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Domain 4 of ILY sensitizes antibody therapy on cancer and HIV through abrogating human CD59 function
Author(s) -
Hu Weiguo,
Giguel Francoise F,
Kuritzkes Daniel R,
Halperin Jose A,
Qin Xuebin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.522
Subject(s) - cd59 , antibody , antibody dependent cell mediated cytotoxicity , immune system , cancer research , cancer immunotherapy , immunology , complement system , in vivo , ex vivo , rituximab , immunotherapy , cytotoxicity , chemistry , monoclonal antibody , biology , in vitro , biochemistry , microbiology and biotechnology
CD59 inhibits assembly of membrane attack complex via binding to C8 and C9. Complement is critical for cancer antibody therapy such as complement‐dependent cytotoxicity (CDC). CD59 is highly expressed in many kinds of cancer cells and HIV that harvests CD59 from infected cells to escape antibody‐mediated response. CD59 appears to be the most effective among complement regulators in protecting from CDC. Extensive studies indicate that expression of CD59 results in lymphoma resistance to rituximab and HIV to antibody‐mediated immune response. Therefore, it is imperative to develop a molecule capable of abrogating CD59 function. Intermedilysin (ILY), a cytotoxin secreted by Streptococcus intermedius, lyses only human cells due to its receptor specificity for human CD59 (hCD59) via its domain 4 (ILYd4). ILYd4 binds to AA42‐58 in hCD59, which also participates in the binding to C8 and C9. Thus, we hypothesize that truncated ILYd4 may abrogate hCD59 function to facilitate CDC effect on cancer and HIV. Indeed, ILYd4 (IC50 = 33 nM ex vivo and effective dose = 2.5 microgram/g body weight in vivo) sensitized a Rituximab‐resistance B lymphoma cells to Rituximab treatment without off target toxicity effects, and sensitized HIV to complement‐mediated virolysis activated by HIV patient's antibody. Therefore, ILYd4 may represent an innovative molecule for cancer and HIV immunotherapy.