Modulation of drug-induced cytotoxicity by a bispecific monoclonal antibody that recognizes the epidermal growth factor receptor and doxorubicin.
A hybrid hybridoma secreting a bispecific hybrid mAb (bsmAb), which recognizes both the epidermal growth factor receptor (EGF-R) and the drug doxorubicin, was produced by somatic hybridization of two hybridomas. The bsmAb obtained was able to retarget doxorubicin cytotoxicity in vitro specifically on EGF-R-positive cells exerting at the same time an antidotal effect on cells that did not overexpress the EGF-R. Distribution studies in mice indicate that the bsmAb selectively delivers the drug to tumour cells and modifies doxorubicin biodistribution with a statistically significant decrease of drug concentration in the intestine, which is the main target of early anthracycline toxicity. In keeping with this finding is the remarkable antidotal activity exerted by bsmAb in mice treated with doxorubicin, which is proved by retardation in loss of body weight and mortality. The effectiveness on tumour growth of the mAb followed by the administration of doxorubicin appears to be equal to that of the drug alone; however, the bsmAb exerts a remarkable antidotal activity.
Morelli
D
D
Department of Immunology, School of Medicine, University of Milan, Italy.
Sardini
A
A
Villa
E
E
Villa
M L
ML
Ménard
S
S
Colnaghi
M I
MI
Balsari
A
A
D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D000915:Antibody Affinity; D004317:Doxorubicin / Q000008:administration & dosage* / Q000276:immunology* / Q000493:pharmacokinetics / Q000633:toxicity; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011993:Recombinant Fusion Proteins; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D066246:ErbB Receptors