Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody–Drug Conjugates

Zhao, Hui; Atkinson, John; Gulesserian, Sara; Zeng, Zhilan; Nater, Jenny; Ou, Jimmy; Yang, Peng; Morrison, Karen; Coleman, Jeffrey D.; Malik, Faisal; Challita-Eid, Pia M.; Karki, Sher; Aviña, Hector; Hubert, René; Capo, Linnette; Snyder, Josh T.; Moon, Sung-Ju; Luethy, Roland; Mendelsohn, Brian A.; Stover, David R.; Doñate, Fernando

doi:10.1158/0008-5472.can-17-3202

Cited by 79 publications

(79 citation statements)

References 32 publications

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“…The ophthalmic observations of our clinical study are also in agreement with the current model proposed to explain the observed changes in the ocular surface, in which corneal damage begins peripherally after ADCs reach the cornea via the vascularized limbal region, followed by internalization and consequent accumulation of the cytotoxic payload into transient amplifying cells. These damaged progenitor cells then migrate centripetally, sufficient to account for the development of microcystic deposits seen in patients (26,27). Overall, the findings validate the use of this rabbit model to assess the pathogenesis of ocular abnormalities, as well as the risks of visual disturbances, induced by mirvetuximab soravtansine exposure in human subjects.…”

Section: Discussionsupporting

confidence: 65%

“…The mechanism of action underlying these offtarget yet selective effects on the corneal epithelium was not determined in this assay. However, a recent report by Zhao and colleagues (26) revealed that macropinocytosis-mediated uptake by corneal epithelial and other primary cells was responsible for ocular toxicity of AGS-16C3F, an ENPP3-targeting ADC containing a MMAF payload. Furthermore, they showed that the TEAEs reported in !15% of patients.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

Matulonis

Birrer

O’Malley

et al. 2019

Clinical Cancer Research

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Purpose: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinumresistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. Patients and Methods: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. Results: FRa expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. Conclusions: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

Matulonis

Birrer

O’Malley

et al. 2019

Clinical Cancer Research

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“…Is phagocyte uptake of mAbs beneficial for efficacy? Based on prior studies, HER2‐independent phagocyte uptake may involve scavenging of interstitial Tzm, for instance via nonspecific macropinocytosis or Fc‐mediated uptake of unbound mAbs by macrophages . In contrast, HER2‐dependent enhancement in phagocyte uptake likely involves the interaction between HER2‐bound Tzm and highly expressed Fcγ receptors (FcγR) on phagocytes.…”

Section: Discussionmentioning

confidence: 99%

Single‐Cell Intravital Microscopy of Trastuzumab Quantifies Heterogeneous in vivo Kinetics

Attari

Prytyskach

et al. 2019

Cytometry Pt A

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Cell-to-cell heterogeneity can substantially impact drug response, especially for monoclonal antibody (mAb) therapies that may exhibit variability in both delivery (pharmacokinetics) and action (pharmacodynamics) within solid tumors. However, it has traditionally been difficult to examine the kinetics of mAb delivery at a single-cell level and in a manner that enables controlled dissection of target-dependent and -independent behaviors. To address this issue, here we developed an in vivo confocal (intravital) microscopy approach to study single-cell mAb pharmacology in a mosaic xenograft comprising a mixture of cancer cells with variable expression of the receptor HER2. As a proof-of-principle, we applied this model to trastuzumab therapy, a HER2-targeted mAb widely used for treating breast and gastric cancer patients. Trastuzumab accumulated to a higher degree in HER2-over expressing tumor cells compared to HER2-low tumor cells (~5:1 ratio at 24 h after administration) but importantly, the majority actually accumulated in tumor-associated phagocytes. For example, 24 h after IV administration over 50% of tumoral trastuzumab was found in phagocytes whereas at 48 h it was >80%. Altogether, these results reveal the dynamics of how phagocytes influence mAb behavior in vivo, and demonstrate an application of intravital microscopy for quantitative single-cell measurement of mAb distribution and retention in tumors with heterogeneous target expression. © 2019 International Society for Advancement of Cytometry Key terms tumor associated macrophage; metastatic breast cancer; human epidermal growth factor receptor 2/HER2/ERBB2; Fc-receptor; antibody-dependent cellular phagocytosis

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“…Some in vitro and in vivo studies have already been conducted to investigate the effectiveness of ADC [ 9 , 12 – 14 ]. In the present study, the in vivo and in vitro experiments confirmed that the antibody portion of an ADC drug (Cetuximab) served as a vector for the effector molecule (tubulin inhibitor MMAE) to bring MMAE to the targeted tumor tissue.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies

Kang

Zhou

Jian³

et al. 2018

Med Sci Monit

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BackgroundHuman lung cancer is still the leading cause of cancer-related mortality around the world, although a variety of new therapies have been used in the treatment of this disease. Antibody-drug conjugate (ADC) has revolutionized the field of cancer therapy in recent decades. Unlike traditional chemotherapy that damages the healthy cells, ADC first utilizes monoclonal antibodies to bind tumor-specific antigen targets and then deliver a highly potent cytotoxic agent to kill tumor cells. Thus, ADC can benefit cancer patients because this drug has less severe adverse effects.Material/MethodsOne type of ADC for non-small cell lung cancer (NSCLC) was designed in this study: Erbitux-vc-PAB-MMAE. It is a mouse/human chimeric monoclonal antibody, Erbitux, conjugating to the tubulin inhibitor auristatin. The efficacy of ADC was investigated through in vitro and in vivo studies.ResultsOur in vitro study demonstrated that Erbitux-vc-PAB-MMAE could effectively inhibit proliferation of human lung cancer A549 cells, and arrested cell cycle at G2/M phase. In a mouse xenograft model, the results indicated that Erbitux-vc-PAB-MMAE could be exactly delivered to tumor tissues, and effectively inhibited tumor growth via promoting apoptosis of cancer cells.ConclusionsThe antibody portion of an ADC drug (Erbitux) was used as a vector to bring the effector molecule (tubulin inhibitor MMAE) to the targeted tumor tissue. This antibody-drug conjugate can exert a strong anti-tumor effect.

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Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody–Drug Conjugates

Cited by 79 publications

References 32 publications

Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody–Drug Conjugate Mirvetuximab Soravtansine

Single‐Cell Intravital Microscopy of Trastuzumab Quantifies Heterogeneous in vivo Kinetics

Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies

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