In vivo potential of recombinant granulysin against human melanoma

Al-Wasaby, Sameer; Guerrero-Ochoa, Patricia; Ibáñez-Pérez, Raquel; Soler, Ruth; Conde, Blanca; Martínez-Lostao, Luis; Anel, Alberto

doi:10.1016/j.ctarc.2021.100355

Cited by 9 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remarkably, the antitumor activity of granulysin was associated with a massive NK cell infiltration, suggesting a possible immunogenic effect of granulysin-induced tumor cell death [15,16]. In addition, no side effects of this type of treatment were detected in those in vivo experiments [15].…”

Section: Discussionmentioning

confidence: 93%

“…Our group has shown that recombinant GRNLY is capable of killing tumor cells in vitro through the mitochondrial apoptotic pathway [17,18,26]. This antitumor activity of recombinant GRNLY was also demonstrated in vivo, initially by intratumoral injection in several tumors types: mammary carcinoma, multiple myeloma and melanoma [15,16]. There are abundant data that relate granulysin expression to an active antitumor immune response and to a good prognosis [31][32][33][34].…”

Section: Discussionmentioning

confidence: 97%

“…In the case of the multiple myeloma NCI-H929, and although the binding of AR20.5GNLY was also high (Figure 3), the cytotoxicity of AR20.5GRNLY was not higher than that of GRNLY (Figure 5). This could be due to the fact that H929 cells are very sensitive to GRNLY cytotoxicity, as previously described both in vitro [17] and in vivo [15], being the targeting mediated by the scFv moiety unable to increase this cytotoxicity level. In A549 lung adenocarcinoma cells, AR20.5GRNLY resulted significantly more cytotoxic than GRNLY at low concentrations, 2.5 and 5 µM, although this level of cytotoxicity did not increase at 10 µM, arriving at a maximum of 60% of cell death for both GRNLY and AR20.5GRNLY (Fig 5).…”

Section: Cytotoxicity Assays On Tn + Tumor Cellsmentioning

confidence: 88%

“…On the other hand, our research group has studied the antitumor capacity of recombinant 9 kDa granulysin (GRNLY) for more than two decades [15][16][17][18]. Previous studies showed the in vivo tumor targeting of MFE23GRNLY, an immunotoxin engineered against the carcinoembryonic antigen (CEA), after systemic injection [19].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Preclinical Studies of Granulysin-Based Anti-Tn Immunotoxins as A New Antitumoral Treatment

Guerrero-Ochoa¹,

Ibáñez-Pérez²,

Berbegal-Pinilla³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosilated MUC1, also known as the Tn antigen, expressed in a variety of tumor cell types. We first demonstrated the affinity of these immunotoxins for their antigen using surface plasmon resonance for the purified antigen and flow cytometry for the antigen expressed on the surface of living tumor cells. The induction of cell death of tumor cell lines of different origin positive for Tn antigen expression was stronger in the cases of the immunotoxins than that induced by GRNLY alone. The mechanism of cell death induced by the immunotoxins was studied, showing that the apoptotic component demonstrated previously for GRNLY was also present, but that cell death induced by the immunotoxins included also necroptotic and necrotic components. Finally, we demonstrated the in vivo tumor targeting by the immunotoxins after systemic injection using a xenograft model of the human pancreatic adenocarcinoma CAPAN-2 in athymic mice. While GRNLY alone did not have a therapeutic effect, SM3GRNLY and AR20.5GRNLY reduced tumor volume by 42 and 60%, respectively, compared with untreated tumor-bearing mice, although the results were not statistically significant in the case of AR20.5GRNLY. Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 97%

Section: Cytotoxicity Assays On Tn + Tumor Cellsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Preclinical Studies of Granulysin-Based Anti-Tn Immunotoxins as A New Antitumoral Treatment

Guerrero-Ochoa¹,

Ibáñez-Pérez²,

Berbegal-Pinilla³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The efficacy of the intra-tumor injection of recombinant granulysin was demonstrated in several in vivo models of tumor development in athymic mice. Interestingly, the antitumor activity of granulysin was associated with a massive NK cell infiltration, suggesting a possible immunogenic effect of granulysin-induced tumor cell death [ 69 , 70 ]. In addition, no side effects of this type of treatment were detected in the athymic mice used in these experiments [ 69 ].…”

Section: Human Cytotoxic Proteinsmentioning

confidence: 99%

Antibody-Based Immunotoxins for Colorectal Cancer Therapy

et al. 2021

Self Cite

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) are included among the treatment options for advanced colorectal cancer (CRC). However, while these mAbs effectively target cancer cells, they may have limited clinical activity. A strategy to improve their therapeutic potential is arming them with a toxic payload. Immunotoxins (ITX) combining the cell-killing ability of a toxin with the specificity of a mAb constitute a promising strategy for CRC therapy. However, several important challenges in optimizing ITX remain, including suboptimal pharmacokinetics and especially the immunogenicity of the toxin moiety. Nonetheless, ongoing research is working to solve these limitations and expand CRC patients’ therapeutic armory. In this review, we provide a comprehensive overview of targets and toxins employed in the design of ITX for CRC and highlight a wide selection of ITX tested in CRC patients as well as preclinical candidates.

show abstract

Human cancer cells xenografts to assess the efficacy of granulysin-based therapeutics

Ibáñez-Pérez,

Anel

2024

Methods in Cell Biology

View full text Add to dashboard Cite

In vivo potential of recombinant granulysin against human melanoma

Cited by 9 publications

References 31 publications

Preclinical Studies of Granulysin-Based Anti-Tn Immunotoxins as A New Antitumoral Treatment

Preclinical Studies of Granulysin-Based Anti-Tn Immunotoxins as A New Antitumoral Treatment

Antibody-Based Immunotoxins for Colorectal Cancer Therapy

Human cancer cells xenografts to assess the efficacy of granulysin-based therapeutics

Contact Info

Product

Resources

About