chFRP5-ZZ-PE38, a large IgG-toxin immunoconjugate
outperforms the corresponding smaller FRP5(Fv)-ETA
immunotoxin in eradicating ErbB2-expressing tumor xenografts
, Roy Noy
, Winfried S. Wels
, Itai Benhar
Department of Molecular Microbiology and Biotechnology the George S. Wise Faculty of Life Sciences, Green Building, Room 202,
Tel-Aviv University, Ramat Aviv 69978, Israel
Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt am Main, Germany
Received 18 May 2007; received in revised form 9 July 2007; accepted 10 July 2007
As therapeutics, antibodies can be used ‘‘un-armed’’ or as immunoconjugates to direct cytotoxic moieties to tumor cells.
Immunoconjugates are made by attaching chemotherapy drugs, radioisotopes or toxins to the antibody. Small recombi-
nant antibody fragments fused to cytotoxic moieties, termed recombinant immunotoxins are also being developed as an
additional approach for a targeted cancer therapy. Key parameters in determining the therapeutic potential of such tar-
geted therapies are target speciﬁcity, aﬃnity, stability and size. With regard to treating solid tumors, tumor penetration
(which is inversely proportional to size) is currently regarded as the prime factor for eﬃcacy, while parameters such as
binding aﬃnity and residence time in the body are thought to contribute to a lesser extent.
When comparing recombinant immunotoxins and antibody-toxin immunoconjugates that target ErbB2/HER2, here we
found that a bivalent antibody-toxin immunoconjugate (200 kDa) was superior to the corresponding recombinant mono-
valent immunotoxin (69 kDa) in killing ErbB2-expressing tumor cells in culture and as xenografts in nude mice, suggesting
that higher avidity and longer residence time may outweigh tumor penetration. Our study suggests that the re-valuation of
currently neglected, large IgG-eﬀector molecule conjugates for anti-cancer therapy may be justiﬁed.
Ó 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: ErbB-2/HER2; chFRP5-ZZ-PE38 immunoconjugate; scFv(FRP5)-ETA immunotoxin; ZZ-PE38
Antibodies are among the most powerful tools in
biological research and are presently the fastest
growing category of new drug entities. Oncology
has been a major area of focus for antibody-based
therapy, because numerous antigens (called tumor-
associated antigens, TAAs) have been identiﬁed that
are overexpressed or expressed in a modiﬁed form
on certain types of cancer cells compared with nor-
mal tissues. Antibody binding is exploited to (a) spe-
ciﬁcally deliver toxic molecules to tumor cells, (b)
recruit cytotoxic immune cells, and (c) activate
0304-3835/$ - see front matter Ó 2007 Elsevier Ireland Ltd. All rights reserved.
Corresponding author. Fax: +972 3 6409407.
E-mail address: email@example.com (I. Benhar).
Present address: Department of Chemical Engineering, Uni-
versity of Texas at Austin, Austin, TX 78712, USA.
Cancer Letters 257 (2007) 124–135