Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m Anti-CD4-mAb fragment scintigraphy

Steinhoff, Karen Geva; Pierer, Matthias; Siegert, Jens; Pigla, U.; Laub, R; Hesse, Swen; Seidel, W.; Sorger, Dietlind; Seese, Anita; Kuenstler, J.U.; Pietzsch, Hans‐Jürgen; Lincke, Thomas; Rullmann, Michael; Emmrich, Frank; Sabri, Osama

doi:10.1016/j.nucmedbio.2013.12.018

Cited by 13 publications

(18 citation statements)

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“…GK1.5 cDb can be used to investigate CD4 + T cells in mouse models of disease and to test treatment efficacy rapidly and noninvasively. The ability to image and quantify total CD4 + T cells has implications for monitoring diseases including HIV infection [2, 3], colitis [6], and rheumatoid arthritis [4, 5]. Recent interest in the potential of CD4 + T cells for tumor immunotherapy also suggests a role for careful monitoring of CD4 + T cells in the context of anti-tumor immunity [7].…”

Section: Discussionmentioning

confidence: 99%

“…Upon antigen recognition, CD4 + T cells become activated, proliferate, produce cytokines for immune cell recruitment and activation, and assist B cells to produce antibodies and activate other immune cells [1]. As a consequence of their role in regulating immunity, accurate measurement of CD4 + T cells has implications for monitoring and treatment of a variety of diseases and disorders, including HIV infection [2, 3], autoimmune diseases such as rheumatoid arthritis [4, 5] and inflammatory bowel disease [6], and cancer [7]. Current methods of collecting CD4 + T cells include peripheral blood draws, which are relatively noninvasive, and biopsies, which allow testing from a precise location of interest.…”

Section: Introductionmentioning

confidence: 99%

“…Clinical use of anti-CD4 immunoSPECT has been explored in the context of rheumatoid arthritis with mixed results. Uptake in inflamed joints correlated well with clinical symptoms in one study, which utilized intact 99m Tc-labeled anti-CD4 antibody Max.16H5 [5], but in a later study, a 99m Tc-labeled Fab fragment of the same antibody identified only 68% of clinically affected joints [4]. These results led the authors to suggest that the presence of CD4 + T cells does not always correlate with pain and swelling in arthritic joints.…”

Section: Introductionmentioning

confidence: 99%

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ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging

et al. 2016

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PURPOSE Molecular imaging of CD4+ T cells throughout the body has implications for monitoring autoimmune disease and immunotherapy of cancer. Given the key role of these cells in regulating immunity, it is important to develop a biologically inert probe. GK1.5 cys-diabody (cDb), a previously developed anti-mouse CD4 antibody fragment, was tested at different doses to assess its effects on positron emission tomography (PET) imaging and CD4+ T cell viability, proliferation, CD4 expression, and function. PROCEDURES The effect of protein dose on image contrast (lymphoid tissue-to-muscle ratio) was assessed by administering different amounts of 89Zr-labeled GK1.5 cDb to mice followed by PET imaging and ex vivo biodistribution analysis. To assess impact of GK1.5 cDb on T cell biology, GK1.5 cDb was incubated with T cells in vitro or administered intravenously to C57BL/6 mice at multiple protein doses. CD4 expression and T cell proliferation were analyzed with flow cytometry and cytokines were assayed. RESULTS For immunoPET imaging, the lowest protein dose of 2 µg 89Zr-labeled GK1.5 cDb resulted in significantly higher % injected dose/gram in inguinal lymph nodes (ILN) and spleen compared to the 12 µg protein dose. In vivo administration of GK1.5 cDb at the high dose of 40 µg caused a transient decrease in CD4 expression in spleen, blood, lymph nodes, and thymus, which recovered within 3 days post-injection; this effect was reduced, although not abrogated, when 2 µg was administered. Proliferation was inhibited in vivo in ILN but not the spleen by injection of 40 µg GK1.5 cDb. Concentrations of GK1.5 cDb in excess of 25 nM significantly inhibited CD4+ T cell proliferation and interferon-γ production in vitro. Overall, using low dose GK1.5 cDb minimized biological effects on CD4+ T cells. CONCLUSIONS Low dose GK1.5 cDb yields high-contrast immunoPET images with minimal effects on T cell biology in vitro and in vivo, and may be a useful tool for investigating CD4+ T cells in the context of preclinical disease models. Future approaches to minimizing biological effects may include the creation of monovalent fragments or selecting anti-CD4 antibodies which target alternative epitopes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging

