A humanized monoclonal antibody targeting secreted anterior gradient 2 effectively inhibits the xenograft tumor growth

Guo, Hao; Chen, Hao; Zhu, Qi; Yu, Xiaoyan; Rong, Rong; Merugu, Siva Bharath; Mangukiya, Hitesh Bhagavanbhai; Li, Dawei

doi:10.1016/j.bbrc.2016.05.033

Cited by 16 publications

(15 citation statements)

References 18 publications

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“…A humanized ɑ-AGR2 (18A4Hu) and its murine version (18A4) alone were reported to have inhibitory effect on AGR2 + ovarian cancer xenograft SK-OV-3 [30]. This result is somewhat perplexing (although not discussed in the paper) because in nude mice with no immunity, antibodies by themselves would have no significant effect on xenograft growth as shown by our mAb in the absence of Gem.…”

Section: Discussionmentioning

confidence: 76%

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

et al. 2019

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Anterior gradient 2 (AGR2), a protein disulfide isomerase, shows two subcellular localizations: intracellular (iAGR2) and extracellular (eAGR2). In healthy cells that express AGR2, the predominant form is iAGR2, which resides in the endoplasmic reticulum. In contrast, cancer cells secrete and express eAGR2 on the cell surface. We wanted to test if AGR2 is a cancer-specific tumor-associated antigen. We utilized two AGR2 antibodies, P3A5 and P1G4, for in vivo tumor localization and tumor growth inhibition. The monoclonal antibodies recognized both human AGR2 and mouse Agr2. Biodistribution experiments using a syngeneic mouse model showed high uptake of P3A5 AGR2 antibody in xenografted eAgr2 + pancreatic tumors, with limited uptake in normal tissues. In implanted human patient-derived eAGR2 + pancreatic cancer xenografts, tumor growth inhibition was evaluated with antibodies and Gemcitabine (Gem). Inhibition was more potent by P1G4 + Gem combination than Gem alone or P3A5 + Gem. We converted these two antibodies to human:mouse chimeric forms: the constructed P3A5 and P1G4 chimeric mV L hC κ and mV H hC γ (γ1, γ2, γ4) genes were inserted in a single mammalian expression plasmid vector, and transfected into human 293F cells. Expressed human:mouse chimeric IgG1, IgG2 and IgG4 antibodies retained AGR2 binding. Increase in IgG yield by transfected cells could be obtained with serial transfection of vectors with different drug resistance. These chimeric antibodies, when incubated with human blood, effectively lysed eAGR2 + PC3 prostate cancer cells. We have, thus, produced humanized anti-AGR2 antibodies that, after further testing, might be suitable for treatment against a variety of eAGR2 + solid tumors.

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Section: Discussionmentioning

confidence: 76%

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

et al. 2019

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“…The antibody-induced blocking of AGR2 in pancreatic ductal adenocarcinoma cell lines revealed a significantly reduced tumor growth and metastasis and led to tumor regression and improved survival [110]. Furthermore, humanized antibodies selected to block the AGR2 protein were shown to effectively inhibit tumor growth in a xenograft model [111]. In a recent study on CML, the eAGR2 protein was used as a vital indicator for monitoring the normalization of blood vessels during an anti-angiogenic therapy utilizing nanoparticles (AuNPs).…”

Section: Therapeutic Potentialmentioning

confidence: 99%

Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer

Alsereihi

Schulten

Bakhashab

et al. 2019

Cancers

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Effective diagnostic, prognostic and therapeutic biomarkers can help in tracking disease progress, predict patients’ survival, and considerably affect the drive for successful clinical management. The present review aims to determine how the metastatic-linked protein anterior gradient homologue 2 (AGR2) operates to affect cancer progression, and to identify associated potential diagnostic, prognostic and therapeutic biomarkers, particularly in central nervous system (CNS) tumors. Studies that show a high expression level of AGR2, and associate the protein expression with the resilience to chemotherapeutic treatments or with poor cancer survival, are reported. The primary protein structures of the seven variants of AGR2, including their functional domains, are summarized. Based on experiments in various biological models, this review shows an orchestra of multiple molecules that regulate AGR2 expression, including a feedback loop with p53. The AGR2-associated molecular functions and pathways including genomic integrity, proliferation, apoptosis, angiogenesis, adhesion, migration, stemness, and inflammation, are detailed. In addition, the mechanisms that can enable the rampant oncogenic effects of AGR2 are clarified. The different strategies used to therapeutically target AGR2-positive cancer cells are evaluated in light of the current evidence. Moreover, novel associated pathways and clinically relevant deregulated genes in AGR2 high CNS tumors are identified using a meta-analysis approach.

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“…The role of extracellular AGR2 (eAGR2) is particularly interesting because it enhances tumor angiogenesis and the invasion of vascular endothelial cells and fibroblasts by interaction with vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) [ 8 ]. Importantly, a humanized murine antibody targeting AGR2 exhibited inhibition of xenograft tumor growth [ 9 ], confirming the therapeutic utility of anti-AGR2 compounds.…”

Section: Introductionmentioning

confidence: 94%

Identification, characterization and application of a new peptide against anterior gradient homolog 2 (AGR2)

et al. 2018

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The cancer-associated protein Anterior Gradient 2 (AGR2) has been described, predominantly in adenocarcinomas. Increased levels of extracellular AGR2 (eAGR2) have been correlated with poor prognosis in cancer patients, making it a potential biomarker. Additionally, neutralizing AGR2 antibodies showed preclinical effectiveness in murine cancer models suggesting eAGR2 may be a therapeutic target.We set out to identify a peptide by mRNA display that would serve as a theranostic tool targeting AGR2. This method enables the selection of peptides from a complex (>1011) library and incorporates a protease incubation step that filters the selection for serum stable peptides. We performed six successive rounds of enrichment using a 10-amino acid mRNA display library and identified several AGR2 binding peptides. One of these peptides (H10), demonstrated high affinity binding to AGR2 with a binding constant (KD) of 6.4 nM. We developed an AGR2 ELISA with the H10 peptide as the capture reagent. Our H10-based ELISA detected eAGR2 from cancer cell spent media with a detection limit of (20-50 ng/ml). Furthermore, we investigated the therapeutic utility of H10 and discovered that it inhibited cell viability at IC50 (9-12 μmoles/L) in cancer cell lines. We also determined that 10 μg/ml of H10 was sufficient to inhibit cancer cell migration in breast and prostate cancer cell lines. A control peptide did not show any appreciable activity in these cells. The H10 peptide showed promise as both a novel diagnostic and a potential therapeutic peptide.

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A humanized monoclonal antibody targeting secreted anterior gradient 2 effectively inhibits the xenograft tumor growth

Cited by 16 publications

References 18 publications

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

AGR2, a unique tumor-associated antigen, is a promising candidate for antibody targeting

Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer

Identification, characterization and application of a new peptide against anterior gradient homolog 2 (AGR2)

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