A human single-chain antibody specific for integrin alpha3beta1 capable of cell internalization and delivery of antitumor agents.
Selective antitumor chemotherapy can be achieved by using antibody-drug conjugates that recognize surface proteins upregulated in cancer cells. One such receptor is integrin alpha3beta1, which is overexpressed on malignant melanoma, prostate carcinoma, and glioma cells. We previously identified a human single-chain Fv antibody (scFv), denoted Pan10, specific for integrin alpha3beta1 that is internalized by human pancreatic cancer cells. Herein, we describe the chemical introduction of reactive thiol groups onto Pan10, the specific conjugation of the modified scFv to maleimide-derivatized analogs of the potent cytotoxic agent duocarmycin SA, and the properties of the resultant conjugates. Our findings provide evidence that Pan10-drug conjugates maintain the internalizing capacity of the parent scFv and are cytotoxic at nanomolar concentrations. Our Pan10-drug conjugates may be promising candidates for targeted chemotherapy of malignant diseases associated with overexpression of integrin alpha3beta1.
Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Antonietta M
AM
Lillo
Chengzao
C
Sun
Changshou
C
Gao
Henrik
H
Ditzel
Jay
J
Parrish
Carla-Marie
CM
Gauss
Jason
J
Moss
Brunhilde
B
Felding-Habermann
Peter
P
Wirsching
Dale L
DL
Boger
Kim D
KD
Janda
D000906:Antibodies / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004705:Endocytosis; D005434:Flow Cytometry; D006801:Humans; D039201:Integrin alpha3beta1 / Q000276:immunology*; D018613:Microscopy, Confocal / Q000379:methods; D011994:Recombinant Proteins / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000906:Antibodies; D000970:Antineoplastic Agents; D017931:DNA Primers; D039201:Integrin alpha3beta1; D011994:Recombinant Proteins