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Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity
Laurent Gauthier1, Ariane Morel1, Nadia Anceriz1
1Innate Pharma, Marseille, France.
Abstract:
Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer. VIDEO ABSTRACT.
Insights
New trifunctional natural killer cell engagers (NKCEs) show potent anti-tumor activity. These novel molecules effectively target cancer cells and activate NK cells, offering a promising new strategy for cancer immunotherapy with reduced toxicity.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Developing therapies to enhance anti-tumor immunity is crucial.
- Bispecific T-cell engagers face challenges like toxicity.
- Novel strategies are needed for effective cancer immunotherapy.
Purpose of the Study:
- To generate and evaluate trifunctional natural killer cell engagers (NKCEs).
- To assess the efficacy and safety of NKCEs in preclinical cancer models.
Main Methods:
- Generation of trifunctional NKCEs targeting NKp46, CD16, and tumor antigens.
- In vitro potency assays comparing NKCEs with existing antibodies.
- In vivo studies in mouse models to evaluate pharmacokinetics, off-target effects, and tumor control.
Main Results:
- Trifunctional NKCEs demonstrated superior in vitro potency compared to clinical antibodies.
- NKCEs exhibited favorable in vivo pharmacokinetics and no off-target effects.
- Efficient control of solid and invasive tumor growth was observed in mouse models.
Conclusions:
- Trifunctional NKCEs represent a novel class of molecules for cancer treatment.
- These engagers offer a promising approach to enhance anti-tumor immunity.
- NKCEs show potential for improved cancer immunotherapy with reduced toxicity.
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