Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors
Daniel V Kalinovsky1, Alexey V Kibardin2, Irina V Kholodenko3
1Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
Background:
Both ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) have demonstrated clinical success as solid tumor therapies in recent years, yet no research has been carried out to develop anti-GD2 ADCs against solid tumors. This is the first study to analyze cytotoxic activity of clinically relevant anti-GD2 ADCs in a wide panel of cell lines with varying GD2 expression and their effects in mouse models of GD2-positive solid cancer.
Methods:
Anti-GD2 ADCs were generated based on the GD2-specific antibody ch14.18 approved for the treatment of neuroblastoma and commonly used drugs monomethyl auristatin E (MMAE) or F (MMAF), conjugated via a cleavable linker by thiol-maleimide chemistry. The antibody was produced in a mammalian expression system, and its specific binding to GD2 was analyzed. Antigen-binding properties and biodistribution of the ADCs in mice were studied in comparison with the parent antibody. Cytotoxic effects of the ADCs were evaluated in a wide panel of GD2-positive and GD2-negative tumor cell lines of neuroblastoma, glioma, sarcoma, melanoma, and breast cancer. Their antitumor effects were studied in the B78-D14 melanoma and EL-4 lymphoma syngeneic mouse models.
Results:
The ch14.18-MMAE and ch14.18-MMAF ADCs retained antigen-binding properties of the parent antibody. Direct dependence of the cytotoxic effect on the level of GD2 expression was observed in cell lines of different origin for both ADCs, with IC50 below 1 nM for the cells with high GD2 expression and no cytotoxic effect for GD2-negative cells. Within the analyzed cell lines, ch14.18-MMAF was more effective in the cells overexpressing GD2, while ch14.18-MMAE had more prominent activity in the cells expressing low GD2 levels. The ADCs had a similar biodistribution profile in the B78-D14 melanoma model compared with the parent antibody, reaching 7.7% ID/g in the tumor at 48 hours postinjection. The average tumor size in groups treated with ch14.18-MMAE or ch14.18-MMAF was 2.6 times and 3.8 times smaller, respectively, compared with the control group. Antitumor effects of the anti-GD2 ADCs were also confirmed in the EL-4 lymphoma model.
Conclusion:
These findings validate the potential of ADCs targeting ganglioside GD2 in treating multiple GD2-expressing solid tumors.
Insights
This study developed antibody-drug conjugates (ADCs) targeting ganglioside GD2, demonstrating potent anti-tumor activity in preclinical models. These GD2-targeted ADCs show promise for treating various solid cancers expressing GD2.
Area of Science:
- Oncology
- Immunotherapy
- Drug Development
Background:
- Ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) show clinical success in solid tumors.
- No prior research explored anti-GD2 ADCs for solid tumors.
Purpose of the Study:
- To analyze the cytotoxic activity of clinically relevant anti-GD2 ADCs.
- To evaluate the effects of anti-GD2 ADCs in mouse models of GD2-positive solid cancer.
Main Methods:
- Generated anti-GD2 ADCs using the ch14.18 antibody and MMAE or MMAF drugs.
- Assessed ADCs' antigen-binding, biodistribution, and cytotoxic effects in diverse GD2-expressing cell lines.
- Evaluated antitumor effects in syngeneic mouse models of melanoma and lymphoma.
Main Results:
- ADCs retained antibody binding; cytotoxic effects correlated with GD2 expression levels (IC50 < 1 nM for high GD2).
- ch14.18-MMAF was more effective in high GD2-expressing cells, ch14.18-MMAE in low GD2-expressing cells.
- ADCs showed favorable tumor biodistribution and significantly reduced tumor size in mouse models.
Conclusions:
- Anti-GD2 ADCs demonstrate potent and specific cytotoxic activity against GD2-expressing tumor cells.
- These findings validate the therapeutic potential of anti-GD2 ADCs for various solid tumors.
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