The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells
Open accessAbstract
Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.
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The hybrid rat/mouse Fc portion efficiently interacted with activating human Fc receptors FcγRI and FcγRIII, but not with inhibitory FcγRIIB.
“Surprisingly, the resulting hybrid rat/mouse Fc portion efficiently interacted with activating human Fc receptors (FcγRI and FcγRIII), but not inhibitory ones (FcγRIIB), thereby reaching the goal that other groups had hoped to achieve using human Fc engineering. 22,23”
From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [22]
An anti-CD3 x anti-EpCAM bispecific antibody created with this approach was capable of binding target cells and human T cells, activating dendritic cells, inducing NK-dependent ADCC, and stimulating tumor cell phagocytosis by macrophages.
“The investigators used this approach to create an anti-CD3 x anti-EpCAM bsAb, and demonstrated that this antibody was capable of binding to target cells and human T cells, but was also capable of activating dendritic cells (DC), inducing NK-dependent ADCC and stimulating tumor cell phagocytosis by macrophages. 22,23”
From Bispecific antibodies for cancer therapy: The light at the end of the tunnel? (2009) · cites this paper as [22]
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Self-citation
- Authors
- Zeidler, R., Mysliwietz, J., Csánady, M., Walz, A., Ziegler, I., Schmitt, B., Wollenberg, B., & Lindhofer, H.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Helmholtz Munich (DE)
- Venue
- British Journal of Cancer
- Published
- 2000-07
- Volume
- 83
- Issue
- 2
- Pages
- 261-266
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2363488
- OpenAlex
- W1918654887
- Cited by
- 189
- References
- 30
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 11 · 2015: 11 · 2014: 18 · 2013: 15 · 2012: 12
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- bispecific antibodies, Fc fragment, Fc gamma receptor, accessory cells, natural killer cells, cancer cells, CD64, CD16, CD83, Fas, neopterin, biopterin, minimal residual disease, antitumor immunity
- MeSH terms
- Antigen-Presenting Cells, Biopterins, Dendritic Cells, Humans, Immunoglobulin Fc Fragments, Killer Cells, Natural, Macrophages, Monocytes, Phagocytosis, Recombinant Fusion Proteins, Tumor Cells, Cultured, Antigens, Tumor-Associated, Carbohydrate, Up-Regulation, CD3 Complex, Antibodies, Bispecific, Lipopolysaccharide Receptors, Neopterin, In Vitro Techniques
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