ImmunoPET imaging of B-cell lymphoma using 124I-anti-CD20 scFv dimers (diabodies) (original) (raw)
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Recombinant Anti-CD20 Antibody Fragments for Small-Animal PET Imaging of B-Cell Lymphomas
Journal of Nuclear Medicine, 2009
The CD20 cell surface antigen is expressed at high levels by over 90% of B cell non-Hodgkin lymphomas (NHL), and is the target of the anti-CD20 monoclonal antibody rituximab. To provide more sensitive, tumor-specific positron emission tomography (PET) imaging of NHL, we sought to develop PET imaging agents targeting CD20.
Theranostic Radiolabeled Anti-CD20 sdAb for Targeted Radionuclide Therapy of Non-Hodgkin Lymphoma
Molecular cancer therapeutics, 2017
Anti-CD20 radioimmunotherapy is an effective approach for therapy of relapsed or refractory CD20pos lymphomas, but faces limitations due to poor tumor penetration and undesirable pharmacokinetics of full antibodies. Camelid single-domain Ab fragments (sdAb) might circumvent some of the limitations of radiolabeled full antibodies. In this study, a set of hCD20-targeting sdAbs was generated, and their capacity to bind hCD20 was evaluated in vitro and in vivo. A lead sdAb, sdAb 9079, was selected on the basis of its specific tumor targeting and significant lower kidney accumulation compared with other sdAbs. SdAb 9079 was then radiolabeled with 68Ga and 177Lu for PET imaging and targeted therapy. The therapeutic potential of 177Lu-DTPA-sdAb was compared with that of 177Lu-DTPA-rituximab and unlabeled rituximab in mice bearing hCD20pos tumors. Radiolabeled with 68Ga, sdAb 9079 showed specific tumor uptake, with very low accumulation in nontarget organs, except kidneys. The tumor uptake ...
Evaluation of CD20, CD22, and HLA-DR Targeting for Radioimmunotherapy of B-Cell Lymphomas
Cancer Research, 2007
Despite the promise of radioimmunotherapy using anti-CD20 antibodies (Ab) for the treatment of relapsed patients with indolent non-Hodgkin lymphoma (NHL), most patients treated with conventional doses of 131 I-tositumomab or 90 Y-ibritumomab eventually relapse. We did comparative assessments using conventional radioimmunotherapy targeting CD20, CD22, and HLA-DR on human Ramos, Raji, and FL-18 lymphoma xenografts in athymic mice to assess the potential for improving the efficacy of radioimmunotherapy by targeting other NHL cell surface antigens. Results of biodistribution studies showed significant differences in tumor localization consistent with variable antigenic expression on the different lymphoma cell lines. Interestingly, the radioimmunoconjugate that yielded the best tumor-to-normal organ ratios differed in each tumor model. We also explored administering all three 111 In-1,4,7,10-tetra-azacylododecane N,N ¶,N ¶ ¶,NØ-tetraacetic acid antibodies in combination, but discovered, surprisingly, that this approach did not augment the localization of radioactivity to tumors compared with the administration of the best single radiolabeled Ab alone. These data suggest that conventional radioimmunotherapy using anti-CD20, anti-HLA-DR, or anti-CD22 Abs is effective when used singly and provides targeted uptake of radiolabel into the tumor that is dependent on the levels of antigen expression. Improvements in tumorto-normal organ ratios of radioactivity cannot be achieved using directly labeled Abs in combination but may be afforded by novel pretargeting methods.
Cancer Research, 2010
Efficient T-cell activation requires two signals. The first signal, which confers specificity, is provided by interaction of the T-cell receptor with peptides presented by MHC molecules. One of the second costimulatory signals is induced by binding of B7 proteins on the surface of antigen-presenting cells to CD28 on the T-cell surface. Expression of B7 molecules on tumor cells can result in the activation of tumor specific T lymphocytes and induce protective antitumor immunity. However, at present such gene-therapeutic approaches are limited by the inability to selectively target B7 gene expression to cancer cells. As an alternative approach we exploited recombinant antibody fragments to localize a costimulatory B7 molecule to the surface of tumor cells. We constructed chimeric proteins that contain in a single polypeptide chain a portion of human B7-2 (CD86) genetically fused to single-chain (sc) Fv antibody domains specific for the tumor-associated antigens epidermal growth factor receptor and the closely related ErbB2 receptor tyrosine kinase. A small recombinant fragment of human CD86 was characterized that corresponds to amino acid residues 1-111 (CD86 111 ) of the mature protein. CD86 111 produced in the yeast Pichia pastoris and CD86 111 expressed in bacteria was functionally active and displayed specific binding to B7 counter receptors. Bacterially expressed CD86 111 -scFv fusion proteins specifically localized to the respective target antigens on the surface of tumor cells and markedly enhanced the proliferation of primary T cells when bound to immobilized tumor antigen.
