Báo cáo khoa học: A novel ErbB2 epitope targeted by human antitumor immunoagents ppt

A novel ErbB2 epitope targeted by human antitumor

immunoagents

Fulvia Troise1,2,*, Maria Monti3,2,*, Antonello Merlino4,5,*, Flora Cozzolino3,2, Carmine Fedele1

,

Irene Russo Krauss4,5, Filomena Sica4,5, Piero Pucci2,3, Giuseppe D’Alessio1 and

Claudia De Lorenzo1,2

1 Dipartimento di Biologia Strutturale e Funzionale, Universita` di Napoli Federico II, Italy

2 CEINGE Biotecnologie avanzate, Napoli, Italy

3 Dipartimento di Chimica Organica e Biochimica, Universita` di Napoli Federico II, Italy

4 Dipartimento di Chimica, Universita` di Napoli Federico II, Italy

5 Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy

Introduction

Overexpression of the ErbB2 tyrosine kinase receptor

frequently occurs in breast cancer, and is associated

with poor prognosis and with more aggressive clinical

behavior [1,2]. Herceptin (trastuzumab), the only

humanized antibody against ErbB2 in clinical use, has

proven to be effective in the immunotherapy of breast

carcinoma [3]. However, it can engender cardiotoxicity,

and a high fraction of breast cancer patients are resis￾tant to Herceptin treatment [4–6].

Two novel human antitumor immunoconjugates

have been engineered in our laboratory by fusion of a

single-chain antibody fragment (scFv) against human

Keywords

breast cancer; cardiotoxicity; ErbB2 ⁄ Her2;

Herceptin ⁄ trastuzumab; immunotherapy

Correspondence

C. De Lorenzo, Dipartimento di Biologia

Strutturale e Funzionale, Universita` di Napoli

Federico II, via Cinthia, 80126 Napoli, Italy

Fax: +39 081679159

Tel: +39 081679158

E-mail: [email protected]

*These authors contributed equally to this

work

(Received 13 December 2010, revised 24

January 2011, accepted 31 January 2011)

doi:10.1111/j.1742-4658.2011.08041.x

Two novel human antitumor immunoconjugates, engineered by fusion of a

single-chain antibody fragment against human ErbB2 receptor, termed

Erbicin, with either a human RNase or the Fc region of a human IgG1,

are selectively cytotoxic for ErbB2-positive cancer cells in vitro and in vivo.

These Erbicin-derived immunoagents (EDIAs) do not show the most nega￾tive properties of Herceptin, the only humanized mAb against ErbB2 used

in the therapy of breast carcinoma: cardiotoxicity and the inability to act

on resistant tumors. These differences are probably attributable to the dif￾ferent ErbB2 epitopes recognized by EDIAs and Herceptin, respectively, as

we have previously reported that they induce different signaling mecha￾nisms that control tumor and cardiac cell viability. Thus, to accurately

identify the novel epitope recognized by EDIAs, three independent and

complementary methodologies were used. They gave coherent results,

which are reported here: EDIAs bind to a different ErbB2 epitope than

Herceptin and the other human ⁄ humanized antibodies against ErbB2

reported so far. The epitope has been successfully located in region

122–195 of extracellular domain I. These findings could lead to the identifi￾cation of novel epitopes on ErbB2 that could be used as potential thera￾peutic targets to mitigate anti-ErbB2-associated cardiotoxicity and

eventually overcome resistance.

Abbreviations

CDR, complementarity-determining region; ECD, extracellular domain of ErbB2 receptor; EDIA, Erbicin-derived immunoagent; ERB-hcAb,

human compact antibody against ErbB2; ERB-hRNase, human anti-ErbB2 immunoRNase with Erbicin fused to human pancreatic RNase;

HRP, horseradish peroxidase; PDB, Protein Data Bank; scFv, single-chain antibody fragment.

1156 FEBS Journal 278 (2011) 1156–1166 ª 2011 The Authors Journal compilation ª 2011 FEBS