Humanized monoclonal antibody against parathyroid hormone-related protein suppresses osteolytic bone metastasis of human breast cancer cells derived from MDA-MB-231.
BACKGROUND
Parathyroid hormone-related protein (PTHrP) has been implicated in bone metastasis. However, the effects on bone metastasis of blocking the PTHrP function have not been tested in the clinic. Here, the effects of a humanized anti-PTHrP monoclonal antibody (mAb) on bone metastasis in a human xenograft model are shown.


METHODS
Subline MDA-5a, with high bone metastatic activity, was established from the human breast cancer cell line MDA-MB-231. Mice were injected with MDA-5a and an anti-PTHrP monoclonal antibody (mAb) raised against human PTHrP (1-34); bone metastasis was evaluated by X-ray photography.


RESULTS
MDA-5a produced elevated levels of PTHrP, Interleukin 8 (IL-8), IL-6 and matrix metalloproteinase 1 (MMP-1) and frequently metastasized to the bone. Administration of the humanized anti-PTHrP mAb significantly suppressed osteolytic bone metastasis of MDA-5a and caused osteogenesis at the sites of metastasis.


CONCLUSIONS
The humanized anti-PTHrP mAb was effective against bone metastasis by inducing osteogenesis and, therefore, will provide a new treatment option for bone metastasis in breast cancer.
Saito
Hidemi
H
Pharmaceutical Research Department III, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247-8530, Japan.
Tsunenari
Toshiaki
T
Onuma
Etsuro
E
Sato
Koh
K
Ogata
Etsuro
E
Yamada-Okabe
Hisafumi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D007378:Interleukins; D044162:Parathyroid Hormone-Related Protein; D020781:Matrix Metalloproteinase 1