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Title: S tructural basis of selectivity and neutralizing activity of a TGFα/epiregulin specific antibody

Journal Article · · Protein Science
DOI:https://doi.org/10.1002/pro.3023· OSTI ID:1401704
 [1];  [2];  [2];  [1];  [1]
  1. Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company Indianapolis Indiana 46285
  2. Eli Lilly Biotechnology Center San Diego California 92121
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Abstract Recent studies have implicated a role of the epidermal growth factor receptor (EGFR) pathway in kidney disease. Skin toxicity associated with therapeutics which completely block the EGFR pathway precludes their use in chronic dosing. Therefore, we developed antibodies which specifically neutralize the EGFR ligands TGFα (transforming growth factor‐alpha) and epiregulin but not EGF (epidermal growth factor), amphiregulin, betacellulin, HB‐EGF (heparin‐binding epidermal growth factor), or epigen. The epitope of one such neutralizing antibody, LY3016859, was characterized in detail to elucidate the structural basis for ligand specificity. Here we report a crystal structure of the LY3016859 Fab fragment in complex with soluble human TGFα. Our data demonstrate a conformational epitope located primarily within the C‐terminal subdomain of the ligand. In addition, point mutagenesis experiments were used to highlight specific amino acids which are critical for both antigen binding and neutralization, most notably Ala 41 , Glu 44 , and His 45 . These results illustrate the structural basis for the ligand specificity/selectivity of LY3016859 and could also provide insight into further engineering to alter specificity and/or affinity of LY3016859.

Sponsoring Organization:
USDOE
Grant/Contract Number:
DE‐AC02‐06CH11357
OSTI ID:
1401704
Journal Information:
Protein Science, Journal Name: Protein Science Vol. 25 Journal Issue: 11; ISSN 0961-8368
Publisher:
Wiley Blackwell (John Wiley & Sons)Copyright Statement
Country of Publication:
United Kingdom
Language:
English
Citation Metrics:
Cited by: 4 works
Citation information provided by
Web of Science

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