Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy

Hingorani, Dina V.; Allevato, Michael; Camargo, M. Fernanda; Lesperance, Jacqueline; Quraishi, Maryam A.; Aguilera, Joseph; Franiak-Pietryga, Ida; Scanderbeg, Daniel J.; Wang, Zhiyong; Molinolo, Alfredo A.; Alvarado, Diego; Sharabi, Andrew B.; Bui, Jack D.; Cohen, Ezra E.W.; Adams, Stephen; Gutkind, J. Silvio; Advani, Sunil J.

doi:10.1038/s41467-022-31601-z

Cited by 28 publications

(12 citation statements)

References 70 publications

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“…We also identified that ADCs against CD71, PTK7, CD74, SLC44A4 and LIV‐1 were not under evaluation in breast, colorectal, prostate and gastric cancer, which suggests potential opportunities for evaluation. A further step will be the identification of indications to evaluate combinations including those with novel immunotherapies where relevant preclinical data has been reported 21–23 …”

Section: Discussionmentioning

confidence: 99%

“…A further step will be the identification of indications to evaluate combinations including those with novel immunotherapies where relevant preclinical data has been reported. [21][22][23] Among important aspects to take into consideration and that could influence ADC activity, we can refer to some of the following: the oncogenic role of the receptor, antibody binding, internalization of the receptor, recycling, linker cleavage, lysosomal processing, payload diffusion through the lysosomal and cellular membranes, 11 or the particular antitumor activity to the payload in specific cancers. In this context, spatial tumour heterogeneity and drug penetration are key concepts, particularly for this kind of compound, that depend on the presence of the target, in addition to their very high molecular weight.…”

Section: Discussionmentioning

confidence: 99%

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Uncovering therapeutic opportunities in the clinical development of antibody‐drug conjugates

Nieto‐Jiménez,

Sanvicente,

Díaz‐Tejeiro

et al. 2023

Clinical & Translational Med

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IntroductionAntibody‐drug conjugates (ADCs) are a family of therapeutic agents that have demonstrated clinical activity in several indications.Material and methodsIn this article, we performed a deep analysis of their clinical landscape matched with public genomic human datasets from tumour antigen targets (TATs), to identify empty areas for clinical development.ResultsWe observed that TATs used in haematological malignancies were more specific than the ones developed in solid cancers. Those included CD19, CD22, CD30, CD33 and CD79b. In solid tumours, we identified TATs, with approved ADCs, widely expressed in non‐explored niche indications like Enfortumab vedotin (anti‐Nectin4) in lung or cervical cancer; Tisotumab vedotin (anti‐TF) in glioblastoma or pancreatic cancer; and Sacituzumab govitecan (anti‐TROP2) in pancreatic, gastric, thyroid or endometrial cancer, among others. Similarly, niche indications for ADCs in clinical development included targets for CD71, PSMA, PTK7 or CD74, in tumours like breast, lung, stomach or colon. Some of these TATs were essential for the survival of tumour cells like CD71, PSMA and PTK7.ConclusionsIn summary, our study opens the door for further evaluation of ADCs in several indications not explored before.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uncovering therapeutic opportunities in the clinical development of antibody‐drug conjugates

Nieto‐Jiménez,

Sanvicente,

Díaz‐Tejeiro

et al. 2023

Clinical & Translational Med

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“…It is known that MMAE can sensitize tumors to irradiation only with sufficient time and concentration by enhancing ionizing radiation-induced DNA double-strand breaks 42 , 43 . Lisa et al reported a significant increase in γH2AX foci formation and CHK1 activation in irradiated cancer cells treated with free drug MMAE 43 .…”

Section: Discussionmentioning

confidence: 99%

Tumor protease-activated theranostic nanoparticles for MRI-guided glioblastoma therapy

