title: Short PEG-linkers improve the performance of targeted, activatable monoclonal antibody-indocyanine green optical imaging probes.
abstract: The ability to switch optical imaging probes from the quenched (off) to the active state (on) has greatly improved target to background ratios. The optimal activation efficiency of an optical probe depends on complete quenching before activation and complete dequenching after activation. For instance, monoclonal antibody-indocyanine green (mAb-ICG) conjugates, which are promising agents for clinical translation, are normally quenched, but can be activated when bound to a cell surface receptor and internalized. However, the small fraction of commonly used ICG derivative (ICG-Sulfo-OSu) can bind noncovalently to its mAb and is, thus, gradually released from the mAb leading to relatively high background signal especially in the liver and the abdomen. In this study, we re-engineered a mAb-ICG conjugate, (Panitumumab-ICG) using bifunctional ICG derivatives (ICG-PEG4-Sulfo-OSu and ICG-PEG8-Sulfo-OSu) with short polyethylene glycol (PEG) linkers. Higher covalent binding (70-86%) was observed using the bifunctional ICG with short PEG linkers resulting in less in vivo noncovalent dissociation. Panitumumab-ICG conjugates with short PEG linkers were able to detect human epidermal growth factor receptor 1 (EGFR)-positive tumors with high tumor-to-background ratios (15.8 and 6.9 for EGFR positive tumor-to-negative tumor and tumor-to-liver ratios, respectively, at 3 d postinjection).
authors.affiliation: Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kiminori
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Yuya
authors.initials: Y
authors.lastname: Ohuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikegami
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001943:Breast Neoplasms / Q000175:diagnosis*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000032:analysis*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry; D007208:Indocyanine Green / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D061848:Optical Imaging; D000077544:Panitumumab; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; C113792:indocyanine green-sulfo-OSu; D011092:Polyethylene Glycols; D000077544:Panitumumab; D066246:ErbB Receptors; D007208:Indocyanine Green