Generation and characterization of a high‐affinity chimeric anti‐OX40 antibody with potent antitumor activity

Yang, Yongli; Chai, Xiaojuan; Xin, Wenfang; Wang, Dongxu; Dai, Chaohui; Feng, Qian; Yang, Teddy

doi:10.1002/1873-3468.14079

Cited by 5 publications

(3 citation statements)

References 38 publications

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“…Such as TNFRSF4 acts on the T cell signaling pathway to promote survival, proliferation, and cytokine production. The TNFRSF4 agonist combination is becoming a promising candidate for new cancer immunotherapy 57 . The relationship between DCAF13 expression and immune checkpoints further suggests that high DCAF13 expression predicts an immunosuppressive microenvironment in tumors and is more susceptible to metastasis and immunotherapy resistance.…”

Section: Discussionmentioning

confidence: 99%

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

Wei

Xing

et al. 2023

The FASEB Journal

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DCAF13 is a substrate recognition protein in the ubiquitin‐proteasome system with oncogenic effects in several malignant tumors. However, it is unclear that the relationship between DCAF13 expression pattern and prognosis across different cancer types. Also unknown is the biological function or effects on the immune microenvironment of DCAF13. In this study, we parsed multiple public databases to explore the potential tumorigenic actions of DCAF13, including correlations with prognosis, microsatellite instability (MSI), tumor mutational burden (TMB), immune checkpoint genes, immune cell infiltration, and immunotherapy response in pan‐cancer. Moreover, we validated DCAF13 expression in a tissue microarray by immunohistochemistry and investigate its effects in vitro and in vivo. The results showed that DCAF13 was upregulated in 17 cancer types and correlated with poor prognosis in many cancers. Also, the correlation between DCAF13 and TMB was found in 14 cancers as well as MSI in nine. The expression level of DCAF13 was found to be notably correlated with immune cell infiltration, showing a negative correlation with CD4 T cell infiltration and a positive correlation with neutrophil infiltration. The oncogene DCAF13 expression was shown to have a positive correlation with CD274 or ADORA2A and negative correlation with VSIR, TNFRSF4, or TNFRSF14 across large subsets of human cancers. Finally, we observed that DCAF13 was highly expressed in a tissue microarray of lung cancer. In immunocompromised mouse models, xenograft growth of human lung cancer cells was significantly inhibited by DCAF13 knockdown. Our results highlighted the value of DCAF13 as a promising independent predictor of poor prognosis through numerous biological processes. High DCAF13 expression often predicts suppressive immune microenvironment and immunotherapy resistance in a pan‐cancer context.

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Section: Discussionmentioning

confidence: 99%

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

Wei

Xing

et al. 2023

The FASEB Journal

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“…Next, the cDNAs encoding the variable regions of the immunoglobulins produced by the hybridoma were cloned into a TA vector. The DNA sequences corresponding to the mouse monoclonal antibody (mAb) variable regions were analyzed by DNA sequencing after PCR amplification, as described previously [ 19 ]. The PCR products (5 μL) were checked by agarose gel electrophoresis and then recovered and purified using the NucleoSpin Gel & PCR Clean‐up kit, according to the manufacturer's instructions (#740609; Macherey‐Nagel, Düren, NRW, Germany).…”

Section: Methodsmentioning

confidence: 99%

Characterization of 405B8H3(D‐E), a newly engineered high affinity chimeric LAG‐3 antibody with potent antitumor activity

