scholarly journals Carbonic Anhydrase IX Expression Predicts Outcome of Interleukin 2 Therapy for Renal Cancer

2005 ◽  
Vol 11 (10) ◽  
pp. 3714-3721 ◽  
Author(s):  
Michael Atkins ◽  
Meredith Regan ◽  
David McDermott ◽  
James Mier ◽  
Eric Stanbridge ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Renal Cancer ◽  
Interleukin 2 ◽  
Carbonic Anhydrase Ix

scholarly journals Sortase-mediated site-specific modification of interleukin-2 for the generation of a tumor targeting acetazolamide-cytokine conjugate

2020 ◽  
Author(s):  
Baptiste Gouyou ◽  
J Millul ◽  
A Villa ◽  
S Cazzamalli ◽  
D Neri ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Tumor Targeting ◽  
Interleukin 2 ◽  
Industrial Applications ◽  
Carbonic Anhydrase Ix ◽  
Site Specific ◽  
Tumor Bearing ◽  
Bioactive Proteins

1.AbstractSmall ligands specific to tumor-associated antigens can be used as alternatives to antibodies for the delivery of small payloads such as radionuclides, cytotoxic drugs and fluorophores. Their use as delivery moiety of bioactive proteins like cytokines remains largely unexplored. Here, we describe the preparation and in vivo characterization of the first small molecule-cytokine conjugate targeting carbonic anhydrase IX (CAIX), a marker of renal cell carcinoma and hypoxia. Site-specific conjugation between interleukin-2 and acetazolamide was obtained by Sortase A-mediated transpeptidation. Binding of the conjugate to the cognate CAIX antigen was confirmed by surface plasmon resonance. The in vivo targeting of structures expressing carbonic anhydrase IX was assessed by biodistribution experiments in tumor bearing mice. Optimization of manufacturability and tumor targeting performance of acetazolamide-cytokine products will be required in order to enable industrial applications.Graphical abstract

scholarly journals Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2

2018 ◽  
Vol 24 (15) ◽  
pp. 3656-3667 ◽  
Author(s):  
Samuele Cazzamalli ◽  
Barbara Ziffels ◽  
Fontaine Widmayer ◽  
Patrizia Murer ◽  
Giovanni Pellegrini ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Small Molecule ◽  
Interleukin 2 ◽  
Carbonic Anhydrase Ix ◽  
Therapeutic Activity ◽  
Small Molecule Drug ◽  
Drug Conjugates

scholarly journals A novel fully-human potency-matched dual cytokine-antibody fusion protein targets carbonic anhydrase IX in renal cell carcinomas

2019 ◽  
Author(s):  
Roberto De Luca ◽  
Baptiste Gouyou ◽  
Tiziano Ongaro ◽  
Alessandra Villa ◽  
Barbara Ziffels ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Carbonic Anhydrase ◽  
Fusion Protein ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Interleukin 2 ◽  
Carbonic Anhydrase Ix ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

AbstractCertain cytokines synergize in activating anti-cancer immunity at the site of disease and it may be desirable to generate biopharmaceutical agents, capable of simultaneous delivery of cytokine pairs to the tumor. In this article, we have described the cloning, expression and characterization of IL2-XE114-TNFmut, a dual-cytokine biopharmaceutical featuring the sequential fusion of interleukin-2 (IL2) with the XE114 antibody in scFv format and a tumor necrosis factor mutant (TNFmut). The fusion protein recognized the cognate antigen (carbonic anhydrase IX, a marker of hypoxia and of renal cell carcinoma) with high affinity and specificity. IL2-XE114-TNFmut formed a stable non-covalent homotrimeric structure, displayed cytokine activity in in vitro tests and preferentially localized to solid tumors in vivo. The product exhibited a partial growth inhibition of murine CT26 tumors transfected for carbonic anhydrase IX. When administered to Cynomolgus monkey as intravenous injection, IL2-XE114-TNFmut showed the expected plasma concentration of ~1500 ng/ml at early time points, indicating the absence of any in vivo trapping events, and a half-life of ~2 hours. IL2-XE114-TNFmut may thus be considered as a promising biopharmaceutical for the treatment of metastatic clear-cell renal cell carcinoma, since these tumors are known to be sensitive to IL2 and to TNF.Contribution to the fieldThere is a growing interest in the antibody-based targeted delivery of pro-inflammatory cytokines for tumor therapy, which may be complementary or alternative to immune checkpoint inhibitors for immunotherapeutic applications. In this article, we have described a novel fusion protein, featuring antibody moieties specific to carbonic anhydrase IX, as well as interleukin-2 and tumor necrosis factor as pro-inflammatory cytokines, which combines the ability to recognize a tumor-associated antigen on the surface of renal cell carcinomas with the simultaneous display of two potent therapeutic payloads. The newly developed product (termed IL2-XE114-TNFmut) exhibited favorable biochemical characteristics, the ability to preferentially localize at the tumor site, a cancer growth inhibition activity and a suitable pharmacokinetic profile in Cynomolgus monkey. IL2-XE114-TNFmut may therefore represent an attractive candidate for the immunotherapy of renal cell carcinoma.

