Development of aGD2-SIRPα Fusion Antibodies Targeting Neuroblastoma and the Innate Immune Checkpoint Receptor CD47
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Fabian Schuurmans1, Anja Wittner2, Renske J E van den Bijgaart1
1Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
Abstract:
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.
Insights
Researchers developed novel anti-GD2-SIRPα fusion antibodies to target neuroblastoma (NB) by blocking CD47. This approach enhances immune cell targeting of NB tumors while minimizing off-tumor toxicities for improved childhood cancer treatment.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Neuroblastoma (NB) is a childhood cancer overexpressing disialoganglioside GD2, with anti-GD2 monoclonal antibodies (aGD2 mAbs) improving survival but needing enhanced efficacy.
- NB tumors evade immune detection by upregulating CD47, an "don't eat me" signal that interacts with Signal regulatory protein alpha (SIRPα) on myeloid cells.
- Targeting CD47 is difficult due to its presence on healthy cells, causing toxicities and acting as an antigen sink.
Purpose of the Study:
- To develop a novel therapeutic strategy for neuroblastoma by creating fusion antibodies that specifically target GD2-expressing NB cells and block CD47 at the tumor site.
- To investigate the efficacy of these novel aGD2-SIRPα fusion mAbs in enhancing innate immune responses against NB tumors.
Main Methods:
- Engineered aGD2-SIRPα fusion mAbs by incorporating the SIRPα extracellular domain 1 with a functional Fc-domain.
- Assessed the binding specificity and CD47 blockade capability of the fusion mAbs on NB cells.
- Evaluated the fusion mAbs' ability to induce phagocytosis and NK cell-mediated killing, and modulate cytokine production in macrophages.
Main Results:
- The aGD2-SIRPα fusion mAbs selectively bind NB cells and mediate CD47 blockade in a GD2-dependent manner.
- Fusion mAbs demonstrated enhanced phagocytosis and NK cell-mediated tumor cell killing compared to conventional aGD2 mAbs.
- These novel antibodies modulated cytokine production by macrophages and outperformed aGD2 mAb against CD47/GD2 co-expressing tumor cells.
Conclusions:
- Successfully developed aGD2-SIRPα fusion mAbs for targeted CD47 blockade in neuroblastoma.
- These fusion antibodies offer a promising strategy to overcome immune evasion in solid NB tumors.
- The findings support the potential of localized CD47 blockade for improved neuroblastoma treatment outcomes.
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