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Updated: Feb 20, 2026
Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
Enhancing NK Cell Activity in Colorectal Cancer with an Fc-Optimized Antibody Targeting CD276 (B7-H3)
Sylwia A Stefańczyk1,2,3, Xenija Kaiser1,2,3, Ilona Hagelstein1,2,3
1Clinical Collaboration Unit Translational Immunology, Department of Internal Medicine, University Hospital of Tübingen, Tübingen, Germany.
Background & Aims:
Colorectal cancer (CRC) represents a major global health burden due to its high incidence and mortality, particularly in the advanced stages, with limited treatment options. While therapies that block the PD-1/PD-L1 pathway have demonstrated clinical benefit, their success in CRC is largely confined to patients with high microsatellite instability (MSI-H) tumors. Innovative immunotherapeutic solutions are critically needed for the majority of CRC cases. CD276 (B7-H3), a B7 family immune checkpoint molecule, is overexpressed in many cancers including CRC. Significant CD276 upregulation in CRC cell lines compared to benign tissues has been previously demonstrated. In this study, the potential of an Fc-optimized anti-CD276 monoclonal antibody to enhance natural killer (NK) cell activity in CRC was evaluated.
Methods:
An Fc-optimized monoclonal antibody, 8H8_SDIE, was developed to enhance NK cell activity by increasing CD16 binding. In vitro experiments were conducted using human CRC cell lines and peripheral blood mononuclear cells (PBMCs) from healthy adult donors to evaluate the binding specificity of 8H8_SDIE to CD276. NK cell activation was assessed by measuring the upregulation of activation markers (CD69, CD25, and CD107a) and secretion of cytotoxic mediators (IFNγ, granzyme B, and perforin). Cytotoxicity assays were performed to determine NK cell-mediated tumor cell lysis.
Results:
8H8_SDIE specifically bound to CD276-positive CRC cells and significantly enhanced NK cell activation. These effects included increased levels of activation and cytotoxic mediators. In cytotoxicity assays, 8H8_SDIE demonstrated potent NK cell-mediated lysis of CRC cells.
Conclusion:
The Fc-optimized anti-CD276 antibody 8H8_SDIE effectively enhanced NK cell reactivity against CD276-positive CRC cells and induced tumor cell lysis in vitro. These findings suggest that 8H8_SDIE holds potential as a novel immunotherapeutic candidate for CRC, particularly for patients with microsatellite-stable disease, and warrants further evaluation in advanced preclinical and future clinical studies.
Insights
An Fc-optimized anti-CD276 antibody (8H8_SDIE) enhances natural killer (NK) cell activity against colorectal cancer (CRC) cells in vitro. This novel immunotherapy shows promise for treating microsatellite-stable CRC, warranting further investigation.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Colorectal cancer (CRC) poses a significant global health challenge, especially in advanced stages with limited treatment options.
- Current immunotherapies like PD-1/PD-L1 inhibitors are effective mainly for microsatellite instability-high (MSI-H) CRC.
- CD276 (B7-H3) is an immune checkpoint molecule overexpressed in CRC, presenting a potential therapeutic target.
Purpose of the Study:
- To evaluate an Fc-optimized anti-CD276 monoclonal antibody (8H8_SDIE) for its ability to enhance natural killer (NK) cell activity in colorectal cancer.
- To assess the binding specificity and NK cell activation potential of 8H8_SDIE against CD276-positive CRC cells.
Main Methods:
- Development of an Fc-optimized anti-CD276 antibody (8H8_SDIE) designed to improve CD16 binding.
- In vitro experiments using human CRC cell lines and healthy donor peripheral blood mononuclear cells (PBMCs).
- Assessment of NK cell activation markers, cytotoxic mediators, and tumor cell lysis induced by 8H8_SDIE.
Main Results:
- 8H8_SDIE demonstrated specific binding to CD276-expressing CRC cells.
- Significant enhancement of NK cell activation, including increased expression of activation markers and secretion of cytotoxic mediators.
- Potent NK cell-mediated lysis of colorectal cancer cells was observed in vitro.
Conclusions:
- The Fc-optimized anti-CD276 antibody 8H8_SDIE effectively boosts NK cell reactivity against CD276-positive CRC cells.
- 8H8_SDIE shows potential as a novel immunotherapeutic agent for colorectal cancer, particularly for microsatellite-stable disease.
- Further preclinical and clinical studies are warranted to explore the therapeutic potential of 8H8_SDIE in CRC treatment.
