Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

Bordeau, Brandon M.; Balthasar, Joseph P.

doi:10.20892/j.issn.2095-3941.2020.0704

Cited by 23 publications

(10 citation statements)

References 115 publications

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“…However, convection is more prevalent in the case of larger drug nanocarriers present in a solid tumor core [ 55 ] and large vessels [ 53 , 56 ]. In this regard, it has been determined that the specific entry of therapeutic payloads into tumors is inhibited when diffusion is involved in the intratumoral transport of nanocarriers due to the increase of interstitial pressure in solid tumors [ 57 , 58 , 59 ]. Hence, diffusion can sometimes be considered an obstacle to yielding novel, effective therapies for solid tumors.…”

Section: Epr-mediated Drug Delivery To Solid Tumorsmentioning

confidence: 99%

“…Tumor vessel development and maturation can also lead to the formation of an integrated structure of endothelial cells and the presence of pericytes, which changes the mechanism of intratumoral transport of drug nanocarriers due to an alteration in the ratios of convection/diffusion status [ 58 , 64 ]. Although reducing the number and size of vascular wall pores moderates the passive transport of drug nanocarriers into the interstitial space, computational models predict that even without vessel pores/gaps due to decreased interstitial fluid retention and reduced leakage into vessel lumen with higher uptake through intercellular and linked vesicles effectively increases the tumor delivery of macromolecular drugs based on the EPR effect ( Figure 2 ) [ 64 ].…”

Section: Epr-mediated Drug Delivery To Solid Tumorsmentioning

confidence: 99%

See 1 more Smart Citation

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

Sharifi

Cho

Ansariesfahani

et al. 2022

Cancers

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The enhanced permeability and retention (EPR) effect in cancer treatment is one of the key mechanisms that enables drug accumulation at the tumor site. However, despite a plethora of virus/inorganic/organic-based nanocarriers designed to rely on the EPR effect to effectively target tumors, most have failed in the clinic. It seems that the non-compliance of research activities with clinical trials, goals unrelated to the EPR effect, and lack of awareness of the impact of solid tumor structure and interactions on the performance of drug nanocarriers have intensified this dissatisfaction. As such, the asymmetric growth and structural complexity of solid tumors, physicochemical properties of drug nanocarriers, EPR analytical combination tools, and EPR description goals should be considered to improve EPR-based cancer therapeutics. This review provides valuable insights into the limitations of the EPR effect in therapeutic efficacy and reports crucial perspectives on how the EPR effect can be modulated to improve the therapeutic effects of nanomedicine.

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Section: Epr-mediated Drug Delivery To Solid Tumorsmentioning

confidence: 99%

Section: Epr-mediated Drug Delivery To Solid Tumorsmentioning

confidence: 99%

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

Sharifi

Cho

Ansariesfahani

et al. 2022

Cancers

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“… 1 2 While the currently approved drugs are indicated for the treatment of both hematologic (6 ADCs) and solid malignancies (5 ADCs), over 80% of ADCs in active clinical trials are being investigated for solid tumor therapy. 1 3 Immunotherapeutics often have reduced efficacy in solid tumors compared with hematologic malignancies, 4 but the increase in the number of ADCs in clinical trials for solid tumors may suggest their high therapeutic potential to overcome problems as antigen heterogeneity or physical barriers in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors

Kalinovsky

Kibardin

Холоденко

et al. 2022

J Immunother Cancer

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BackgroundBoth ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) have demonstrated clinical success as solid tumor therapies in recent years, yet no research has been carried out to develop anti-GD2 ADCs against solid tumors. This is the first study to analyze cytotoxic activity of clinically relevant anti-GD2 ADCs in a wide panel of cell lines with varying GD2 expression and their effects in mouse models of GD2-positive solid cancer.MethodsAnti-GD2 ADCs were generated based on the GD2-specific antibody ch14.18 approved for the treatment of neuroblastoma and commonly used drugs monomethyl auristatin E (MMAE) or F (MMAF), conjugated via a cleavable linker by thiol-maleimide chemistry. The antibody was produced in a mammalian expression system, and its specific binding to GD2 was analyzed. Antigen-binding properties and biodistribution of the ADCs in mice were studied in comparison with the parent antibody. Cytotoxic effects of the ADCs were evaluated in a wide panel of GD2-positive and GD2-negative tumor cell lines of neuroblastoma, glioma, sarcoma, melanoma, and breast cancer. Their antitumor effects were studied in the B78-D14 melanoma and EL-4 lymphoma syngeneic mouse models.ResultsThe ch14.18-MMAE and ch14.18-MMAF ADCs retained antigen-binding properties of the parent antibody. Direct dependence of the cytotoxic effect on the level of GD2 expression was observed in cell lines of different origin for both ADCs, with IC50 below 1 nM for the cells with high GD2 expression and no cytotoxic effect for GD2-negative cells. Within the analyzed cell lines, ch14.18-MMAF was more effective in the cells overexpressing GD2, while ch14.18-MMAE had more prominent activity in the cells expressing low GD2 levels. The ADCs had a similar biodistribution profile in the B78-D14 melanoma model compared with the parent antibody, reaching 7.7% ID/g in the tumor at 48 hours postinjection. The average tumor size in groups treated with ch14.18-MMAE or ch14.18-MMAF was 2.6 times and 3.8 times smaller, respectively, compared with the control group. Antitumor effects of the anti-GD2 ADCs were also confirmed in the EL-4 lymphoma model.ConclusionThese findings validate the potential of ADCs targeting ganglioside GD2 in treating multiple GD2-expressing solid tumors.

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“…The MRI-PBPK approach may also be of value in predicting the impact of methods to enhance mAb tumor uptake and penetration. Many strategies to improve mAb tumor disposition have been developed pre-clinically [ 21 , 41 , 42 , 43 , 44 , 45 ]; however, evaluating the impact of a given approach on mAb tumor PK requires complicated experimental methods (i.e., radioactive tracers, LC-MS/MS) with tumor samples collected across a range of timepoints. The DCE-MRI-PBPK approach may help to predict the impact of a given enhancement strategy on mAb tumor disposition.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition

Bordeau

Polli

Schweser

et al. 2022

IJMS

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The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h–6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σTUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and σTUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities.

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Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

Cited by 23 publications

References 115 publications

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment

Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition

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