title: In vivo and in vitro activity of an immunoglobulin Fc fragment (Fcab) with engineered Her-2/neu binding sites.
abstract: 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.
authors.affiliation: F-star GmbH, Vienna, Austria.
authors.forename: Max
authors.initials: M
authors.lastname: Woisetschläger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Antes
authors.forename: Radha
authors.initials: R
authors.lastname: Borrowdale
authors.forename: Susanne
authors.initials: S
authors.lastname: Wiederkum
authors.forename: Manuela
authors.initials: M
authors.lastname: Kainer
authors.forename: Herta
authors.initials: H
authors.lastname: Steinkellner
authors.forename: Gordana
authors.initials: G
authors.lastname: Wozniak-Knopp
authors.forename: Kevin
authors.initials: K
authors.lastname: Moulder
authors.forename: Florian
authors.initials: F
authors.lastname: Rüker
authors.forename: Geert C
authors.initials: GC
authors.lastname: Mudde
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007141:Immunoglobulin Fc Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: ADCC; CD16a; Fc fragment; Human tumor xenograft; Immunotherapy