Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma

Abstract

BackgroundOsteosarcoma 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 ResultsA 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.ConclusionOur results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies.

METCAM/MUC18 Promotes Tumor Progression and Metastasis in Most Human Cancers

“…Furthermore, ABX-MA1 reduced the in vitro invasiveness of osteosarcoma cells in the Matrigel-coated trans-well assay and disturbed the homotypic adhesion among osteosarcoma cells and the heterotypic interaction of them with vascular endothelial cells. Osteosarcoma is effectively treated with anti-METCAM/MUC18 monoclonal antibodies [73][74]. Taken together, METCAM/MUC18 plays a positive role in the metastasis of osteosarcoma [72][73][74].…”

“…Osteosarcoma is effectively treated with anti-METCAM/MUC18 monoclonal antibodies [73][74]. Taken together, METCAM/MUC18 plays a positive role in the metastasis of osteosarcoma [72][73][74].…”

“…In summary, the positive role played by the METCAM/MUC18 in the progression of solid tumors has been extended from breast cancer, human and mouse melanoma, and prostate cancer to angiosarcoma [40,59], gastric cancer [60], glioblastoma [61], hepatocellular carcinoma [63,64], non-small cell lung adenocarcinoma [65][66][67][68][69][70], small cell lung cancer [71], osteosarcoma [72][73][74], human and mouse pancreatic cancer [75,76], and prostate cancer [32][33][34][35][36]58]. Taken together, METCAM/MCU18 appears to be more prevalently playing a positive role than a negative role in the tumor formation and/or cancer metastasis of various tumors/ cancers.…”

“…Since the huMETCAM/MUC18 was first discovered in the 1980s, three groups have worked on the role of huMETCAM/MUC18 in melanoma metastasis [38,39,55,56], another group on the role of huMETCAM/MUC18 in the biology of endothelial cells [41,83], and one group on breast cancer [45], and our group joined in the effort to study the role of huMETCAM/MUC18 in the progression of mouse melanoma [43] and prostate cancer [31][32][33][34][35][36] and later breast cancer [18][19][20], ovarian cancer [27][28][29][30], and NPC [23][24][25][26], as described above. Recently, more research groups have participated in further exploring the possible role of METCAM/MUC18 in other solid tumors in different organs, such as the colorectum [77], gastro-organ [60], glial cells [61], liver [63,64], lung [65][66][67][68][69][70][71], bone [72][73][74], and pancreas [75,76,81]. Furthermore, preliminary work in leiomyosarcoma, esophagus squamo...…”

METCAM/MUC18: A Novel Tumor Suppressor for Some Cancers

“…METCAM/MUC18 is expressed in osteosarcoma cell lines, but not in normal osteoblast cells [67]. Osteosarcoma is effectively treated with METCAM/MUC18 monoclonal antibodies [68,69]. Transcription factor MEIS1 activates METCAM/MUC18 expression to promote migration of mouse pancreatic tumor cell lines [70].…”