Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study

Negi, Hema; Merugu, Siva Bharath; Mangukiya, Hitesh Bhagavanbhai; Li, Zheqi; Zhou, Bingjie; Qudsia, Sehar; Kamle, Suchitra; Yunus, Fakhar-un-Nisa; Mashausi, Dhahiri Saidi; Wu, Zhenghua; Li, Dawei

doi:10.1016/j.canlet.2019.01.025

Cited by 24 publications

(19 citation statements)

References 45 publications

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“…The internal organs of liver, spleen, stomach, intestine, colon, and pancreas were histologically examined, and no visible pathologic changes were identified. The sparing of organs in anti-AGR2 tumor targeting was also reported by another group [46]. The mechanism behind this epitope-dependent phenomenon is unknown but could be related to a reported observation of increased tumor inhibition by an antibody to AGR3 in combination with the chemodrug cisplatin [47].…”

Section: Enhancement Of Chemodrug Inhibition Of Tumor By Antibodysupporting

confidence: 54%

Antibody Therapy Targeting Cancer-Specific Cell Surface Antigen AGR2

Liu¹,

Crnogorac‐Jurčević²,

Lai³

et al. 2021

Advances in Precision Medicine Oncology

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For anterior gradient 2 (AGR2), normal cells express the intracellular form iAGR2 localized to the endoplasmic reticulum while cancer cells express the extracellular form eAGR2 localized on the cell surface and secreted. Antibodies targeting eAGR2+ cancer cells for eradication will spare normal cells. Two AGR2 monoclonal antibodies, P1G4 and P3A5, were shown to recognize specifically eAGR2+ pancreatic tumors implanted in mice. In addition, P1G4 showed enhancement in drug inhibition of tumor growth. Human:mouse chimeric antibodies of IgG1, IgG2, IgG4 were generated for both antibodies. These human IgG were shown to lyse eAGR2+ prostate cancer cells in vitro with human serum. AGR2 has an important function in distal spread of cancer cells, and is highly expressed in prostate, pancreatic, bladder metastases. Therefore, immunotherapy based on AGR2 antibody-mediated ADCC and CDC is highly promising. Cancer specificity of eAGR2 predicts possibly minimal collateral damage to healthy tissues and organs. Moreover, AGR2 therapy, once fully developed and approved, can be used to treat other solid tumors since AGR2 is an adenocarcinoma antigen found in many common malignancies.

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Section: Enhancement Of Chemodrug Inhibition Of Tumor By Antibodysupporting

confidence: 54%

Antibody Therapy Targeting Cancer-Specific Cell Surface Antigen AGR2

Liu¹,

Crnogorac‐Jurčević²,

Lai³

et al. 2021

Advances in Precision Medicine Oncology

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show abstract

“…The common expression of AGR2 in other solid tumors suggests that such treatments may also be effective in other cancer types, and in the orthotopic setting, but these still remain to be established. Similarly, the anti-metastatic activity of ɑ-AGR2, as recently shown in the lung metastasis mouse model [35], warrants further investigation. Cancer-specific cell surface expression of eAGR2 makes cancer vaccination an exciting possibility, where a primed immune response could potentially eliminate any newly arisen eAGR2 + cancer cells.…”

Section: Discussionmentioning

confidence: 81%

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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“…A pre-clinical in-vitro and in-vivo study showed that the same antibody was able to inhibit lung cancer growth. Treatment of lung cancer cell lines with monoclonal 18A4 antibody activated the p53 pathway, resulting in reduced cell proliferation [ 112 ]. Treating the mouse xenograft model with this monoclonal antibody led to impaired angiogenesis and reduced the tumour size without exerting adverse effects to major organs.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Secretion of pro-oncogenic AGR2 protein in cancer

Moidu¹,

Rahman²,

Syafruddin

et al. 2020

Heliyon

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Anterior gradient-2 (AGR2) protein mediates the formation, breakage and isomerization of disulphide bonds during protein maturation in the endoplasmic reticulum (ER) and contributes to the homoeostasis of the secretory pathway. AGR2 promotes tumour development and metastasis and its elevated expression is almost completely restricted to malignant tumours. Interestingly, this supposedly ER-resident protein can be localised to other compartments of cancer cells and can also be secreted into the extracellular milieu. There are emerging evidences that describe the gain-of-function activities of the extracellular AGR2, particularly in cancer development. Here, we reviewed studies detailing the expression, pathological and physiological roles associated with AGR2 and compared the duality of localization, intracellular and extracellular, with special emphasis on the later. We also discussed the possible mechanisms of AGR2 secretion as well as deliberating the functional impacts of AGR2 in cancer settings. Last, we deliberate the current therapeutic strategies and posit the potential use AGR2, as a prognosis and diagnosis marker in cancer.

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Anterior Gradient-2 monoclonal antibody inhibits lung cancer growth and metastasis by upregulating p53 pathway and without exerting any toxicological effects: A preclinical study

Cited by 24 publications

References 45 publications

Antibody Therapy Targeting Cancer-Specific Cell Surface Antigen AGR2

Antibody Therapy Targeting Cancer-Specific Cell Surface Antigen AGR2

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

Secretion of pro-oncogenic AGR2 protein in cancer

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