Development and characterization of human monoclonal antibodies that neutralize multiple TGFβ isoforms
Open accessAbstract
Transforming growth factor (TGF)β levels are elevated in, and drive the progression of, numerous disease states such as advanced metastatic cancer and systemic and ocular fibrosis. There are 3 main isoforms, TGFβ1, 2, and 3. As multiple TGFβ isoforms are involved in disease processes, maximal therapeutic efficacy may require neutralization of 2 or more of the TGFβ isoforms. Fully human antibody phage display libraries were used to discover a number of antibodies that bind and neutralize various combinations of TGFβ1, 2 or 3. The primary panning did not yield any uniformly potent pan-isoform neutralizing antibodies; therefore, an antibody that displayed potent TGFβ 1, 2 inhibition, but more modest affinity versus TGFβ3, was affinity matured by shuffling with a light chain sub-library and further screening. This process yielded a high affinity pan-isoform neutralizing clone. Antibodies were analyzed and compared by binding affinity, as well as receptor and epitope competition by surface plasmon resonance methods. The antibodies were also shown to neutralize TGFβ effects in vitro in 3 assays: 1) interleukin (IL)-4 induced HT-2 cell proliferation; 2) TGFβ-mediated IL-11 release by A549 cells; and 3) decreasing SMAD2 phosphorylation in Detroit 562 cells. The antibodies' potency in these in vitro assays correlated well with their isoform-specific affinities. Furthermore, the ability of the affinity-matured clone to decrease tumor burden in a Detroit 562 xenograft study was superior to that of the parent clone. This affinity-matured antibody acts as a very potent inhibitor of all 3 main isoforms of TGFβ and may have utility for therapeutic intervention in human disease.
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Eli Lilly's TGF-β1-specific neutralizing antibody, developed for renal fibrosis, did not show clinical benefit in a small biomarker study of patients with metastatic cancer.
“In contrast, Eli Lilly’s TGF-β1-specific neutralizing antibody, developed for renal fibrosis, did not show clinical benefit in a small biomarker study of patients with metastatic cancer303.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [303]
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- Authors
- Bedinger, D., Lao, L., Khan, S., Lee, S., Takeuchi, T., & Mirza, A. M.
- Affiliations
- XOMA (United States) (US)
- Corresponding author
- Mirza, Amer M.
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2016-01-20
- Volume
- 8
- Issue
- 2
- Pages
- 389-404
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC4966579
- OpenAlex
- W2251943031
- Cited by
- 42
- References
- 62
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 7 · 2019: 1 · 2017: 1 · 2016: 1 · 2015: 1
- FWCI
- 0.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mAbs (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TGF-beta isoforms, TGF-β1, TGF-beta2, TGF-beta3, monoclonal antibodies, affinity maturation, phage display, Smad2 phosphorylation, TGF-beta receptor, tumor xenografts, fibrosis, metastatic cancer
- MeSH terms
- Animals, Antibodies, Monoclonal, Antibodies, Neoplasm, Antibody Affinity, Antibody Specificity, Humans, Mice, Nude, Transforming Growth Factor beta, Protein Isoforms, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Antibodies, Neutralizing
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