Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma
Sara Westrøm1,2,3, Tina B Bønsdorff1, Nasir Abbas1
1Oncoinvent AS, Oslo, Norway.
Background:
Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo.
Methods And Results:
A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of 125I-labeled OI-3 antibody variants was compared with 125I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI-3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, 177Lu, and their biodistributions were studied in the nude mouse model. The 177Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant.
Conclusion:
Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies.
Insights
New radiolabeled antibodies targeting CD146 show promise for osteosarcoma treatment. These OI-3 antibody variants effectively target CD146-expressing tumors in vivo, offering a potential new therapy for metastatic osteosarcoma.
Area of Science:
- Oncology
- Immunotherapy
- Radiopharmaceuticals
Background:
- Osteosarcoma necessitates novel targeted therapies, especially for metastatic disease.
- Antibody conjugates offer a strategy to target osteosarcoma metastases and circulating tumor cells.
- CD146 is a potential therapeutic target on osteosarcoma cells.
Purpose of the Study:
- To evaluate a novel radiolabeled monoclonal antibody targeting CD146 (OI-3) for osteosarcoma.
- To assess the in vitro and in vivo efficacy of OI-3 antibody variants.
- To compare OI-3 targeting with an existing antibody (cetuximab).
Main Methods:
- Development of murine and chimeric anti-CD146 (OI-3) antibodies.
- Flow cytometry to confirm CD146 expression on osteosarcoma cell lines.
- Biodistribution studies of radiolabeled OI-3 variants (125I and 177Lu) in mice with osteosarcoma xenografts.
- Comparison with radiolabeled anti-EGFR antibody (cetuximab).
Main Results:
- OI-3 selectively bound to human osteosarcoma cells, showing higher CD146 expression than HER2/EGFR.
- 125I-labeled OI-3 demonstrated in vivo tumor targeting with improved ratios compared to cetuximab.
- 177Lu-labeled OI-3 variants showed stable and therapeutically relevant biodistribution.
- Dosimetry indicated a higher absorbed radiation dose to the tumor with the chimeric IgG1 OI-3 variant.
Conclusions:
- CD146 is a viable in vivo target for osteosarcoma using radiolabeled OI-3 antibodies.
- The study supports the potential of CD146-targeted radionuclide therapy for osteosarcoma.