et al. 2016

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“…In a phase I proof of principle study using 99m Tc-labeled anti-CD4-Fab to image CD4 + T cells in patients with rheumatoid arthritis, 70% of clinically affected (painful or swollen) joints were positive on the scan (Steinhoff et al, 2014). The authors suggest that the low detection rate may be due to non-correlation between symptoms and presence of CD4 + T cells in the synovial joints, and that other cells may be involved in joint inflammation.…”

Section: Applications Of Antibody-based Imagingmentioning

confidence: 99%

In vivo imaging with antibodies and engineered fragments

Freise

2015

Molecular Immunology

188

168

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Antibodies have clearly demonstrated their utility as therapeutics, providing highly selective and effective drugs to treat diseases in oncology, hematology, cardiology, immunology and autoimmunity, and infectious diseases. More recently, a pressing need for equally specific and targeted imaging agents for assessing disease in vivo, in preclinical models and patients, has emerged. This review summarizes strategies for developing and optimizing antibodies as targeted probes for use in non-invasive imaging using radioactive, optical, magnetic resonance, and ultrasound approaches. Recent advances in engineered antibody fragments and scaffolds, conjugation and labeling methods, and multimodality probes are highlighted. Importantly, antibody-based imaging probes are seeing new applications in detection and quantitation of cell surface biomarkers, imaging specific responses to targeted therapies, and monitoring immune responses in oncology and other diseases. Antibody-based imaging will provide essential tools to facilitate the transition to truly precision medicine.

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“…The first clinical study of 99m Tc‐anti‐CD4‐Fab ( 99m Tc‐EP1645) was performed by Steinhoff et al. in 2014 . It was found that 99m Tc‐EP1645 showed good tolerability and could detect inflamed joints in arthritis patients with a rate of 68 %.…”

Section: Targeting Surface Markers On Immune Cellsmentioning

confidence: 99%

Antibody‐Based Tracers for PET/SPECT Imaging of Chronic Inflammatory Diseases

Lee

Cai

2018

ChemBioChem

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Chronic inflammatory diseases are often progressive, resulting not only in physical damage to patients but also social and economic burdens, making early diagnosis of them critical. Nuclear medicine techniques can enhance the detection of inflammation by providing functional as well as anatomical information when combined with other modalities such as magnetic resonance imaging, computed tomography or ultrasonography. Although small molecules and peptides were mainly used for the treatment and imaging of chronic inflammatory diseases in the past, antibodies and their fragments have also been emerging for chronic inflammatory diseases as they show high specificity to their targets and can have various biological half‐lives depending on how they are engineered. In addition, imaging with antibodies or their fragments can visualize the in vivo biodistribution of the probes or help monitor therapeutic responses, thereby providing physicians with a greater understanding of drug behavior in vivo and another means of monitoring their patients. In this review, we introduce various targets and radiolabeled antibody‐based probes for the molecular imaging of chronic inflammatory diseases in preclinical and clinical studies. Targets can be classified into three different categories: 1) cell‐adhesion molecules, 2) surface markers on immune cells, and 3) cytokines or enzymes. The limitations and future directions of using radiolabeled antibodies for imaging inflammatory diseases are also discussed.

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Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m Anti-CD4-mAb fragment scintigraphy

Cited by 13 publications

References 13 publications

ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging

ImmunoPET Imaging of Murine CD4+ T Cells Using Anti-CD4 Cys-Diabody: Effects of Protein Dose on T Cell Function and Imaging

In vivo imaging with antibodies and engineered fragments

Antibody‐Based Tracers for PET/SPECT Imaging of Chronic Inflammatory Diseases

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