Comparison of a tetravalent single-chain antibody-streptavidin fusion protein and an antibody-streptavidin chemical conjugate for pretargeted anti-CD20 radioimmunotherapy of B-cell lymphomas.
The efficacy of radioimmunotherapy (RIT) for patients with relapsed non-Hodgkin lymphoma (NHL) is limited by nonspecific delivery of radiation to normal tissues due to the long circulating half-life of radiolabeled anti-CD20 antibodies (Abs). Pretargeted RIT using a covalent conjugate of the 1F5 anti-CD20 Ab with streptavidin (SA) has been shown to augment the efficacy of RIT and decrease toxicity compared with a directly labeled 1F5 Ab. We have engineered a tetravalent singlechain 1F5 (scFv)4SA fusion protein and compared it to the 1F5-SA conjugate. Athymic mice bearing Ramos lymphoma xenografts received either the conjugate or fusion protein, followed 20 hours later by a biotin-N-acetyl-galactosamine clearing agent, followed 4 hours later by 111In-DOTA-biotin. After 24 hours, 11.4% +/- 2.1% of the injected dose of radionuclide was present per gram of tumor (% ID/g) using 1F5 (scFv)4SA compared with 10.8% +/- 2.5% ID/g with 1F5 Ab-SA. Superior tumor-to-normal organ ratios of radioactivity were consistently seen using the fusion protein compared with the chemical conjugate (eg, tumor-to-blood ratio > 65:1 after 48 hours with the fusion protein, but < 7:1 with the conjugate). More than 90% of lymphomabearing mice could be cured with minimal toxicity using either reagent followed by 1200 muCi (44.4 MBq) 90Y-DOTA-biotin.
Fred Hutchinson Cancer Research Center, and the Department of Medicine, the Univerisity of Washington, Seattle, WA 98109, USA.
John M
JM
Pagel
Yukang
Y
Lin
Nathan
N
Hedin
Anastasia
A
Pantelias
Donald
D
Axworthy
Diane
D
Stone
Don K
DK
Hamlin
D Scott
DS
Wilbur
Oliver W
OW
Press
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D016499:Radioimmunotherapy; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D019809:Streptavidin / Q000276:immunology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D019809:Streptavidin