A 99mTc-labelled scFv antibody fragment that binds to prostate-specific membrane antigen

Nawaz, Saima; Mullen, Gregory; Blower, Philip J.; Ballinger, James R.

doi:10.1097/mnm.0000000000000698

Cited by 21 publications

(14 citation statements)

References 22 publications

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“…Lastly, given its recombinant nature and inherent versatility [ 64 ], 4LB5 can be conjugated to other molecules or protein domains to boost its clinical efficacy (e.g., adding immunoreactive Fc domain or active RNAse enzyme [ 65 ]). In fact, scFv antibodies are currently being investigated in PCa to target cell surface molecules such as PSMA for diagnostic purposes [ 66 , 67 ]. The ability to bind a surface protein highly expressed in PCa makes 4LB5 a powerful potential theranostic tool.…”

Section: Discussionmentioning

confidence: 99%

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Sheetz

Mills

Tessari

et al. 2020

Cancers

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Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.

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Section: Discussionmentioning

confidence: 99%

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Sheetz

Mills

Tessari

et al. 2020

Cancers

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“…The PSMA-targeted scFv constructs were also developed from the huJ591 antibody (DOTA-cysteine-modified scFv fragment labeled with 64 Cu and its conjugate to DSPE-PEG micelles) for PET imaging [89]. Another studies reported that the scFvhuJ549 fragments labeled with 68 Ga ( 68 Ga-THPscFv), 99m Tc ( 99m Tc-scFv) and 89 Zr ( 89 Zr-scFv) showed also selective binding to the PSMA-expressing cells in vitro [84,94,95].…”

Section: Minibodies Diabodies Single-chain Variable Region Fragmentmentioning

confidence: 99%

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

et al. 2020

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Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides.

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“…The efficient and highly specific binding of PSMA in vivo predetermines 5D3 antibody fragments for further clinical development. This could be directed in parallel to development of other PSMA-specific tools such as bispecific molecules and fusions with toxins and immunological molecules combined alternatively with antimitotic drugs [35,78], conjugates with fluorescent dyes or radioisotopes [16,20,72], and multimeric molecules with potential to activate immune cells [31].…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, PSMA-specific antibodies are being developed as new PCa-targeting theranostics. Various constructs have already been tested in vitro on PSMA-expressing cells [20] as well as in vivo in relevant xenograft models [16,[21][22][23][24][25]. Notably, PCa imaging in human patients has also been performed using a PSMA-specific 89 Zr-IAB2M minibody [26].…”

Section: Introductionmentioning

confidence: 99%

Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization

Nováková

Belousova

Foss

et al. 2020

IJMS

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Prostate-Specific Membrane Antigen (PSMA) is an established biomarker for the imaging and experimental therapy of prostate cancer (PCa), as it is strongly upregulated in high-grade primary, androgen-independent, and metastatic lesions. Here, we report on the development and functional characterization of recombinant single-chain Fv (scFv) and Fab fragments derived from the 5D3 PSMA-specific monoclonal antibody (mAb). These fragments were engineered, heterologously expressed in insect S2 cells, and purified to homogeneity with yields up to 20 mg/L. In vitro assays including ELISA, immunofluorescence and flow cytometry, revealed that the fragments retain the nanomolar affinity and single target specificity of the parent 5D3 antibody. Importantly, using a murine xenograft model of PCa, we verified the suitability of fluorescently labeled fragments for in vivo imaging of PSMA-positive tumors and compared their pharmacokinetics and tissue distribution to the parent mAb. Collectively, our data provide an experimental basis for the further development of 5D3 recombinant fragments for future clinical use.

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A 99mTc-labelled scFv antibody fragment that binds to prostate-specific membrane antigen

Abstract: Supplemental Digital Content is available in the text.

Cited by 21 publications

References 22 publications

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives

Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization

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