Laboratory studies in the PhD research project by Chilam Chan (UMC Utrecht) show that immunoglobulin A (IgA)-based antibodies can effectively activate neutrophils to fight cancer, and offers a promising alternative for patients who do not respond to IgG-based monoclonal antibodies in the treatment of cancer.
Monoclonal antibodies play an important role in recognizing and eradicating cancer and have demonstrated efficacy in both hematological and solid tumors. This success has resulted in more than 100 monoclonal antibody-based immunotherapy drugs – all based on immunoglobulin G (IgG) – now approved for cancer therapy. The PhD thesis of Chilam Chan (Center for Translational Immunology, UMC Utrecht) investigated the use of IgA antibodies as a new approach in cancer treatment, offering an alternative to IgG antibodies currently used in immunotherapy. While IgG antibodies are widely used due to their stability and long half-life, they are not effective for everyone, and some patients develop resistance, highlighting the need for new treatment modalities. IgA antibodies, particularly in their monomeric form, offer distinct advantages by activating a different type of immune cells as compared to regular immune therapy, that are neutrophils, through the Fc-α receptor (CD89). Neutrophils, the most abundant immune cell in the body, can kill cancer cells when activated. However, producing IgA antibodies on a large scale is challenging due to stability issues and their complex structure, and IgA has a short half-life.
To overcome these challenges, Chilam Chan and colleagues developed a modified IgA antibody, called IgA3.0, which is more stable and easier to produce and has a longer half-life. IgA3.0 showed strong anti-cancer responses in their experiments by effectively activating neutrophils. Additionally, research showed that IgA works best when tumor cells have high levels of specific tumor antigens, potentially reducing side effects by sparing healthy cells.
Furthermore, checkpoint molecules like CD47 on tumor cells inhibit immune responses by binding to SIRPα on myeloid cells, including neutrophils. Chilam’s research showed that combining IgA therapy with CD47 blockade significantly improved anti-tumor responses. This combination increased neutrophil infiltration and activity in the tumor microenvironment, leading to better tumor suppression in various cancer cell lines and a preclinical neuroblastoma mouse model. In addition, this combination treatment was also efficacious in vitro when added to tumor cells from pediatric patients with Non-Hodgkin Lymphoma. Therefore, blocking of myeloid checkpoint molecules is a promising strategy to enhance the efficacy of IgA and deserves further research.
In summary, the work by Chilam Chan shows that IgA antibodies can effectively activate neutrophils to fight cancer, offering a promising alternative for patients who do not respond to current IgG-based anticancer therapies. In 2018, the spin-off company TigaTx was started from UMC Utrecht by Jeanette Leusen PhD (professor of Antibody Therapy, UMC Utrecht) to bring IgA to the clinic. This company has now moved to Boston MA (USA), and expects to receive a large grant soon to start GMP production and develop clinical trials in oncology.
Chilam Chan, MSc (1994, Delfzijl) defended her PhD thesis on September 11, 2024 at Utrecht University. The title of her thesis was “From Evasion to Elimination: Enhancing IgA therapy through myeloid checkpoint inhibition”. Supervisor was prof. Jeanette Leusen PhD and co-supervisor was Geert van Tetering PhD (both Center for Translational Immunology, UMC Utrecht). Chilam will continue her career as a post-doctoral researcher.
