Development of aGD2-SIRPα Fusion Antibodies Targeting Neuroblastoma and the Innate Immune Checkpoint Receptor CD47.
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Neuroblastoma is a childhood malignancy characterized by overexpression of disialoganglioside GD2. Treatment with anti-GD2 monoclonal antibodies (aGD2 mAb) has prolonged the survival of patients with neuroblastoma; however, long-term efficacy needs further improvement. Neuroblastoma tumor cells upregulate expression of the innate immune checkpoint and do not eat me signal CD47 to evade immune recognition and phagocytosis by signal regulatory protein alpha (SIRPα)-expressing myeloid cells. Targeting of CD47 remains challenging because ubiquitous CD47 expression on healthy cells causes on-target off-tumor related toxicities and functions as an antigen sink. To locally restrict CD47 blockade to the neuroblastoma tumor site, we successfully developed aGD2-SIRPα fusion mAbs for the murine and human setting. These fusion mAbs are equipped with a functional Fc-domain and the extracellular SIRPα domain 1 either fused to the N-terminus of the light chain or to the C-terminus of the heavy chain. Both aGD2-SIRPα fusion mAbs selectively bind neuroblastoma tumor cells and provide GD2-dependent SIRPα domain-mediated CD47 blockade. Furthermore, they potently induce innate immune effector mechanisms through the interaction of the mAbs Fc-domain with Fcγ receptors. Functional analysis of the fusion mAbs demonstrated enhanced phagocytosis and NK cell-mediated killing of neuroblastoma tumor cells compared with the conventional aGD2 mAb. In addition, these novel antibodies modulate the cytokine production by primary macrophages. The aGD2-SIRPα fusion mAbs outperformed aGD2 mAb across a broad range of CD47/GD2 coexpressing tumor cells. This research shows the successful development of aGD2-SIRPα fusion mAbs to provide targeted blockade of CD47 for the treatment of solid neuroblastoma tumors.