title: A series of anti-CEA/anti-DOTA bispecific antibody formats evaluated for pre-targeting: comparison of tumor uptake and blood clearance.
abstract: A series of anti-tumor/anti-chelate bispecific antibody formats were developed for pre-targeted radioimmunotherapy. Based on the anti-carcinoembryonic antigen humanized hT84.66-M5A monoclonal antibody and the anti-DOTA C8.2.5 scFv antibody fragment, this cognate series of bispecific antibodies were radioiodinated to determine their tumor targeting, biodistribution and pharmacokinetic properties in a mouse xenograft tumor model. The in vivo biodistribution studies showed that all the bispecific antibodies exhibited specific high tumor uptake but the tumor targeting was approximately one-half of the parental anti-CEA mAb due to faster blood clearance. Serum stability and FcRn studies showed no apparent reason for the faster blood clearance. A dual radiolabel biodistribution study revealed that the (111)In-DOTA bispecific antibody had increased liver and spleen uptake, not seen for the (125)I-version due to metabolism and release of the radioiodine from the cells. These data suggest increased clearance of the antibody fusion formats by the mononuclear phagocyte system. Importantly, a pre-targeted study showed specific tumor uptake of (177)Lu-DOTA and a tumor : blood ratio of 199 : 1. This pre-targeted radiotherapeutic and substantial reduction in the radioactive exposure to the bone marrow should enhance the therapeutic potential of RIT.
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA. pyazaki@coh.org
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yazaki
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
authors.forename: Divya
authors.initials: D
authors.lastname: Channappa
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Cheung
authors.forename: Desiree
authors.initials: D
authors.lastname: Crow
authors.forename: Junie
authors.initials: J
authors.lastname: Chea
authors.forename: Erasmus
authors.initials: E
authors.lastname: Poku
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Jan Terje
authors.initials: JT
authors.lastname: Andersen
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Kelly Davis
authors.initials: KD
authors.lastname: Orcutt
authors.forename: K Dane
authors.initials: KD
authors.lastname: Wittrup
authors.forename: John E
authors.initials: JE
authors.lastname: Shively
authors.forename: Andrew
authors.initials: A
authors.lastname: Raubitschek
authors.forename: David
authors.initials: D
authors.lastname: Colcher
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000276:immunology*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000532:radiotherapy*; D015202:Protein Engineering; D055550:Protein Stability; D016499:Radioimmunotherapy; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology; D014018:Tissue Distribution
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D006573:Heterocyclic Compounds, 1-Ring; D007457:Iodine Radioisotopes; D057127:Single-Chain Antibodies; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid