In vitro affinity maturation of human GM-CSF antibodies by targeted CDR-diversification

Steidl, Stefan; Ratsch, Olaf; Brocks, Bodo; Dürr, Manuela; Thomassen-Wolf, Elisabeth

doi:10.1016/j.molimm.2008.07.013

Cited by 81 publications

(76 citation statements)

References 57 publications

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“…There is evidence of B-cell anergy for soluble antigens at serum concentration of >0.1 nM (34). Even in inflammatory conditions like rheumatoid arthritis, GM-CSF is present in synovial fluid at <35 pM (31,35). One group has reported that the frequency of autoantibodies in normal subjects reaches 100% if cytokine-autoantibody complexes are dissociated at low pH before autoantibodies are measured against IL-2, granulocyte colony-stimulating factor (G-CSF), VEGF, TNF, IL-8 (32), and GM-CSF (33).…”

Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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Section: Discussionmentioning

confidence: 99%

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, we prepared fully human monoclonal anti-FGFR2IIIc antibody using HuCAL phage display technologies that have reported the usefulness and low toxicity in in vivo studies (31) and clinical trials (32,33). Administration of anti-FGFR2IIIc monoclonal antibody inhibited colorectal carcinoma cell growth and migration through the alteration of cell migration, cell death, and cell development-related genes.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor Receptor 2 IIIc as a Therapeutic Target for Colorectal Cancer Cells

Matsuda

Hagio

Seya

et al. 2012

Molecular Cancer Therapeutics

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A high percentage of colorectal carcinomas overexpress a lot of growth factors and their receptors, including fibroblast growth factor (FGF) and FGF receptor (FGFR). We previously reported that FGFR2 overexpression was associated with distant metastasis and that FGFR2 inhibition suppressed cell growth, migration, and invasion. The FGFR2 splicing isoform FGFR2IIIb is associated with well-differentiated histologic type, tumor angiogenesis, and adhesion to extracellular matrices. Another isoform, FGFR2IIIc, correlates with the aggressiveness of various types of cancer. In the present study, we examined the expression and roles of FGFR2IIIc in colorectal carcinoma to determine the effectiveness of FGFR2IIIc-targeting therapy. In normal colorectal tissues, FGFR2IIIc expression was weakly detected in superficial colorectal epithelial cells and was not detected in proliferative zone cells. FGFR2IIIc-positive cells were detected by immunohistochemistry in the following lesions, listed in the order of increasing percentage: hyperplastic polyps < low-grade adenomas < high-grade adenomas < carcinomas. FGFR2IIIc immunoreactivity was expressed in 27% of colorectal carcinoma cases, and this expression correlated with distant metastasis and poor prognosis. FGFR2IIIc-transfected colorectal carcinoma cells showed increased cell growth, soft agar colony formation, migration, and invasion, as well as decreased adhesion to extracellular matrices. Furthermore, FGFR2IIIc-transfected colorectal carcinoma cells formed larger tumors in subcutaneous tissues and the cecum of nude mice. Fully human anti-FGFR2IIIc monoclonal antibody inhibited the growth and migration of colorectal carcinoma cells through alterations in cell migration, cell death, and development-related genes. In conclusion, FGFR2IIIc plays an important role in colorectal carcinogenesis and tumor progression. Monoclonal antibody against FGFR2IIIc has promising potential in colorectal carcinoma therapy.

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“…10,11 Phage display selection of large antibody repertoires routinely results in a high number of hits recognizing the target of interest. 12,13 Thus, the identification of a lead candidate with the greatest possibility of success in clinical development requires extensive screening, as well as functional 14 and physico-chemical characterization. 15 Testing for binding specificity is typically done at multiple stages of the discovery process.…”

Section: Resultsmentioning

confidence: 99%