Generation of humanized single-chain fragment variable immunotherapeutic against EGFR variant III using baculovirus expression system and in vitro validation

Xavier, Serene; Mohan, C. Gopi; Nair, Shantikumar V.; Menon, Krishnakumar N.; Vijayachandran, Lakshmi Sumitra

doi:10.1016/j.ijbiomac.2018.11.202

Cited by 6 publications

(4 citation statements)

References 24 publications

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“…A recent publication from our institution has demonstrated the significance of humanized anti-EGFR vIII single-chain fragment variable as a potential immunotherapeutic agent as well as a targeting agent for specific delivery of drugs to EGFR vIII-expressing cancer cells. 14 Work on orthotopic mice models has suggested that tumor-selective, bitargeted anti-EGFR/EGFR vIII CAR T-cells may be a promising modality for the treatment of patients with EGFR/EGFR vIII-overexpressing GBM. 15 The limitation of our study is its small sample size.…”

Section: Discussionmentioning

confidence: 99%

Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

Jose

Munirathnam

Narendranath

et al. 2020

South Asian J Cancer

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Background Glioblastoma multiforme (GBM) is a disease with poor outcome. Alterations or mutations in epidermal growth factor receptors (EGFRs) are found in GBM and may be targeted to improve outcomes. Aims We analyzed the frequency of EGFR variant III (vIII) mutations in patients with GBM and their outcomes after standard treatment. Materials and Methods This is a retrospective study conducted in a single tertiary cancer center in south India. Forty patients with GBM who had their entire treatment done at this center were identified, and their primary tumor tissue blocks were retrieved. Genomic DNA was extracted, and molecular analysis was performed and analyzed. The results of mutational analysis were correlated with treatment outcome of the patients. Statistical Analysis Survival outcome was analyzed using the Kaplan–Meier method. The log-rank test was used to assess the association between the groups and various parameters. Results Our study showed a similar incidence of EGFR vIII alterations as published in world literature, but we did not find any difference in overall survival (OS) and progression-free survival (PFS) in patients with EGFR vIII mutation compared with nonmutant cohort. Conclusions Contrary to the existing literature which indicated EGFR vIII alterations to be a negative prognostic indicator, our study did not find it to be an independent predictor of prognosis among Indian GBM patients treated with present standard of care.

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Section: Discussionmentioning

confidence: 99%

Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

Jose

Munirathnam

Narendranath

et al. 2020

South Asian J Cancer

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“…LYN is a member of the Src family of tyrosine kinases and is mainly expressed in hematopoietic cells, nerves, liver, and adipose tissue (Xu et al, 2005). Several studies have shown that LYN activation can promote the progression of human glioma (Moncayo et al, 2018;Yang et al, 2018;Xavier et al, 2019). Furthermore, through the overexpression of LYN in U251 cells, we found that LYN promoted the expression of ADAM10, which in turn promoted the cleavage of NLGN3; LYN inhibitors could not rescue the effect of ADAM10.…”

Section: Discussionmentioning

confidence: 65%

NLGN3 Upregulates Expression of ADAM10 to Promote the Cleavage of NLGN3 via Activating the LYN Pathway in Human Gliomas

Zhang

Han

et al. 2021

Front. Cell Dev. Biol.

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The neuron derived synaptic adhesion molecular neuroligin-3 (NLGN3) plays an important role in glioma growth. While the role of autocrine NLGN3 in glioma has not been well-studied. The expression of NLGN3 in glioma was detected using immunohistochemistry. We further explored its function and regulatory mechanism in U251 and U87 cells with high expression of NLGN3. Knockdown of endogenous NLGN3 significantly reduced the proliferation, migration, and invasion of glioma cells and down-regulated the activity of the PI3K-AKT, ERK1/2, and LYN signaling pathways. In comparison, overexpression of NLGN3 yielded opposite results. Our results further demonstrate that LYN functions as a feedback mechanism to promote NLGN3 cleavage. This feedback regulation was achieved by upregulating the ADAM10 sheddase responsible for NLGN3 cleavage. Inhibition of ADAM10 suppressed the proliferation, migration, and invasion of glioma cells; oppositely, the expression of ADAM10 was correlated with a higher likelihood of lower grade glioma (LGG) in the brain. Our study demonstrates that glioma-derived NLGN3 promotes glioma progression by upregulating activity of LYN and ADAM10, which in turn promote NLGN3 cleavage to form a positive feedback loop. This pathway may open a potential therapeutic window for the treatment of human glioma.

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“…In reference to the abovementioned strategy, many targeted therapies are currently under investigation. As of now, the utilization of small molecule tyrosine kinases inhibitors (TKIs) (Gao et al, 2018) and monoclonal antibodies against EGFR (Xavier et al, 2019) have been assessed in stage II clinical preliminaries as the significant anti‐growth factor receptor tactics. An outline of fundamental ongoing stage II clinical preliminaries of focused treatments alone or in blend with other treatment modalities in GBM are tabulated in Table 1.…”

Section: “Out‐of‐the‐box” Approaches For Gbm Treatmentmentioning

confidence: 99%

Disentangling the therapeutic tactics in GBM: From bench to bedside and beyond

Precilla

Kuduvalli

Sivasubramanian

2020

Cell Biology International

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Glioblastoma multiforme (GBM) is one of the most common and malignant form of adult brain tumor with a high mortality rate and dismal prognosis. The present standard treatment comprising surgical resection followed by radiation and chemotherapy using temozolomide can broaden patient's survival to some extent. However, the advantages are not palliative due to the development of resistance to the drug and tumor recurrence following the multimodal treatment approaches due to both intra‐ and intertumoral heterogeneity of GBM. One of the major contributors to temozolomide resistance is O6‐methylguanine‐DNA methyltransferase. Furthermore, deficiency of mismatch repair, base excision repair, and cytoprotective autophagy adds to temozolomide obstruction. Rising proof additionally showed that a small population of cells displaying certain stem cell markers, known as glioma stem cells, adds on to the resistance and tumor progression. Collectively, these findings necessitate the discovery of novel therapeutic avenues for treating glioblastoma. As of late, after understanding the pathophysiology and biology of GBM, some novel therapeutic discoveries, such as drug repurposing, targeted molecules, immunotherapies, antimitotic therapies, and microRNAs, have been developed as new potential treatments for glioblastoma. To help illustrate, “what are the mechanisms of resistance to temozolomide” and “what kind of alternative therapeutics can be suggested” with this fatal disease, a detailed history of these has been discussed in this review article, all with a hope to develop an effective treatment strategy for GBM.

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Generation of humanized single-chain fragment variable immunotherapeutic against EGFR variant III using baculovirus expression system and in vitro validation

Cited by 6 publications

References 24 publications

Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study

NLGN3 Upregulates Expression of ADAM10 to Promote the Cleavage of NLGN3 via Activating the LYN Pathway in Human Gliomas

Disentangling the therapeutic tactics in GBM: From bench to bedside and beyond

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