Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates

Ritchie, Michael; Tchistiakova, Lioudmila; Scott, Nathan

doi:10.4161/mabs.22854

Cited by 237 publications

(172 citation statements)

References 67 publications

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“…In breast cancers expressing high levels of HER2, experience with T-DM1 has shown that tumor-selective expression of an ADC target and its ability to deliver DM1 to lysosomes are of paramount importance (43). However, despite its ability to effectively kill breast cancer cells expressing high levels of HER2, T-DM1 does not efficiently kill cells expressing low and intermediate levels of HER2, possibly because a relatively small amount of cell surface HER2 reaches lysosomes (14,15).…”

Section: Discussionmentioning

confidence: 99%

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Andreev

Thambi

Bay

et al. 2017

Molecular Cancer Therapeutics

126

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The properties of cell surface proteins targeted by antibodydrug conjugates (ADCs) have not been fully exploited; of particular importance are the rate of internalization and the route of intracellular trafficking. In this study, we compared the trafficking of HER2, which is the target of the clinically approved ADC ado-trastuzumab emtansine (T-DM1), with that of prolactin receptor (PRLR), another potential target in breast cancer. In contrast to HER2, we found that PRLR is rapidly and constitutively internalized, and traffics efficiently to lysosomes, where it is degraded. The PRLR cytoplasmic domain is necessary to promote rapid internalization and degradation, and when transferred to HER2, enhances HER2 degradation. In accordance with these findings, low levels of cell surface PRLR ($30,000 surface receptors per cell) are sufficient to mediate effective killing by PRLR ADC, whereas cell killing by HER2 ADC requires higher levels of cell surface HER2 ($10 6 surface receptors per cell). Noncovalently crosslinking HER2 to PRLR at the cell surface, using a bispecific antibody that binds to both receptors, dramatically enhances the degradation of HER2 as well as the cell killing activity of a noncompeting HER2 ADC. Furthermore, in breast cancer cells that coexpress HER2 and PRLR, a HER2xPRLR bispecific ADC kills more effectively than HER2 ADC. These results emphasize that intracellular trafficking of ADC targets is a key property for their activity and, further, that coupling an ADC target to a rapidly internalizing protein may be a useful approach to enhance internalization and cell killing activity of ADCs.

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Section: Discussionmentioning

confidence: 99%

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Andreev

Thambi

Bay

et al. 2017

Molecular Cancer Therapeutics

126

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“…While conceptually simple, the effectiveness of an antibody-drug conjugate depends on the effectiveness of the antibody, drug, and the linker fastening the drug to the antibody. After systemic administration, the antibodydrug conjugate binds the targeted epitope on the surface of the cancer cell which then internalizes the antibody-drug conjugate by receptor mediated endocytosis (147). Once internalized, the cytotoxic drug is released from the antibody through either hydrolysis, enzymatic cleavage, of degradation of the antibody depending on the linker used.…”

Section: Antibody-drug Conjugatesmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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“…Given that some of the pathways regulated by Endo II are being considered in targeted therapies, the relative levels of Endo II expression in these patient samples may be relevant to the response to therapy. It is also worth noting that in the rapidly emerging field of antibody-drug conjugates for cancer therapy, biomarkers related to the endocytic pathways may be useful to predict response, since receptor internalization is a necessary step for release of these anticancer drugs (57).…”

Section: Discussionmentioning

confidence: 99%

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Baldassarre

Watt

Truesdell

et al. 2015

Molecular Cancer Research

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Triple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, EGFR is frequently activated in a subset of TNBCs and represents a viable clinical target. Because the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared with normal breast epithelial cells. Stable knockdown (KD) of Endo II was achieved in two TNBC cell lines, and although cell viability was unaffected, defects in receptor-mediated endocytosis were observed. EGFR signaling to Erk and Akt kinases was impaired in Endo II KD cells, and this correlated with reduced rates of EGFR internalization and cell motility. Endo II KD cells also displayed defects in three dimensional (3D) cell invasion, and this correlated with impaired extracellular matrix degradation and internalization of MT1-MMP. Endo II silencing also caused a significant reduction in TNBC tumor growth and lung metastasis in mammary orthotopic tumor xenograft assays. In human breast tumor specimens, Endo II expression was highest in TNBC tumors compared with other subtypes, and at the level of gene expression, high Endo II was associated with reduced relapse-free survival in patients with basal-like breast cancers. Together, these results identify a positive role for Endo II in TNBC tumor metastasis and a potential link with poor prognosis.Implications: Endophilin A2 and related adaptor proteins represent important signaling hubs to target in metastatic cancers. Mol Cancer Res; 13(6); 1044-55. Ó2015 AACR.

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Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates

Cited by 237 publications

References 67 publications

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

Novel systemic therapy against malignant pleural mesothelioma

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

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