Sortase-Mediated Site-Specific Modification of Interleukin-2 for the Generation of a Tumor-Targeting Acetazolamide–Cytokine Conjugate

Gouyou, Baptiste; Millul, Jacopo; Villa, Alessandra; Cazzamalli, Samuele; Neri, Dario; Matasci, Mattia

doi:10.1021/acsomega.0c03592

Cited by 9 publications

(8 citation statements)

References 42 publications

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“…The same approach has been thereafter explored and enriched for acetazolamide/benzenesulfonamide CAIs serving as selective delivery vehicles for radionuclides ( 99m Tc), 67 antibodies, 68 dipeptide-linked renal cell carcinoma-targeting agents, 68 cytokines (such as IL-2) 70 , 72 and other small molecule toxins (e.g., auristatin methyl ester, cryptophycin) 69 , 71 as drug conjugates. All these approaches were highly successful in leading to SMDCs, antibody-drug conjugates (ADACs) or cytokine-drug conjugates with an enhanced antitumor effect compared with the parent molecules from which they were obtained.…”

Section: Antitumor Cais Developed In Zurichmentioning

confidence: 99%

<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

Supuran¹

2020

JEP

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Carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are overexpressed in many hypoxic tumors as a consequence of the hypoxia inducible factor (HIF) activation cascade, being present in limited amounts in normal tissues. These enzymes together with many others are involved in the pH regulation and metabolism of hypoxic cancer cells, and were validated as antitumor targets recently. A multitude of targeting strategies against these enzymes have been proposed and are reviewed in this article. The small molecule inhibitors, small molecule drug conjugates (SMDCs), antibody-drug conjugates (ADACs) or cytokine-drug conjugates but not the monoclonal antibodies against CA IX/XII will be discussed. Relevant synthetic chemistry efforts, coupled with a multitude of preclinical studies, demonstrated that CA IX/XII inhibition leads to the inhibition of growth of primary tumors and metastases and depletes cancer stem cell populations, all factors highly relevant in clinical settings. One small molecule inhibitor, sulfonamide SLC-0111, is the most advanced candidate, having completed Phase I and being now in Phase Ib/II clinical trials for the treatment of advanced hypoxic solid tumors.

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Section: Antitumor Cais Developed In Zurichmentioning

confidence: 99%

<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

Supuran¹

2020

JEP

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“…According to biodistribution studies, more AAZ‐IL‐2 accumulates in tumor sites than nontargeting IL‐2. [ 18 ]…”

Section: Engineered Therapeutic Systems For Exogenous Cytokine Deliverymentioning

confidence: 99%

Molecular and Macroscopic Therapeutic Systems for Cytokine‐Based Cancer Immunotherapy

Jin

Lee

Yoo

et al. 2021

Advanced Therapeutics

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Cytokines are proteins that mediate and regulate inflammation and immune responses in the body. While several cytokines have been investigated as antitumor agents in multiple clinical trials due to their potent immunomodulatory activities, the unfavorable pharmacokinetics of recombinant cytokines resulted in substantial side effects and a low therapeutic index. Because these factors have hampered the further development of cytokine-based immunotherapy, bioengineered technologies that can enhance therapeutic efficacy and lower systemic toxicities are in high demand. In this review, the molecular modification of cytokines and delivery system for the spatiotemporal distribution of exogenous cytokines as well as macroscopic delivery systems for endogenous cytokine production based on gene therapy and immunomodulator-mediated therapy will be discussed.

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“…Indeed, CA IX and XII, members of the superfamily of α-CAs, zinc enzymes that catalyze the hydration of CO 2 to bicarbonate and protons, are significantly overexpressed in many tumors while being present in few normal tissues at rather low expression levels, which makes them excellent drug targets . As a consequence, a variety of small-molecule CA inhibitors (CAIs) belonging to many diverse chemical classes, − small-molecule drug conjugates (SMDCs), antibody–drug conjugates (ADACs), or cytokine–drug conjugates targeting CA IX/XII have been proposed over the last decade and showed significant antitumor activity . Nanoparticles decorated with CAIs of the sulphonamide type also showed promising in vitro antiproliferative action .…”

Section: Introductionmentioning

confidence: 99%

Glyco-Coated CdSe/ZnS Quantum Dots as Nanoprobes for Carbonic Anhydrase IX Imaging in Cancer Cells

Biagiotti

Angeli

Giacomini

et al. 2021

ACS Appl. Nano Mater.

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The bioimaging of cancer cells by the specific targeting of overexpressed biomarkers is an approach that holds great promise in the identification of selective diagnostic tools. Tumor-associated human carbonic anhydrase (hCA) isoforms IX and XII have been considered so far as well-defined biomarkers, with their expression correlating with cancer progression and aggressiveness. Therefore, the availability of highly performant fluorescent tools tailored for their targeting and able to efficiently visualize such key targets is in high demand. We report here on the design and synthesis of a kind of quantum dot (QD)-based fluorescent glyconanoprobe coated with a binary mixture of ligands, which, according to the structure of the terminal domains, impart specific property sets to the fluorescent probe. Specifically, monosaccharide residues ensured the dispersibility in the biological medium, CA inhibitor residues provided specific targeting of membrane-anchored hCA IX overexpressed on bladder cancer cells, and the quantum dots imparted the optical/fluorescence properties.

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Sortase-Mediated Site-Specific Modification of Interleukin-2 for the Generation of a Tumor-Targeting Acetazolamide–Cytokine Conjugate

Cited by 9 publications

References 42 publications

<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

Molecular and Macroscopic Therapeutic Systems for Cytokine‐Based Cancer Immunotherapy

Glyco-Coated CdSe/ZnS Quantum Dots as Nanoprobes for Carbonic Anhydrase IX Imaging in Cancer Cells

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