Huang¹,

Chang²,

Li³

et al. 2023

Theranostics

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Rationale: As a cancer, Glioblastoma (GBM) is a highly lethal and difficult-to-treat. With the aim of improving therapies to GBM, we developed novel and target-specific theranostic nanoparticles (TNPs) that can be selectively cleaved by cathepsin B (Cat B) to release the potent toxin monomethyl auristatin E (MMAE). Methods: We synthesized TNPs composed of a ferumoxytol-based nanoparticle carrier and a peptide prodrug with a Cat-B-responsive linker and the tubulin inhibitor MMAE. We hypothesized that intratumoral Cat B can cleave our TNPs and release MMAE to kill GBM cells. The ferumoxytol core enables in vivo drug tracking with magnetic resonance imaging (MRI). We incubated U87-MG GBM cells with TNPs or ferumoxytol and evaluated the TNP content in the cells with transmission electron microscopy and Prussian blue staining. In addition, we stereotaxically implanted 6- to 8-week-old nude mice with U87-MG with U87-MG GBM cells that express a fusion protein of Green Fluorescence Protein and firefly Luciferase (U87-MG/GFP-fLuc). We then treated the animals with an intravenous dose of TNPs (25 mg/kg of ferumoxytol, 0.3 mg/kg of MMAE) or control. We also evaluated the combination of TNP treatment with radiation therapy. We performed MRI before and after TNP injection. We compared the results for tumor and normal brain tissue between the TNP and control groups. We also monitored tumor growth for a period of 21 days. Results: We successfully synthesized TNPs with a hydrodynamic size of 41 ± 5 nm and a zeta potential of 6 ± 3 mV. TNP-treated cells demonstrated a significantly higher iron content than ferumoxytol-treated cells (98 ± 1% vs. 3 ± 1% of cells were iron-positive, respectively). We also found significantly fewer live attached cells in the TNP-treated group (3.8 ± 2.0 px 2 ) than in the ferumoxytol-treated group (80.0 ± 14.5 px 2 , p < 0001). In vivo MRI studies demonstrated a decline in the tumor signal after TNP (T 2 = 28 ms) but not control (T 2 = 32 ms) injections. When TNP injection was combined with radiation therapy, the tumor signals dropped further (T 2 = 24 ms). The combination therapy of radiation therapy and TNPs extended the median survival from 14.5 days for the control group to 45 days for the combination therapy group. Conclusion: The new cleavable TNPs reported in this work accumulate in GBM, cause tumor cell death, and have synergistic effects with radiation therapy.

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“…Monomethyl auristatin-E sculpts the tumor immune infiltration in conjunction with ionizing radiation to enhance immune checkpoint inhibition. This is how drug resistance is overcome by PDCs, which will be beneficial for treating trimodal cancers [ 153 ]. Efficiency of PDCs depends on the targeted receptor, the pathway of receptor-mediated-endocytosis, and intracellular trafficking.…”

Section: Delivery Of Peptide–drug-conjugates To the Desired Targeted ...mentioning

confidence: 99%

Peptide-Drug Conjugates: A New Hope for Cancer Management

et al. 2022

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Cancer remains the leading cause of death worldwide despite advances in treatment options for patients. As such, safe and effective therapeutics are required. Short peptides provide advantages to be used in cancer management due to their unique properties, amazing versatility, and progress in biotechnology to overcome peptide limitations. Several appealing peptide-based therapeutic strategies have been developed. Here, we provide an overview of peptide conjugates, the better equivalents of antibody-drug conjugates, as the next generation of drugs for required precise targeting, enhanced cellular permeability, improved drug selectivity, and reduced toxicity for the efficient treatment of cancers. We discuss the basic components of drug conjugates and their release action, including the release of cytotoxins from the linker. We also present peptide-drug conjugates under different stages of clinical development as well as regulatory and other challenges.

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Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy

Cited by 28 publications

References 70 publications

Uncovering therapeutic opportunities in the clinical development of antibody‐drug conjugates

Uncovering therapeutic opportunities in the clinical development of antibody‐drug conjugates

Tumor protease-activated theranostic nanoparticles for MRI-guided glioblastoma therapy

Peptide-Drug Conjugates: A New Hope for Cancer Management

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