89Zr-trastuzumab and 89Zr-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients

Gaykema, Sietske B.M.; Schröder, Carolien P.; Vitfell-Rasmussen, Joanna; Chua, Sue; Munnink, Thijs H. Oude; Brouwers, Adrienne H.; Bongaerts, Alphons H.H.; Akimov, Mikhail; Fernandez-Ibarra, Cristina; Hooge, Marjolijn N. Lub-de; Vries, Elisabeth G.E. de; Swanton, Charles; Banerji, Udai

doi:10.1158/1078-0432.ccr-14-0491

Cited by 103 publications

(82 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The radiotracer was found to be stable, with high immunoreactivity in vitro and in vivo. In terms of absolute tumor uptake and relative tumor-to-background tissue contrast ratios, the performance of 89 Zr-DFO-AC-10 for immuno-PET imaging of CD30-positive lesions was equivalent to the reported performance of many other 89 Zr-DFO-mAbs, including 89 Zr-DFO-J591 for imaging prostate-specific membrane antigen in prostate cancer (21,25,26), as well as 89 Zr-trastuzumab for imaging HER2/neu (27) and 89 Zrbevacizumab imaging VEGF-A in breast cancers (28).…”

Section: Autoradiography and Histologymentioning

confidence: 73%

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

et al. 2015

View full text Add to dashboard Cite

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 CD30-positive 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. CD30,amemberoft he tumor necrosis factor receptor superfamily, is expressed by Reed-Sternberg cells and used as a primary diagnostic marker for Hodgkin lymphoma (1). CD30 is also highly expressed on the surface of some T-cell lymphomas, especially on anaplastic large cell lymphoma, and at variable levels on a subset of other non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (2-4). Expression of CD30 in healthy tissues is restricted to activated T and B cells, and the receptor cannot be found outside the immune system (2,5). High expression levels on specific cancers and limited presentation in healthy tissues make CD30 an ideal target for antibody-based molecular therapies.Brentuximab vedotin (Adcentri...

show abstract

Section: Autoradiography and Histologymentioning

confidence: 73%

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Trastuzumab labeled with 89 Zr is currently being investigated in several locations for this purpose, and reports have shown promising results (10,14,29). With the imminent increase in the use of 89 Zr-labeled antibodies in the clinic, we set out to develop a method for creating a dose on demand.…”

Section: Discussionmentioning

confidence: 99%

“…89 Zr has a half-life of 3.27 d, an attractive decay pathway, and quickly clears from the body when chelated, making it well suited for labeling mAbs (7). 89 Zr-labeled mAbs have been examined both preclinically and in clinical trials extensively (8)(9)(10)(11)(12). One antibody in particular, trastuzumab, more commonly known under the trade name Herceptin (Genentech), is currently used in the treatment of metastatic breast cancer.…”

mentioning

confidence: 99%

Microfluidic Preparation of a ⁸⁹Zr-Labeled Trastuzumab Single-Patient Dose

et al. 2016

View full text Add to dashboard Cite

89 Zr-labeled antibodies are being investigated in several clinical trials; however, the time requirement for synthesis of clinical doses can hinder patient throughput because of scheduling difficulties. Additionally, low specific activity due to poor labeling efficiency can require larger amounts of the radiopharmaceutical to be administered, possibly leading to adverse side effects. Here, we describe the design and evaluation of a microfluidic reactor capable of synthesizing a single clinical dose of 89 Zr-labeled antibody. 89 Zr-labeled trastuzumab was chosen for this validation because it is currently being evaluated in clinical trials for imaging human epidermal growth factor receptor 2-positive cancer patients. Methods: A microreactor fabricated from polydimethylsiloxane/glass was silanated with trimethoxy(octadecyl) silane to reduce antibody adsorption. Desferrioxamine-p-benzylisothiocyanate (DFO-Bz-NCS) was conjugated to trastuzumab in an 8:1 molar ratio following the literature procedures using aseptic techniques. Radiolabeling was performed by pumping 89 Zr-oxalate and DFO-Bz-trastuzumab into the microfluidic reactor at a total rate of 20 μL/min in ratios varying from 1:37 to 1:592 mg:MBq at 37°C to achieve optimal labeling. Results: Silanated reactors showed low antibody adsorption in comparison to unmodified reactors (95% monoclonal antibody recovered vs. 0% recovered). Labeling of the modified trastuzumab was shown to be achievable at a specific activity above the reported literature value of 220 MBq/mg. A high radiochemical purity was achieved without an incubation period at specific activities of less than 148 MBq/mg; however, specific activities up to 592 MBq/mg could be achieved with an incubation period. Clinical doses were able to be prepared and passed all quality control guidelines set by the Food and Drug Administration. Samples were sterile, colorless, and radiochemically pure (100%); maintained the ability to bind to the intended receptor; formed a minimal amount of aggregates (1%-4%); and were completed within 45-60 min. Conclusion: 89 Zr-labeled trastuzumab for use in a clinical setting was synthesized in a microfluidic reactor in under an hour while reducing the amount of handling required by a technician. Use of this compact platform not only could enable the use of radiolabeled antibodies to become a common practice, but also could spread the use of radiolabeled antibodies beyond locations with cyclotron facilities.

show abstract

“…such as heat shock protein HSP90 inhibitor AUY922 (19). The ongoing IMPACT study is evaluating the clinical utility of 89 Zrtrastuzumab PET and 18 F-fluoroestradiol PET imaging in 200 newly diagnosed metastatic breast cancer patients (ClinicalTrials.gov identifier NCT01957332).…”

Section: Use Of Theranostics In Clinical Decision Makingmentioning

confidence: 99%

Theranostics Using Antibodies and Antibody-Related Therapeutics

et al. 2017

Self Cite

View full text Add to dashboard Cite

In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibodyrelated therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as 89 Zr. In this review, we provide an overview of ongoing research on mAbs and antibodyrelated theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required.

show abstract

89Zr-trastuzumab and 89Zr-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients

Abstract: Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using 89 Zr-

Cited by 103 publications

References 38 publications

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

Microfluidic Preparation of a ⁸⁹Zr-Labeled Trastuzumab Single-Patient Dose

Theranostics Using Antibodies and Antibody-Related Therapeutics

Contact Info

Product

Resources

About

89Zr-trastuzumab and 89Zr-bevacizumab PET to Evaluate the Effect of the HSP90 Inhibitor NVP-AUY922 in Metastatic Breast Cancer Patients

Abstract: Purpose: HSP90 chaperones have key client proteins that are involved in all hallmarks of breast cancer growth and progression. The primary aim of this clinical trial was to evaluate the feasibility of using 89 Zr-

Cited by 103 publications

References 38 publications

Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

Microfluidic Preparation of a 89Zr-Labeled Trastuzumab Single-Patient Dose

Theranostics Using Antibodies and Antibody-Related Therapeutics

Contact Info

Product

Resources

About

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

Immuno-PET Imaging of CD30-Positive Lymphoma Using ⁸⁹Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

Microfluidic Preparation of a ⁸⁹Zr-Labeled Trastuzumab Single-Patient Dose