IgA anti-GD2 for the treatment of high-risk neuroblastoma

Marjolein Stip

In 2015 the antibody dinutuximab, directed against ganglioside GD2, was FDA-approved for neuroblastoma treatment. Dinutuximab significantly improved event-free survival in comparison to standard treatment. This antibody triggers neuroblastoma destruction by Complement Dependent Cytotoxicity (CDC) and Antibody Dependent Cellular Cytotoxicity (ADCC) as effector mechanisms. Intriguingly, dinutuximab mediated ADCC is mainly executed by granulocytes, while for most other therapeutic antibodies to solid tumors NK cells are the dedicated effector cells. In the case of neuroblastoma, dinutuximab therapy causes severe toxicity manifested as spontaneous intense visceral pain and perceived pain in response to light touch (allodynia), evoked by CDC on peripheral nerve fibers.

In this project, we intend to markedly improve the efficacy of dinutuximab therapy, while also resolving the severe CDC mediated toxicity. To achieve this we propose to convert dinutuximab to the IgA isotype, because 1) the absence of a C1q binding site on IgA makes it a poor activator of CDC, and 2) IgA is a more potent activator of granulocytes through the IgA receptor (FcαR), as we have shown recently for tumor-associated antigens like EGFR and HER2, and the hematological target CD20.

Our lab is in the unique position to carry out this research, since we have ample experience with the production and purification of IgA antibodies, but also testing IgA-based therapeutics in vitro and in the appropriate in vivo model, i.e. human FcgammaR transgenic mice. Our preliminary data show IgA dinutuximab is indeed superior to the currently used IgG isotype in killing (ADCC) of neuroblastoma cells with no CDC activity, likely to cause less or no side effects. In this project, we would like to expand our in vitro data to organoids and in vivo experiments. Furthermore, we plan to generate novel anti-neuroblastoma antibodies with the expertise of our UMAB facility.