HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldenberg, D. M. Articles by Chang, C.-H. Search for Related Content PubMed PubMed Citation Articles by Goldenberg, D. M. Articles by Chang, C.-H.

Multifunctional Antibodies by the Dock-and-Lock Method for Improved Cancer Imaging and Therapy by Pretargeting

¹ Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey; ² IBC Pharmaceuticals, Inc., Morris Plains, New Jersey; and ³ Immunomedics, Inc., Morris Plains, New Jersey

View larger version (29K): [in this window] [in a new window]   FIGURE 1.  Schematic representation of how a tri-Fab (TF) bispecific antibody is formed by the DNL method. Component A links a cysteine-modified DDD to a Fab of an antitumor antibody, which results in spontaneous formation of component A2. Component B links an anchoring domain (AD) to a Fab of an antihapten antibody. The AD is modified with cysteine on each end. AD will naturally "dock" with the DDD when components A and B are mixed, which brings the 2 molecules together in a well-defined orientation and also results in disulfide bonds across the 2 proteins.

View larger version (43K): [in this window] [in a new window]   FIGURE 2.  Components of TF2 anti-CEA x anti-HSG bs-mAb. (A) C-DDD2-Fab-hMN-14 was formed by linking a cysteine-modified peptide sequence (DDD2), which is composed of amino acids 1–44 of human RII, to the carboxyl-terminal end of the Fd chain via a 14-residue flexible peptide linker. (B) Antihapten binding arm was made by linking the 17-residue amino-acid sequence derived from AKAP-IS, a synthetic peptide optimized for RII-selective binding, to the carboxyl end of the Fd via a 15-residue flexible peptide linker with the addition of cysteine residues to both the amino- and carboxyl-terminal ends of AD2. TF2 is the anti-CEA x anti-HSG recombinant humanized protein formed by combining A and B.

View larger version (86K): [in this window] [in a new window]   FIGURE 3.  Localization of a micrometastatic human colon cancer cell line disseminated in lungs of nude mice using small-animal PET. Necropsy data showed all animals with 80 to 120 tumor nodules in lungs, ranging in size from a few cells to colonies that were <0.3 mm in diameter. (A) Activity is seen in lungs of coronal section 1.5 h after anti-CEA pretargeted 124I-hapten-peptide injection. Additionally, uptake was seen in kidneys (Kid) due to peptide clearance through this organ and stomach (Stom) as a result of catabolized iodide. (B) A tumor-bearing animal given only 124I-hapten peptide without bs-mAb showed no selective uptake in chest. In this slice, activity is also seen in kidneys, stomach, and urinary bladder (UB). (C) Transverse section through the chest shows uptake, with appearance of individual nodules (arrows). (D) Autoradiography study was performed in separate animals pretargeted with an 111In-labeled peptide at a later time after tumor implantation, but, even in these animals, individual tumor nodules did not exceed 0.5 mm. Autoradiography revealed selective uptake in and around tumor nodules within lungs.

View larger version (125K): [in this window] [in a new window]   FIGURE 4.  From the same study described in Figure 3, (A) is coronal section of an animal 1.5 h after 18F-FDG injection. Arrow indicates the lung plane, where no evidence of tumor involvement was seen. br = brain. (B and C) Transverse sections through different region of chest also failed to show tumor. Strong uptake was seen in bone marrow (BM) of ribs and shoulder blades surrounding the chest and, as expected, in heart wall (HW) and brain.

View larger version (15K): [in this window] [in a new window]   FIGURE 5.  Therapeutic efficacy of 90Y-labeled peptide pretargeted with an anti-MUC1 DNL bs-mAb. Nude mice bearing 0.5 cm3 CaPan1 human pancreatic cancer subcutaneous xenografts were untreated (A; n = 10 mice) or were treated with 18.5 MBq (0.5 mCi) of a pretargeted 90Y-labeled hapten-peptide (B; n = 10 mice).