Lan

Yang²,

Wang³

et al. 2023

FEBS Open Bio

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Lymphocyte activation gene-3 (LAG-3) is a type I transmembrane protein with structural similarities to CD4. Overexpression of LAG-3 enables cancer cells to escape immune surveillance, while its blockade reinvigorates exhausted T cells and strengthens anti-infection immunity. Blockade of LAG-3 may have antitumor effects. Here, we generated a novel anti-LAG-3 chimeric antibody, 405B8H3(D-E), through hybridoma technology from monoclonal antibodies produced in mice. The heavy-chain variable region of the selected mouse antibody was grafted onto a human IgG4 scaffold, while a modified light-chain variable region was coupled to the human kappa light-chain constant region. 405B8H3(D-E) could effectively bind LAG-3-expressing HEK293 cells. Moreover, it could bind cynomolgus monkey (cyno) LAG-3 expressed on HEK293 cells with a higher affinity than the reference anti-LAG-3 antibody BMS-986016. Furthermore, 405B8H3(D-E) promoted interleukin-2 secretion and was able to block the interactions of LAG-3 with liver sinusoidal endothelial cell lectin and major histocompatibility complex II molecules. Finally, 405B8H3(D-E) combined with anti-mPD-1-antibody showed effective therapeutic potential in the MC38 tumor mouse model. Therefore, 405B8H3(D-E) is likely to be a promising candidate therapeutic antibody for immunotherapy. Triebel et al.[1] first discovered lymphocyte activation gene-3 (LAG-3) among molecules differentially expressed in interleukin-2 (IL-2)-dependent natural killer cells (NK). LAG-3 is composed of 525 amino acids, with four Ig-like domains, termed domain 1 (D1) to domain 4 (D4). The D1 region contains a proline-rich ring structure, which specifically binds to major histocompatibility complex II (MHC-II) molecules [2]. Like CD4, LAG-3 binds the MHC-II on antigen-presenting cells, but with a much stronger affinity, which effectively inhibit T-cell activation [2]. LAG-3 is expressed on CD4+ and CD8+ T cells,

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“…Chimeric antibodies were generated by, respectively, immunizing H2L2 transgenic mice (Harbor H2L2) with hCD137-ECD-Fc protein, HEK293-hCD137, and NIH3T3-hCD137 cell, and hybridoma developed as described [35]. The antibody titer in mice serum and hybridoma supernatant was measured by ELISA, flow cytometry, and luciferase reporter assay.…”

Section: Antibody Productionmentioning

confidence: 99%

Development and characterization of a novel human CD137 agonistic antibody with anti‐tumor activity and a good safety profile in non‐human primates

et al. 2022

Self Cite

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CD137 (4‐1BB, TNFRSF9), an inducible T‐cell costimulatory receptor, is expressed on activated T cells, activated NK cells, Treg cells, and several innate immune cells, including DCs, monocytes, neutrophils, mast cells, and eosinophils. In animal models and clinical trials, anti‐CD137 agonistic monoclonal antibodies have shown anti‐tumor potential, but balancing the efficacy and toxicity of anti‐CD137 agonistic monoclonal antibodies is a considerable hindrance for clinical applications. Here, we describe a novel fully human CD137 agonistic antibody (PE0116) generated from immunized harbor H2L2 human transgenic mice. PE0116 is a ligand blocker, which is also the case for Utomilumab (one of the leading CD137 agonistic drugs); PE0116 partially overlaps with Urelumab's recognized epitope. In vitro, PE0116 activates NF‐κB signaling, significantly promotes T‐cell proliferation, and increases cytokine secretion in the presence of cross‐linking. Importantly, PE0116 possesses robust anti‐tumor activity in the MC38 tumor model. In vivo, PE0116 exhibits a good safety profile and has typical pharmacokinetic characteristics of an IgG antibody in preclinical studies of non‐human primates. In summary, PE0116 is a promising anti‐CD137 antibody with a good safety profile in preclinical studies.

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Generation and characterization of a high‐affinity chimeric anti‐OX40 antibody with potent antitumor activity

Cited by 5 publications

References 38 publications

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

Characterization of 405B8H3(D‐E), a newly engineered high affinity chimeric LAG‐3 antibody with potent antitumor activity

Development and characterization of a novel human CD137 agonistic antibody with anti‐tumor activity and a good safety profile in non‐human primates

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