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: Gang Niu, Yanal M Murad, Haokao Gao, Shuo Hu, Ning Guo, Orit Jacobson, Thanh-Dung Nguyen, Jianbing Zhang, Xiaoyuan Chen
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 161 Issue 1 Pg. 18-24 (Jul 10 2012) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 22568933 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier B.V.

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• CEACAM6 protein, human
• Cell Adhesion Molecules
• Copper Radioisotopes
• GPI-Linked Proteins
• Gm5893 protein, mouse

Topics

• Animals
• Antibodies, Monoclonal (chemistry, pharmacokinetics)
• Antigens, CD (analysis, immunology)
• Cell Adhesion Molecules (analysis, antagonists & inhibitors, immunology)
• Cell Line
• Cell Line, Tumor
• Copper Radioisotopes (chemistry, pharmacokinetics)
• Female
• GPI-Linked Proteins (analysis, antagonists & inhibitors, immunology)
• Humans
• Mice
• Mice, Nude
• Molecular Imaging
• Neoplasm Transplantation
• Pancreatic Neoplasms (diagnosis, diagnostic imaging)
• Positron-Emission Tomography (methods)
• Spleen (diagnostic imaging)
• Transplantation, Heterologous