Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

Holland, Jason P.; Caldas‐Lopes, Eloisi; Divilov, Vadim; Longo, Valerie A.; Taldone, Tony; Zatorska, Danuta; Chiosis, Gabriela; Lewis, Jason S.

doi:10.1371/journal.pone.0008859

Cited by 118 publications

(152 citation statements)

References 47 publications

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“…5 and 6B). 89 Zr-DFO-AC-10 uptake in the CD30-negative model is attributed to passive accumulation via the established mechanism of enhanced permeability and retention, and our data are consistent with other reports of 89 Zr-DFO-mAb radiotracers in equivalent antigen-negative tumor models (21,23,24).…”

Section: Pet/ct Imagingsupporting

confidence: 91%

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

et al. 2015

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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...

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Section: Pet/ct Imagingsupporting

confidence: 91%

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

et al. 2015

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“…Active pathways may also be imaged as a basis for choosing patients who are likely to respond to a particular drug; for example, the deoxyribonucleoside salvage pathway may be imaged with new PET probes such as 1-(2 0 -deoxy-2 0 - (18) (Shu et al, 2010). Antibodies comprise one of the largest growing shares of the market for cancer therapies, and more than $30 billion is spent each year on agents such as bevacizumab, cetuximab, and trastuzumab (Holland et al, 2010) to treat human tumors. Molecular imaging is likely to evolve as a basis for monitoring the likelihood of response to individual antibody drugs in cancer patients.…”

Section: Molecular Imaging In Drug Developmentmentioning

confidence: 99%

Molecular imaging for personalized cancer care

2012

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Molecular imaging is rapidly gaining recognition as a tool with the capacity to improve every facet of cancer care. Molecular imaging in oncology can be defined as in vivo characterization and measurement of the key biomolecules and molecularly based events that are fundamental to the malignant state. This article outlines the basic principles of molecular imaging as applied in oncology with both established and emerging techniques. It provides examples of the advantages that current molecular imaging techniques offer for improving clinical cancer care as well as drug development. It also discusses the importance of molecular imaging for the emerging field of theranostics and offers a vision of how molecular imaging may one day be integrated with other diagnostic techniques to dramatically increase the efficiency and effectiveness of cancer care.

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“…Like the 89 Zr-aHGF-Nanobodies, 89 Zrbevacizumab showed selective uptake in VEGF-producing xenografts in mice (35), whereas uptake decreased when VEGF expression was inhibited by treatment with HSP90 inhibitors (36,37), indicating a relationship between 89 Zr-bevacizumab tumor uptake and VEGF expression. What is more, 89 Zr-bevacizumab biodistribution could be imaged quantitatively and at excellent resolution, and in the mean time clinical trials have been started with 89 Zr-bevacizumab, as a follow-up of singlephoton emission computed tomography (SPECT) studies with 111 In-bevacizumab in patients with melanoma (38).…”

Section: Mol Cancer Ther; 11(4) April 2012mentioning

confidence: 98%

Nanobodies Targeting the Hepatocyte Growth Factor: Potential New Drugs for Molecular Cancer Therapy

Vosjan

Vercammen

Kolkman

et al. 2012

Molecular Cancer Therapeutics

114

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Hepatocyte growth factor (HGF) and its receptor c-Met are associated with increased aggressiveness of tumors and poor prognostic outcome of patients with cancer. Here, we report the development and characterization of therapeutic anti-HGF (aHGF)-Nanobodies and their potential for positron emission tomographic (PET) imaging to assess HGF expression in vivo. Two aHGF-Nanobodies designated 1E2 and 6E10 were identified, characterized, and molecularly fused to an albumin-binding Nanobody unit (Alb8) to obtain serum half-life extension. The resulting Nanobody formats were radiolabeled with the positron emitter zirconium-89 ( 89 Zr, t1/ 2 ¼ 78 hours), administered to nude mice bearing U87 MG glioblastoma xenografts, and their biodistribution was assessed. In addition, their therapeutic effect was evaluated in the same animal model at doses of 10, 30, or 100 mg per mouse. The 89 Zr-Nanobodies showed similar biodistribution with selective tumor targeting. For example, 1E2-Alb8 showed decreased blood levels of 12.6%ID/g AE 0.6%ID/g, 7.2%ID/g AE 1.0%ID/g, 3.4%ID/g AE 0.3%ID/g, and 0.3%ID/g AE 0.1%ID/g at 1, 2, 3, and 7 days after injection, whereas tumor uptake levels remained relatively stable at these time points: 7.8%ID/g AE 1.1%ID/g, 8.9%ID/g AE 1.0%ID/g, 8.7%ID/g AE 1.5%ID/g, and 7.2%ID/g AE1.6%ID/g. Uptake in normal tissues was lower than in tumor, except for kidneys. In a therapy study, all Nanobody-treated mice showed tumor growth delay compared with the control saline group. In the 100-mg group, four of six mice were cured after treatment with 1E2-Alb8 and 73 days follow-up, and three of six mice when treated with 6E10-Alb8. These results provide evidence that Nanobodies 1E2-Alb8 and 6E10-Alb8 have potential for therapy and PET imaging of HGFexpressing tumors.

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Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

Cited by 118 publications

References 47 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

Molecular imaging for personalized cancer care

Nanobodies Targeting the Hepatocyte Growth Factor: Potential New Drugs for Molecular Cancer Therapy

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Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

Cited by 118 publications

References 47 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

Molecular imaging for personalized cancer care

Nanobodies Targeting the Hepatocyte Growth Factor: Potential New Drugs for Molecular Cancer Therapy

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