Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model

Pastuskovas, Cinthia V.; Mundo, Eduardo E.; Williams, Simon P.; Nayak, Tapan K.; Ho, Jason; Ulufatu, Sheila; Clark, Suzanna; Ross, Sarajane; Chen, Fang-You; Parsons-Reponte, Kathryn; Cain, Gary A.; Hoy, Marjie Van; Majidy, Nicholas; Bheddah, Sheila; Chuh, Josefa; Kozak, Katherine R.; Lewin‐Koh, Nicholas; Nauka, Peter; Bumbaca, Daniela; Sliwkowski, Mark X.; Tibbitts, Jay; Theil, Frank‐Peter; Fielder, Paul J.; Khawli, Leslie A.; Boswell, C. Andrew

doi:10.1158/1535-7163.mct-11-0742-t

Cited by 96 publications

(89 citation statements)

References 47 publications

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“…This explains the roughly 4-fold higher tumor levels of residualizing 111 In in Figure 4C relative to non-residualizing 125 I in Figure 4A. Roughly consistent with previous 111 In-labeled anti-HER2 antibodies, 48 111 In-DOTA 2 -7C2 exhibited tumor labeling at 40.5 %ID/g and kidney distribution at 7 %ID/g (Figure 4C). However, the traditional labeling method allowed for a total of 48 hours for the internalizing 111 In-DOTA 2 -7C2 reagent to distribute, bind and accumulate, making direct comparisons difficult since 111 In-labeled tetrazines had only 24 hours to accumulate.…”

Section: Resultssupporting

confidence: 85%

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Mandikian¹,

Rafidi²,

Adhikari³

et al. 2018

mAbs

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Antibody pretargeting is a promising strategy for improving molecular imaging, wherein the separation in time of antibody targeting and radiolabeling can lead to rapid attainment of high contrast, potentially increased sensitivity, and reduced patient radiation exposure. The inverse electron demand Diels-Alder ‘click’ reaction between trans-cyclooctene (TCO) conjugated antibodies and radiolabeled tetrazines presents an ideal platform for pretargeted imaging due to rapid reaction kinetics, bioorthogonality, and potential for optimization of both slow and fast clearing components. Herein, we evaluated a series of anti-human epidermal growth factor receptor 2 (HER2) pretargeting antibodies containing distinct molar ratios of site-specifically incorporated TCO. The effect of stoichiometry on tissue distribution was assessed for pretargeting TCO-modified antibodies (monitored by 125I) and subsequent accumulation of an 111In-labeled tetrazine in a therapeutically relevant HER2+tumor-bearing mouse model. Single photon emission computed tomography (SPECT) imaging was also employed to assess tumor imaging at various TCO-to-monoclonal antibody (mAb) ratios. Increasing TCO-to-mAb molar ratios correlated with increased in vivo click reaction efficiency evident by increased tumor distribution and systemic exposure of 111In-labeled tetrazines. The pharmacokinetics of TCO-modified antibodies did not vary with stoichiometry. Pretargeted SPECT imaging of HER2-expressing tumors using 111In-labeled tetrazine demonstrated robust click reaction with circulating antibody at ~2 hours and good tumor delineation for both the 2 and 6 TCO-to-mAb ratio variants at 24 hours, consistent with a limited cell-surface pool of pretargeted antibody and benefit from further distribution and internalization. To our knowledge, this represents the first reported systematic analysis of how pretargeted imaging is affected solely by variation in click reaction stoichiometry through site-specific conjugation chemistry.

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Section: Resultssupporting

confidence: 85%

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Mandikian¹,

Rafidi²,

Adhikari³

et al. 2018

mAbs

Self Cite

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“…S5): 1) 95% tumor receptor saturation is needed for efficacy; 2) the tumor I:P ratio is 0.30 based on tissue distribution data in tumor-bearing mice (Fig. 5); and 3) combination with bevacizumab will decrease tumor penetration by at least »30% based on Genentech's historical data 27 if combination therapy with bevacizumab is considered. Based on the interim MPDL3280A PK data in humans, the minimum dose to maintain C trough,ss 6 mg¢mL ¡1 in 90% patients is 4 mg¢kg ¡1 every 3 weeks (q3w).…”

Section: Discussionmentioning

confidence: 99%

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Deng¹,

Bumbaca²,

Pastuskovas³

et al. 2016

mAbs

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169

167

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MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg¢kg ¡1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg¢kg ¡1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above »0.5 mg¢mL ¡1 . Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was »0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

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“…These results are in agreement with a recently published study showing that an anti-VEGF antibody caused reduced tumor accumulation of trastuzumab in mice bearing HER2-expressing KPL-4 breast cancer xenografts. 31 Reduced target accessibility limits the delivery of cetuximab and other antibodies to the tumor, which potentially results in a reduced therapeutic effect of these antibodies. Our results underline the importance of a careful evaluation of timing and sequencing of bevacizumab and other targeted agents.…”

Section: Cancer Cell Biologymentioning

confidence: 99%

Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

Heskamp

Boerman

Molkenboer-Kuenen

et al. 2013

Intl Journal of Cancer

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Bevacizumab (antivascular endothelial growth factor [anti‐VEGF]) and cetuximab (antiepidermal growth factor receptor [anti‐EGFR]) are approved antibodies for treatment of cancer. However, in advanced colorectal cancer, the combination fails to improve survival. As the reason for the lack of activity is unknown, our study aims to determine the effect of bevacizumab on targeting of anti‐EGFR and insulin‐like growth factor 1 receptor (IGF‐1R) antibodies in tumors with single‐photon emission computed tomography (SPECT)/CT imaging. Mice with subcutaneous EGFR and IGF‐1R‐expressing SUM149 xenografts received a single dose of bevacizumab (10 mg/kg) or saline. After 4 days, mice were injected with radiolabeled cetuximab or R1507, an anti‐IGF‐1R antibody. A control group received a radiolabeled irrelevant IgG (hLL2). Three days later, SPECT/CT images were acquired and mice were dissected to determine the concentration of antibodies in the tissues. Tumors were analyzed immunohistochemically to determine vascular density (CD34), VEGF, EGFR and IGF‐1R expression. SPECT/CT imaging revealed that bevacizumab treatment significantly reduced tumor targeting of radiolabeled cetuximab by 40% from 33.1 ± 1.1 %ID/g to 19.8 ± 5.7 %ID/g (p = 0.009) for untreated and bevacizumab‐treated tumors, respectively. A similar effect was found for 111In‐R1507: tumor targeting of R1507 decreased by 35%. No significant differences in tumor uptake were observed in mice that received an irrelevant IgG. Uptake in normal organs was not altered by bevacizumab. Immunohistochemical analysis showed that vascular density decreased with 43%, whereas EGFR and IGF‐1R expression was unaltered. In conclusion, bevacizumab treatment significantly reduces tumor targeting of anti‐EGFR and anti‐IGF‐1R antibodies. This emphasizes the importance of timing and sequencing of bevacizumab in combination with other antibodies.

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Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model

Abstract: Both human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-

Cited by 96 publications

References 47 publications

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Site-specific conjugation allows modulation of click reaction stoichiometry for pretargeted SPECT imaging

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor

Bevacizumab reduces tumor targeting of antiepidermal growth factor and anti‐insulin‐like growth factor 1 receptor antibodies

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