The relevance of tumor target expression levels on IgA-mediated cytotoxicity in cancer immunotherapy.

Recent advances in cancer immunotherapy, particularly the success of immune checkpoint inhibitors, have reignited interest in targeted monoclonal antibodies for immunotherapy. Antibody therapies aim to minimize on-target, off-tumor toxicity by targeting antigens overexpressed on tumor cells but not on healthy cells. Despite considerable efforts, some therapeutic antibodies have been linked to dose-limiting side effects.

Enhancing IgA-mediated neutrophil cytotoxicity against neuroblastoma by CD47 blockade.

Background: Approximately half of the neuroblastoma patients develop high-risk neuroblastoma. Current treatment involves a multimodal strategy, including immunotherapy with dinutuximab (IgG ch14.18) targeting GD2.

IgA antibody immunotherapy targeting GD2 is effective in preclinical neuroblastoma models.

Background: Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic pain by binding GD2-expressing sensory neurons. Previously, the IgG1 ch14.18 (dinutuximab) antibody was reformatted into the IgA1 isotype, which abolishes neuropathic pain and induces efficient neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) via activation of the Fc alpha receptor (FcαRI/CD89).

Sialic Acids on Tumor Cells Modulate IgA Therapy by Neutrophils via Inhibitory Receptors Siglec-7 and Siglec-9.

Immunotherapy with targeted therapeutic antibodies is often ineffective in long-term responses in cancer patients due to resistance mechanisms such as overexpression of checkpoint molecules. Similar to T lymphocytes, myeloid immune cells express inhibitory checkpoint receptors that interact with ligands overexpressed on cancer cells, contributing to treatment resistance. While CD47/SIRPα-axis inhibitors in combination with IgA therapy have shown promise, complete tumor eradication remains a challenge, indicating the presence of other checkpoints.

Corrigendum: Targeting myeloid checkpoint molecules in combination with antibody therapy: A novel anti-cancer strategy with IgA antibodies?

[This corrects the article DOI: 10.3389/fimmu.2022.