Radioimmunodetection of Membrane Type-1 Matrix Metalloproteinase Relevant to Tumor Malignancy with a Pre-targeting Method

Sano, Kohei; Temma, Takashi; Kuge, Yuji; Kudo, Takashi; Kamihashi, Junko; Saji, Hideo

doi:10.1248/bpb.33.1589

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…To improve the T ⁄ B ratio, we previously reported using a pre-targeting method. (24) While this modification improved the T ⁄ B ratio, the method required multiple administrations, which would be undesirable for clinical use. In this study, the newly developed 111 In-MT1-scFv and 111 In-MT1-diabody showed specific affinity for MT1-MMP hinge region and gave high T ⁄ B ratios.…”

Section: Discussionmentioning

confidence: 99%

Miniaturized antibodies for imaging membrane type‐1 matrix metalloproteinase in cancers

et al. 2013

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Since membrane type-1 matrix metalloproteinase (MT1-MMP) plays pivotal roles in tumor progression and metastasis and holds great promise as an early biomarker for malignant tumors, a method of evaluating MT1-MMP expression levels would be valuable for molecular biological and clinical studies. Although we have previously developed a 99m Tc-labeled anti-MT1-MMP monoclonal IgG ( 99m Tc-MT1-mAb) as an MT1-MMP imaging probe by nuclear medical techniques for this purpose, slow pharmacokinetics were a problem due to its large molecular size. Thus, in this study, our aim was to develop miniaturized antibodies, a single chain antibody fragment (MT1-scFv) and a dimer of two molecules of scFv (MT1-diabody), as the basic structures of MT1-MMP imaging probes followed by in vitro and in vivo evaluation with an 111 In radiolabel. Phage display screening successfully provided MT1-scFv and MT1-diabody, which had sufficiently high affinity for MT1-MMP (K D = 29.8 and 17.1 nM). Both 111 In labeled miniaturized antibodies showed higher uptake in MT1-MMP expressing HT1080 cells than in non-expressing MCF7 cells. An in vivo biodistribution study showed rapid pharmacokinetics for both probes, which exhibited >20-fold higher tumor to blood radioactivity ratios (T ⁄ B ratio), an index for in vivo imaging, than 99m Tc-MT1-mAb 6 h post-administration, and significantly higher tumor accumulation in HT1080 than MCF7 cells. SPECT images showed heterogeneous distribution and ex vivo autoradiographic analysis revealed that the radioactivity distribution profiles in tumors corresponded to MT1-MMP-positive areas. These findings suggest that the newly developed miniaturized antibodies are promising probes for detection of MT1-MMP in cancer cells. (Cancer Sci 2013; 104: 495-501) T umor metastasis is the most frequent cause of death for cancer patients. In order to metastasize, tumor cells must acquire the ability to break through the basement membrane and invade dense networks of interstitial ECM proteins.(1) Matrix metalloproteinases (MMPs) are a family of enzymes responsible for degrading the various ECM components. While most MMPs are secreted as soluble zymogens, members of the subfamily of membrane-type MMPs (MT-MMPs) anchored to the cell membrane are suited for pericellular proteolysis. MT1-MMP is the major pericellular protease involved in processing triple helical collagen type I.(4) In addition, MT1-MMP activates MMP zymogens such as proMMP-2 and proMMP-13 that have significant involvement in tumor cell invasion and metastasis.(5,6) As MT1-MMP has a close relationship with tumor malignancy and holds great promise as an early biomarker of malignant tumors, (7,8) in vivo monitoring and ⁄ or quantitation of MT1-MMP expression could be valuable tools for molecular biological and clinical studies.Recently, in the course of focusing on nuclear medical techniques for noninvasive quantitative evaluation of biological molecules deep within the body, we developed a 99m Tc-labeled anti-MT1-MMP monoclonal IgG ( 99m Tc-MT1-mAb) as a radiolabeled...

