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In vivo and in vitro activity of an immunoglobulin Fc fragment (Fcab) with engineered Her‐2/neu binding sites
Author(s) -
Woisetschläger Max,
Antes Bernhard,
Borrowdale Radha,
Wiederkum Susanne,
Kainer Manuela,
Steinkellner Herta,
WozniakKnopp Gordana,
Moulder Kevin,
Rüker Florian,
Mudde Geert C.
Publication year - 2014
Publication title -
biotechnology journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.144
H-Index - 84
eISSN - 1860-7314
pISSN - 1860-6768
DOI - 10.1002/biot.201300387
Subject(s) - antibody dependent cell mediated cytotoxicity , epitope , antibody , monoclonal antibody , effector , in vivo , cytotoxicity , in vitro , biology , trastuzumab , antigen , microbiology and biotechnology , cancer research , chemistry , immunology , biochemistry , cancer , genetics , breast cancer
Antigen‐binding Fc fragments (Fcabs) are a new unique class of immunotherapeutics. They are small (50 kD) fully functional antibody alternatives that bind antigen and elicit effector functions such as antibody‐dependent cytotoxicity (ADCC) and complement‐dependent cytotoxicity. Since Fcabs carry the natural FcRn binding site of antibodies, they have very favorable pharmacokinetics. We showed recently that Fcab H10‐03‐6 is a high‐affinity binder of Her‐2/neu (ErbB2/neu) mediating killing of Her‐2/neu‐overexpressing tumor cells in the presence of immune effector cells, strongly suggesting that the mechanism of killing is due to ADCC. The present study further confirms ADCC as the mechanism by which H10‐03‐6 mediates tumor cell killing, since H10‐03‐6 was shown to interact simultaneously with Her‐2/neu and the Fc receptor CD16a. The epitope recognized by H10‐03‐6 overlaps with that of the clinically used monoclonal antibody trastuzumab. However, unlike trastuzumab, Fcab H10‐03‐6 did not inhibit proliferation of human tumor cells in vitro even under conditions favoring Her‐2/neu crosslinking. Treatment of mice harboring human BT‐474 cell xenograft tumors with Fcab H10‐03‐6 led to statistically significant retardation of tumor growth. For the first time, in vivo properties of an Fcab are presented, supporting the view that Fcabs could become highly efficacious immunotherapeutics for human use.