780: Carbonic Anhydrase IX (CAIX) Expression and VHL Gene Alteration as Predictors of Survival in Renal Cell Carcinoma

2004 ◽  
Vol 171 (4S) ◽  
pp. 206-207 ◽  
Author(s):  
Hideki Mukouyama ◽  
Masahiro Yao ◽  
David B. Seligson ◽  
John S. Lam ◽  
Yoji Nagashima ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Carbonic Anhydrase ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Carbonic Anhydrase Ix ◽  
Vhl Gene ◽  
Gene Alteration ◽  
Caix Expression

scholarly journals Distinct Expression Patterns of Carbonic Anhydrase IX in Clear Cell, Microcystic, and Angiomatous Meningiomas

2019 ◽  
Vol 78 (12) ◽  
pp. 1081-1088
Author(s):  
Rati Chkheidze ◽  
Patrick J Cimino ◽  
Kimmo J Hatanpaa ◽  
Charles L White ◽  
Manuel Ferreira ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Clear Cell ◽  
Expression Patterns ◽  
Carbonic Anhydrase Ix ◽  
World Health ◽  
Loss Of Function ◽  
Ca Ix ◽  
Hypoxia Marker ◽  
Other World ◽  
Health Organization

Abstract Clear cell, microcytic, and angiomatous meningiomas are 3 vasculature-rich variants with overlapping morphological features but different prognostic and treatment implications. Distinction between them is not always straightforward. We compared the expression patterns of the hypoxia marker carbonic anhydrase IX (CA-IX) in meningiomas with predominant clear cell (n = 15), microcystic (n = 9), or angiomatous (n = 11) morphologies, as well as 117 cases of other World Health Organization recognized histological meningioma variants. Immunostaining for SMARCE1 protein, whose loss-of-function has been associated with clear cell meningiomas, was performed on all clear cell meningiomas, and selected variants of meningiomas as controls. All clear cell meningiomas showed absence of CA-IX expression and loss of nuclear SMARCE1 expression. All microcystic and angiomatous meningiomas showed diffuse CA-IX immunoreactivity and retained nuclear SMARCE1 expression. In other meningioma variants, CA-IX was expressed in a hypoxia-restricted pattern and was highly associated with atypical features such as necrosis, small cell change, and focal clear cell change. In conclusion, CA-IX may serve as a useful diagnostic marker in differentiating clear cell, microcystic, and angiomatous meningiomas.

scholarly journals Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 6098
Author(s):  
Ebru Temiz ◽  
Ismail Koyuncu ◽  
Mustafa Durgun ◽  
Murat Caglayan ◽  
Ataman Gonel ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Intracellular Ph ◽  
Hela Cells ◽  
Protein Level ◽  
Caspase 3 ◽  
Solid Tumours ◽  
Carbonic Anhydrase Ix ◽  
Parp Activation ◽  
Ca Ix ◽  
Cervical Cancer Cells

Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO/EB, AnnexinV-PI, and γ-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib/II clinical trials as an antitumour/antimetastatic drug.

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