Two novel human anti-ErbB2 immunoagents are active on trastuzumab-resistant tumours.
BACKGROUND
Overexpression of ErbB2 receptor in breast cancer is associated with disease progression and poor prognosis. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer, has proven to be effective; however, a relevant problem for clinical practice is that a high fraction of breast cancer patients shows primary or acquired resistance to trastuzumab treatment.


METHODS
We tested on trastuzumab-resistant cells two novel human anti-tumour immunoconjugates engineered in our laboratory by fusion of a human anti-ErbB2 scFv, termed Erbicin, with either a human RNase or the Fc region of a human IgG1. Both Erbicin-derived immunoagents (EDIAs) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo, target an ErbB2 epitope different from that recognised by trastuzumab and do not show cardiotoxic effects.


RESULTS
We report that EDIAs are active also on trastuzumab-resistant tumour cells both in vitro and in vivo, most likely because of the different epitope recognised, as EDIAs, unlike trastuzumab, were found to be able to inhibit the signalling pathway downstream of ErbB2.


CONCLUSIONS
These results suggest that EDIAs are immunoagents that could not only fulfil the therapeutic need of patients ineligible to trastuzumab treatment due to cardiac dysfunction but also prove to be useful for breast cancer patients unresponsive to trastuzumab treatment.
Gelardi
T
T
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, via Pansini 5, Napoli 80131, Italy.
Damiano
V
V
Rosa
R
R
Bianco
R
R
Cozzolino
R
R
Tortora
G
G
Laccetti
P
P
D'Alessio
G
G
De Lorenzo
C
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000939:Epitopes; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D012260:Ribonucleases / Q000627:therapeutic use; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000939:Epitopes; D018796:Immunoconjugates; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D012260:Ribonucleases; D000068878:Trastuzumab; C525747:Erb-hcAb; C508053:ERBB2 protein, human