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PDBsum entry 6ddr
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Immune system
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PDB id
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6ddr
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Contents |
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214 a.a.
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221 a.a.
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94 a.a.
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References listed in PDB file
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Key reference
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Title
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High-Resolution glycosylation site-Engineering method identifies mica epitope critical for shedding inhibition activity of anti-Mica antibodies.
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Authors
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T.N.Lombana,
M.L.Matsumoto,
A.M.Berkley,
E.Toy,
R.Cook,
Y.Gan,
C.Du,
P.Schnier,
W.Sandoval,
Z.Ye,
J.M.Schartner,
J.Kim,
C.Spiess.
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Ref.
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MAbs, 2019,
11,
75-93.
[DOI no: ]
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PubMed id
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Abstract
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As an immune evasion strategy, MICA and MICB, the major histocompatibility
complex class I homologs, are proteolytically cleaved from the surface of cancer
cells leading to impairment of CD8 + T cell- and natural killer cell-mediated
immune responses. Antibodies that inhibit MICA/B shedding from tumors have
therapeutic potential, but the optimal epitopes are unknown. Therefore, we
developed a high-resolution, high-throughput glycosylation-engineered epitope
mapping (GEM) method, which utilizes site-specific insertion of N-linked glycans
onto the antigen surface to mask local regions. We apply GEM to the discovery of
epitopes important for shedding inhibition of MICA/B and validate the epitopes
at the residue level by alanine scanning and X-ray crystallography (Protein Data
Bank accession numbers 6DDM (1D5 Fab-MICA*008), 6DDR (13A9 Fab-MICA*008), 6DDV
(6E1 Fab-MICA*008). Furthermore, we show that potent inhibition of MICA shedding
can be achieved by antibodies that bind GEM epitopes adjacent to previously
reported cleavage sites, and that these anti-MICA/B antibodies can prevent tumor
growth in vivo.
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