From Evasion to Elimination: Enhancing IgA therapy through myeloid checkpoint inhibition

Abstract

This thesis explores the potential of IgA antibodies in cancer treatment, presenting a promising alternative to the currently used IgG antibodies in immunotherapy. Although IgG antibodies have been the main antibody isotype used in cancer therapy due to their stability and long half-life, they are not effective for all patients, with some developing resistance. This highlights the urgent need for new therapeutic strategies. IgA antibodies, particularly in their monomeric form, offer a unique opportunity. They activate different immune cells, including neutrophils, through the Fc-alpha receptor (CD89). Neutrophils are abundant in the body and can be activated to strongly induce antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis, which lead to the destruction of cancer cells. However, IgA antibodies face challenges such as complex glycosylation, complicating large-scale production, and a shorter half-life compared to IgG. To address these challenges, we have modified IgA antibodies to improve their stability and production feasibility. This modified version, named IgA3.0, has shown promising results. In both in vitro experiments and mouse models, IgA3.0 antibodies demonstrated strong anti-tumor responses by effectively activating neutrophils upon binding to tumor antigens. Furthermore, we explored the optimal conditions for IgA therapy, revealing that IgA's effectiveness is highly dependent on the level of tumor antigens. A system allowing for the controlled expression of antigens on tumor cells indicated that higher antigen levels are necessary for IgA to be effective compared to IgG. This specificity could potentially lead to fewer side effects, as healthy cells with lower antigen levels would be less likely to be targeted. To address the limitation of IgA's shorter half-life, we investigated methods to extend it. We attached albumin or its DIII domain to IgA, leveraging albumin's ability to bind to the neonatal Fc receptor (FcRn) and undergo recycling, thus protecting the antibody from degradation. This modification successfully extended IgA's half-life without compromising its effectiveness. Furthermore, checkpoint molecules like CD47 on tumor cells inhibit immune responses by binding to SIRPα on myeloid cells, including neutrophils. Blocking this interaction can enhance the efficacy of IgA. Our research showed that combining IgA therapy with CD47 blockade significantly improved anti-tumor responses in vitro and in mouse models. This combination increased neutrophil infiltration and activity in the tumor microenvironment, leading to better tumor control. In conclusion, this thesis demonstrates that IgA antibodies can effectively recruit and activate neutrophils against cancer cells, offering a viable alternative to IgG-based therapies. By optimizing IgA and understanding which cancer types benefit most from neutrophil activation, this research aims to improve outcomes for patients who do not respond to existing treatments.