Biology subjects

Fiorito, E.

Publications and source records attributed to Fiorito, E..

3 recordsLinked to original sources

bioRxiv2023

NNV024, a novel humanized anti-CD37 antibody with enhanced ADCC and prolonged plasma half-life in human FcRn transgenic mice for treatment of NHL

There is an unmet medical need for new therapeutic approaches and targets for patients with non- Hodgkin lymphoma (NHL) who relapse or are refractory to anti-CD20 immunotherapy. Therefore, we developed a humanized IgG1 antibody targeting CD37, which was tailored to be afucosylated for enhanced antibody-dependent cellular cytotoxicity (ADCC) (NNV024). In line with this, NNV024 induced three-fold more potent ADCC activity against patient-derived chronic lymphocytic leukemia (CLL) cells compared with anti-CD20 obinutuzumab. Moreover, NNV024 showed 2-fold higher ADCC activity than anti-CD20 rituximab and a recombinant version of DuoHexaBody-CD37 against both NHL and CLL cells. Survival was significantly longer after NNV024 treatment than with obinutuzumab in a mouse model. In addition, NNV024 showed a favourable plasma half-life in human FcRn transgenic mice of about 9-days, which was 2-fold longer than that of obinutuzumab and DuoHexaBody-CD37. These results warrant the further development of NNV024 as a treatment for NHL.

cancer biology↗

bioRxiv2020

Breast tumors escape endocrine therapy by ER-independent mechanisms triggered by the coordinated activities of HER2/HER3 and deacetylated FOXA1

Hormone-resistance in ER positive breast cancer is associated with high HER2 activity. Yet, the interplay between HER2 and FOXA1 in hormone resistant tumors is not elucidated. Now, we demonstrate that hormone resistant tumors have increased HER2 expression and that FOXA1 mediates the signals of HER2/3 in an Estrogen Receptor independent manner. Our in vitro and in vivo experiments reveal that HER2/HER3 triggers FOXA1 binding at chromatin regions of ER-regulated genes associated with poor prognosis, facilitating their expression and leading to ER-independent growth. Furthermore, our study supports that FOXA1 acetylated by the acetyltransferase EP300 is retained at ER chromatin regions, which enables ER function. By contrast, HER2/3 activation hinders FOXA1 acetylation and facilitates FOXA1 binding at non-ER interacting regions enriched towards poor prognosis genes. Moreover, FOXA1 deacetylation confers insensitivity to anti-ER drugs inhibitory effect in ER positive cells. These results elucidate how post-translational modifications of FOXA1 control transcription independently of ER in hormone-resistant tumors with enhanced HER2/3 signaling.

cancer biology↗

bioRxiv2017

The phosphatase PTPRG controls FGFR1 activity and influences sensitivity to FGFR kinase inhibitors

FGFR1 represents an important target for precision medicine and a detailed molecular understanding of the target is important in order to increase the efficacy of FGFR inhibitors. We have here applied proximity labelling of FGFR1 in an osteosarcoma cell line to identify determinants of FGFR1 activity. Many known FGFR interactors were identified (e.g. FRS2, PLC{gamma}, RSK2, SHC4, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

cell biology↗