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.
Lillo
Antonietta M
AM
Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Sun
Chengzao
C
Gao
Changshou
C
Ditzel
Henrik
H
Parrish
Jay
J
Gauss
Carla-Marie
CM
Moss
Jason
J
Felding-Habermann
Brunhilde
B
Wirsching
Peter
P
Boger
Dale L
DL
Janda
Kim D
KD
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