAg and
Core proteins can bind to HLA-E and that the most stable
peptides bind to both HLA-E alleles, HLA-E*01:01 and 01:03
Here, we have demonstrated the ability to isolate and affinity
enhance HBV-HLA-E specific TCRs to generate bispecific
ImmTAV molecules. An HBV-specific ImmTAV mediated the
elimination of cells containing HBV DNA in vitro, without killing
antigen negative cells Furthermore, ImmTAV molecules were
specific for target peptide presented by both HLA-E alleles
and did not recognize non-target self-peptide complexes
(Figure 1) Conclusion: We have successfully engineered
an HBV-specific ImmTAV that targets a virus-derived peptide
presented by the universally expressed HLA-E molecule,
regardless of polymorphism This allows universal application
of the ImmTAV platform to eliminate HBV-antigen positive
cells.
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发表于 2020-10-19 12:11