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Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs
Gigi N C Chiu1, Lincoln A Edwards, Anita I Kapanen
1Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. phacncg@nus.edu.sg
Abstract:
Various methods have been explored to enhance antibody-based cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-kappaB, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/antibody complex.
Insights
Researchers developed multivalent antibodies on liposomes to boost cancer therapy. This liposome technology significantly enhanced antibody potency and antitumor activity by cross-linking target antigens, offering a promising approach for cancer treatment.
Area of Science:
- Biotechnology
- Immunology
- Oncology
Background:
- Antibody-based cancer therapies aim to enhance treatment efficacy through various strategies.
- Multivalent antibodies, which bind to multiple target antigens simultaneously, show potential for improved cellular signaling and therapeutic outcomes.
- Extensive cross-linking of antibody-target complexes can trigger or enhance crucial cellular signals like apoptosis and inhibit cell growth.
Purpose of the Study:
- To develop novel multivalent antibody constructs by immobilizing antibodies onto liposome membranes.
- To enhance the therapeutic activity of antibodies, specifically trastuzumab and rituximab, through a liposomal formulation.
- To investigate the impact of multivalent antibody presentation on cell survival signaling pathways and in vivo antitumor efficacy.
Main Methods:
- Antibody molecules (trastuzumab, rituximab) were grafted onto liposome membranes to create multivalent constructs.
- Cell viability assays were performed to quantify the potency of the liposomal antibody formulations.
- Western blotting was used to analyze the modulation of key cell survival signaling molecules (e.g., phosphorylated Akt, NF-κB).
Main Results:
- The multivalent liposomal antibody formulations demonstrated up to a 25-fold increase in potency compared to unconjugated antibodies in cell viability assays.
- Treatment with multivalent liposomal trastuzumab and rituximab led to the down-regulation of key cell survival signaling molecules.
- Liposomal trastuzumab exhibited potent in vivo antitumor activity in preclinical models.
Conclusions:
- Liposome technology provides a viable platform for creating multivalent antibody constructs with enhanced therapeutic potential.
- The enhanced antibody activity is mediated by the clustering of target/antibody complexes, leading to modulation of cell survival pathways.
- This approach holds significant promise for improving antibody-based cancer therapies.
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