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Section: Discussionmentioning

confidence: 99%

Miniaturized antibodies for imaging membrane type‐1 matrix metalloproteinase in cancers

et al. 2013

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“…After allowing sufficient time for POS to degrade in normal tissues, We also developed probes using anti-MT1-MMP antibody or its reduced-molecular-weight form for the target recognition unit and succeeded in imaging of MT1-MMP. [46][47][48][49][50][51] In addition, we performed research on structure-activity-distribution rela- tions of an asymmetric urea compound that binds to prostatespecific membrane antigen (PSMA) expressed in prostate cancer cell membrane, and developed a nuclear medical molecular imaging probe for PSMA-positive tumor. [52][53][54] We are currently preparing a clinical study using this probe.…”

Section: Molecular Imaging Of Tumorsmentioning

confidence: 99%

<i>In Vivo</i> Molecular Imaging

Saji

2017

Biological & Pharmaceutical Bulletin

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In vivo molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Among the methodologies used in in vivo molecular imaging, two methodologies are of great interest from the view of high sensitivity. One is nuclear medical imaging, and distribution and kinetics of a radiolabeled molecular probe are measured using positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The other is optical molecular imaging, and distribution and kinetics of a fluorescent probe are measured using a fluorescent imaging instrument. In this review, the development of imaging probes for these two methodologies is briefly discussed. In nuclear medical molecular imaging, based on structure-activity-biodistribution relationship studies for small molecule and the concept of "functional unit-binding multifunctional molecular probe" containing 3 functional units (target recognition unit, signal-releasing unit, linker unit) for peptides and proteins, we developed radiolabeled probes with high and specific accumulation to the target for neuroreceptors, β-amyloid plaques, and tau aggregates in the brain, tumors, atherosclerotic plaques, pancreatic β-cell, myocardial sympathetic nerves, and so on. We also discuss the progression of molecular imaging toward therapy (radiotheranotics). In in vivo optical molecular imaging, taking into account the characteristics of optical imaging, we designed tumor-specific optical imaging probes with characteristic imaging mechanism, including near-infrared (NIR) fluorescent probes and activatable probes. Furthermore, we developed a photoacoustic imaging probe, which enables highly sensitive and high-resolution imaging in deep tissues.

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“…Streptavidin-conjugated anti-MT1-MMP mAb and streptavidinconjugated negative control IgG were synthesized according to a previously described method [14]. Briefly, EZ-Link® sulfosuccinimidyl-6-(biotinamido) hexanoate (sulfo-NHS-LC-biotin; Pierce, Inc.) was added to a solution of anti-MT1-MMP mAb (113-5B7, Daiichi Fine Chemical Co.) in a molar ratio of 12:1.…”

Section: Synthesis Of Streptavidin-conjugated Anti-mt1-mmp Mabmentioning

confidence: 99%

“…As the post-administration contrast agent, polyamidoamine dendrimer (PAMAM) was selected as the base structure since it is structurally well-defined and functional moieties including biotins and Gd chelates for both targeting and signal emission functions can easily be attached to the large number of its surface amino groups. The pre-targeting strategy is expected to provide selective and effective accumulation of the PAMAM-based contrast agent to the targeted site and a high S/N ratio during the first hours following administration, as has been observed in radioimmunotherapy and radioimmunodetection [13][14][15][16], and to potentially lead to lower in vivo toxicity [17,18].…”

Section: Introductionmentioning

confidence: 99%

A Pre-targeting Strategy for MR Imaging of Functional Molecules Using Dendritic Gd-Based Contrast Agents

et al. 2010

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Radioimmunodetection of Membrane Type-1 Matrix Metalloproteinase Relevant to Tumor Malignancy with a Pre-targeting Method

Cited by 11 publications

References 26 publications

Miniaturized antibodies for imaging membrane type‐1 matrix metalloproteinase in cancers

Miniaturized antibodies for imaging membrane type‐1 matrix metalloproteinase in cancers

<i>In Vivo</i> Molecular Imaging

A Pre-targeting Strategy for MR Imaging of Functional Molecules Using Dendritic Gd-Based Contrast Agents

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