ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

Lamberts, Laetitia E.; Oordt, C. Willemien Menke-van der Houven van; Weele, Eva J. ter; Bensch, Frederike; Smeenk, Michiel M.; Voortman, Johannes; Hoekstra, Otto S.; Williams, Simon P.; Fine, Bernard M.; Maslyar, Daniel; Jong, Johan R. de; Gietema, Jourik A.; Schröder, Carolien P.; Bongaerts, Alphons H.H.; Hooge, Marjolijn N. Lub-de; Verheul, Henk M.W.; Bohórquez, Sandra M. Sanabria; Glaudemans, Andor W J M; Vries, Elisabeth G.E. de

doi:10.1158/1078-0432.ccr-15-1272

Cited by 77 publications

(97 citation statements)

References 55 publications

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“…For imaging of a number of antibodies without dose-dependent PK, such as bevacizumab, fresolizumab or the mesothelin-targeting antibody MMOT0530A, a dose of 5 or 10 mg unlabeled antibody was already sufficient for optimal PET imaging (24,29,32,42). However, for HER2 imaging with 89 Zr-trastuzumab, an antibody with clear dose-dependent PK, an additional dose of 50 mg unlabeled trastuzumab is needed for optimal imaging (43, 44).…”

Section: Discussionmentioning

confidence: 99%

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89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Bensch

Lamberts

Smeenk

et al. 2017

Clinical Cancer Research

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# These authors contributed equally to this work. AbstractPurpose-We evaluated biodistribution and tumor targeting of 89 Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental design-20 patients with histologically confirmed HER3-expressing tumors received 89 Zr-lumretuzumab and underwent Positron Emission Tomography (PET). In Part A, 89 Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab and scans were performed 2, 4 and 7 days postinjection to determine optimal imaging conditions. In Part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results-Optimal PET conditions were found to be 4 and 7 days after administration of 89 Zrlumretuzumab with 100 mg unlabeled lumretuzumab. At baseline using 100 mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days postinjection. SUVmean for normal blood, liver, lung and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n=7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5) and 24.6% (±20.9) at PD-active doses of 400, 800 and 1600 mg, respectively, when compared to baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400 mg lumretuzumab.Conclusions-PET imaging showed biodistribution and tumor specific 89 Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89 Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses.

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Section: Discussionmentioning

confidence: 99%

“…As often, an additional dose of unlabeled antibody was required for imaging to guarantee sufficient circulating labeled antibody and thereby to improve tumor visualization (23,26,29,32). We first verified the tracer biodistribution with escalating doses of 10, 50 and 100 mg of unlabeled lumretuzumab.…”

Section: Methodsmentioning

confidence: 99%

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Bensch

Lamberts

Smeenk

et al. 2017

Clinical Cancer Research

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“…Tumor uptake decreased with increasing doses of the naked mAb (38), indicating dose-dependent and saturable tracer distribution at doses of 25 and 100 mg in mice. Biodistribution and tumor uptake were also investigated with an 89 Zr-labeled antimesothelin naked antibody in patients subsequently treated with a mesothelin-directed ADC (41). The results showed uptake of the radiolabeled naked antibody in pancreatic and ovarian tumors.…”

Section: Use Of Molecular Imaging To Study Antibodies With Payloadmentioning

confidence: 99%

Theranostics Using Antibodies and Antibody-Related Therapeutics

et al. 2017

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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.

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“…In a clinical phase I imaging trial, the 89 Zr-labeled MSLN antibody 89 Zr-MMOT0530A was administered in 11 metastatic cancer patients, 7 with PDA and 4 with ovarian cancer. In all patients, at least 1 tumor lesion could be visualized (21). In addition to this PET tracer, a MSLN-specific tracer has been developed for single-photon emission tomography.…”

Section: Target Prioritization For Theranostic Approaches In Pda Basementioning

confidence: 99%

Data-Driven Prioritization and Review of Targets for Molecular-Based Theranostic Approaches in Pancreatic Cancer

et al. 2017

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Molecularly targeted therapeutic and imaging strategies directed at aberrant signaling pathways in pancreatic tumor cells may improve the poor outcome of pancreatic ductal adenocarcinoma (PDA). Therefore, relevant molecular targets need to be identified. Methods: We collected publicly available expression profiles of patient-derived normal pancreatic tissue (n 5 77) and PDA samples (n 5 103). Functional genomic messenger RNA profiling was applied to predict target upregulation on the protein level. We prioritized these targets based on current status of preclinical therapeutic and imaging evaluation in PDA. Results: We identified 213 significantly upregulated proteins in PDA compared with normal pancreatic tissue. We prioritized mucin-1, mesothelin, g-glutamyltransferase 5, and cathepsin-E as the most interesting targets, because studies already demonstrated their potential for both therapeutic and imaging strategies in literature. Conclusion: This study can assist clinicians and drug developers in deciding which theranostic targets should be taken for further clinical evaluation in PDA.

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ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody–Drug Conjugate Treatment

Abstract: Purpose: Mesothelin (MSLN) is frequently overexpressed in pancreatic and ovarian cancers, making it a potential drug target. We performed an 89

Cited by 77 publications

References 55 publications

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Theranostics Using Antibodies and Antibody-Related Therapeutics

Data-Driven Prioritization and Review of Targets for Molecular-Based Theranostic Approaches in Pancreatic Cancer

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