Pharmacokinetics of radiolabeled dimeric sdAbs constructs targeting human CD20
New Biotechnology, 2018
Single-domain antibody fragments (sdAbs) are the smallest functional antigenbinding fragments, derived from heavy chain-only camelid antibodies. When designed as radiolabeled monomeric probes for imaging and therapy of cancer, their fast and specific targeting results in high tumor-to-background ratios early after injection. However, their moderate absolute uptake into tumors might not always be sufficient to treat cancerous lesions. We have evaluated the pharmacokinetics of seven constructs derived from a CD20-targeting monomeric sdAb (CD20). The constructs differed in affinity or avidity towards CD20 (dimeric CD20-CD20 and CD20 fused to a non-targeting control sdAb, referred to as CD20-ctrl) and blood half-lives (CD20 fused to an albumintargeting sdAb (Alb) = CD20-Alb). The constructs were radiolabeled with 111 In (imaging) and 177 Lu (therapy) using the bifunctional chelator CHX-A"-DTPA and evaluated in vitro and in vivo. In mice, tumor uptake of 177 Lu-DTPA-CD20 decreased from 4.821.80 to 0.130.05% IA/g over 72 h. Due to its rapid blood clearance, tumor-to-blood (T/B) ratios of >100 were obtained within 24h. Although in vitro internalization indicated that dimeric 177 Lu-DTPA-CD20-CD20 was superior in terms of total cell-associated radioactivity, this was not confirmed in vivo. Blood clearance was slower and absolute tumor uptake became significantly higher for CD20-Alb. Blood levels of 177 Lu-DTPA-CD20-Alb decreased from 68.3010.53 to 3.580.66% IA/g over 120h, while tumor uptake increased from 6.210.94 to 24.902.83% IA/g, resulting in lower T/B ratios. Taken together, these results indicate that the increased size of dimeric CD20-CD20 or the fusion of monomeric CD20 to an albumin-targeting moiety (Alb) counterbalance their improved tumor targeting capacity compared to monomeric CD20.
European Journal of Nuclear Medicine and Molecular Imaging, 2009
Purpose 131I- and 90Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin’s lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was
The Journal of Nuclear Medicine, 2015
The CD30-specific antibody-drug conjugate, brentuximab vedotin, is approved for the treatment of relapsed, refractory Hodgkin lymphomas and systemic anaplastic large T-cell lymphomas. Multiple ongoing clinical trials are investigating brentuximab vedotin efficacy in other CD30-positive hematologic malignancies. Because CD30 expression varies among different types of lymphoma and can also change during the course of treatment, companion diagnostic imaging of CD30 could be a valuable tool in optimizing patient-specific brentuximab vedotin treatment regimens. Methods: The mouse antihuman CD30 antibody AC-10 was radiolabeled with the positron-emitting radionuclide 89 Zr. The stability and specificity of 89 Zr-desferrioxamine (DFO)-labeled CD30-specific AC-10 antibody (89 Zr-DFO-AC-10) was evaluated in vitro. The pharmacokinetics of 89 Zr-DFO-AC-10 was studied in BALB/c nude mice bearing subcutaneous human Karpas 299 tumors (CD30-positive model) or A-431 tumors (CD30-negative model) using PET/CT imaging, biodistribution studies, and autoradiography. Results: AC-10 was conjugated with a DFO B chelator and radiolabeled with 89 Zr to give formulated 89 Zr-DFO-AC-10 with a radiochemical yield of 80%, radiochemical purity greater than 99%, and specific activity of 111-148 MBq/mg. 89 Zr-DFO-AC-10 was stable in mouse and human sera and preserved the immunoreactivity toward CD30. Biodistribution data showed the highest tissue accumulation of 89 Zr-DFO-AC-10 in CD30-positive tumors, with 37.9% ± 8.2% injected activity per gram of tissue at 72 h after injection, whereas uptake in CD30-negative tumors was 11.0% ± 0.4%. The specificity of 89 Zr-DFO-AC-10 binding to CD30 in vivo was confirmed by blocking studies. Time-activity curves showed that between 24 and 144 h after injection, tumor-to-muscle ratios increased from 18.9 to 51.8 in the CD30positive model and from 4.8 to 8.7 in the CD30-negative model. Tumor-to-blood ratios also increased, from 3.2 to 13.6 and from 1 to 2 in the CD30-positive and-negative models, respectively. Conclusion: Our results demonstrate that for measuring CD30 expression, 89 Zr-DFO-AC-10 is a sensitive PET agent with high tumor-to-normal-tissue contrast. 89 Zr-DFO-AC-10 is a promising CD30-imaging radiotracer for clinical translation in patients with various lymphomas and other diseases.