title: Molecular targeting of CEACAM6 using antibody probes of different sizes.
abstract: Carcinocinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is overexpressed in a number of human malignancies, especially in pancreatic cancer. It has been demonstrated that CEACAM6 is a potential target for monoclonal antibody (mAb) therapy with a safe therapeutic index. Here, we labeled three anti-CEACAM6 antibodies of different sizes, including a single-domain antibody 2A3 (16 kDa), a heavy chain antibody 2A3-mFc (80 kDa) and a full length antibody 9A6 (150 kDa), with ⁶⁴Cu to image CEACAM6 expression in a xenografted pancreatic tumor model. For positron emission tomography (PET) imaging, the tumor mice were intravenously injected with ⁶⁴Cu-DOTA-antibodies and static scans were obtained at 5 min, 0.5, 1, 2, 4, 8 and 24h post-injection (p.i.). All three antibodies showed strong CEACAM6 binding. Ex vivo immunostaining on tumor sections at 24 h after Ab injection demonstrated specific tumor targeting of both 2A3-mFc and 9A6. ⁶⁴Cu-DOTA-2A3 showed fast BxPC3 tumor uptake and rapid whole-body clearance. At 24 h p.i., the tumor uptakes were 98.2±6.12%ID/g for ⁶⁴Cu-DOTA-2A3-mFc and 57.8±3.73%ID/g for ⁶⁴Cu-DOTA-9A6, respectively. Compared with the full length antibody 9A6, the heavy chain antibody 2A3-mFc showed higher tumor uptake, lower liver uptake and shorter circulation half-life. All the data supported that the heavy chain antibody 2A3-mFc is superior to the single domain antibody and the full-length antibody with regard to tumor detection and pharmacokinetics, which has great potential to be developed for CEACAM6-targeted pancreatic cancer imaging and therapy.
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine-LOMIN, National Institute of Biomedical Imaging and Bioengineering-NIBIB, National Institutes of Health-NIH, Bethesda, MD 20892, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Yanal M
authors.initials: YM
authors.lastname: Murad
authors.forename: Haokao
authors.initials: H
authors.lastname: Gao
authors.forename: Shuo
authors.initials: S
authors.lastname: Hu
authors.forename: Ning
authors.initials: N
authors.lastname: Guo
authors.forename: Orit
authors.initials: O
authors.lastname: Jacobson
authors.forename: Thanh-Dung
authors.initials: TD
authors.lastname: Nguyen
authors.forename: Jianbing
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics; D015703:Antigens, CD / Q000032:analysis* / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography / Q000379:methods; D013154:Spleen / Q000000981:diagnostic imaging; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D003301:Copper Radioisotopes; D058851:GPI-Linked Proteins; C575659:Gm5893 protein, mouse