Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

Ciprotti, Marika; Tebbutt, Niall C.; Lee, Fook-Thean; Lee, Sze-Ting; Gan, Hui; McKee, David C.; O’Keefe, Graeme; Gong, Sylvia; Chong, Geoffrey; Hopkins, Wendie; Chappell, Bridget; Scott, Fiona E.; Brechbiel, Martin W.; Tse, Archie; Jansen, Mendel; Matsumura, Manabu; Kotsuma, Masakatsu; Watanabe, Rira; Venhaus, Ralph; Beckman, Robert A.; Greenberg, Jonathan; Scott, Andrew

doi:10.1200/jco.2014.60.4256

Cited by 31 publications

(34 citation statements)

References 39 publications

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“…Another trial assessing the biodistribution and PD of the Indium-111-labeled, anti-human death receptor 5 (DR5) monoclonal antibody tigatuzumab, seven out of 19 patients (37%) with metastatic colorectal cancer also had no SPECT-positive lesions and tumor tracer uptake did not correlate with DR5 expression or tumor response (40). In both trials, target heterogeneity and tissue-dependent properties were proposed factors to influence general tracer availability and tumor tracer uptake.…”

Section: Discussionmentioning

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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# 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%

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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“…It could provide useful information about the pharmacologic behavior and tumor-targeting properties of these agents, facilitating patient selection and the management of clinical dose-finding studies (13,28). PET imaging in patients will likely give us additional information on MSB0010853 in vivo behavior and tumor targeting.…”

Section: Discussionmentioning

confidence: 99%

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of⁸⁹Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging

et al. 2017

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The human epidermal growth factor receptor 3 (HER3) is an interesting target for antitumor therapy. For optimal HER3 signaling inhibition, a biparatopic Nanobody construct (MSB0010853) was developed that binds 2 different HER3 epitopes. In addition, MSB0010853 contains a third HER3 epitope that binds albumin to extend its circulation time. MSB0010853 is cross-reactive with HER3 and albumin of mouse origin. We aimed to gain insight into MSB0010853 biodistribution and tumor uptake by radiolabeling the Nanobody construct with 89 Zr. Methods: MSB0010853 was radiolabeled with 89 Zr. Dose-and time-dependent tumor uptake was studied in nude BALB/c mice bearing a subcutaneous HER3 overexpressing H441 non-small cell lung cancer xenograft. Dose-dependent biodistribution of 89 Zr-MSB0010853 was assessed ex vivo at 24 h after intravenous injection. Protein doses of 5, 10, 25, 100, and 1,000 mg were used. Time-dependent biodistribution of MSB0010853 was analyzed ex vivo at 3, 6, 24, and 96 h after intravenous administration of 25 mg of 89 Zr-MSB0010853. PET imaging and biodistribution were performed 24 h after administration of 25 mg of 89 Zr-MSB0010853 to mice bearing human H441, FaDu (high HER3 expression), or Calu-1 (no HER3 expression) tumor xenografts. Results: Radiolabeling of MSB0010853 with 89 Zr was performed with a radiochemical purity of greater than 95%. Ex vivo biodistribution showed protein dose-and time-dependent distribution of 89 Zr-MSB0010853 in all organs. Uptake of 89 Zr-MSB0010853 in H441 tumors was only time-dependent. Tumor could be visualized up to at least 96 h after injection. The highest mean SUV of 0.6 6 0.2 was observed at 24 h after injection of 25 mg of 89 Zr-MSB0010853. 89 Zr-MSB0010853 tumor uptake correlated with HER3 expression and was highest in H441 (6.2 6 1.1 percentage injected dose per gram [%ID/g]) and lowest in Calu-1 (2.3 6 0.3 %ID/g) xenografts. Conclusion: 89 Zr-MSB0010853 organ distribution and tumor uptake in mice are time-dependent, and tumor uptake correlates with HER3 expression. In contrast to tumor uptake except for kidney uptake, organ distribution of 89 Zr-MSB0010853 is protein dose-dependent for the tested doses. 89 Zr-MSB0010853 PET imaging gives insight into the in vivo behavior of MSB0010853.

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“…In addition, several kinetic features, such as perfusion and vascularization, may influence tumor visualization. For example, tumor uptake of 111 In-labeled death receptor 5-targeting antibody CS-1008 was observed in only 63% of 19 patients with metastatic colorectal cancer even though all patients were considered to have death receptor 5-positive lesions (10).…”

Section: Pharmacokinetics and Target Visualization Of Radiolabeled Mabsmentioning

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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Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

Cited by 31 publications

References 39 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

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of⁸⁹Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging

Theranostics Using Antibodies and Antibody-Related Therapeutics

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Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer

Cited by 31 publications

References 39 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

Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of89Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging

Theranostics Using Antibodies and Antibody-Related Therapeutics

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Product

Resources

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Human Epidermal Growth Factor Receptor 3–Specific Tumor Uptake and Biodistribution of⁸⁹Zr-MSB0010853 Visualized by Real-Time and Noninvasive PET Imaging