Osteoporosis (OP), including postmenopausal Osteoporosis (PMO) and senile osteoporosis, is a systemic disorder of bone metabolism, characterized by low bone mass and degradation of bone microstructure, resulting in decreased bone strength, increased bone fragility, and susceptibility to fracture. According to statistics, about 200 million people in the world suffer from osteoporosis, and the incidence rose into the top seven most common diseases and frequently occurring diseases. The prevalence rate of osteoporosis in Chinese females over 60 years old is as high as 60%, and the prevalence rate for males is also 40-50%.
In addition to strengthening exercise, taking calcium and vitamin D, the spread of knowledge for fracture prevention and other traditional measures, the current medical treatment is mainly limited to reducing bone absorption to prevent fracture. The anti-bone absorption drugs include calcitonin, bisphosphonates, estrogen replacement agents and selective estrogen receptor modulators (SERMs), etc. These bone absorption inhibitors, which are represented by bisphosphonates, can prevent further bone loss, but fail to reconstruct the lost bone. Also, these bone absorption inhibitors fail to inhibit osteogenesis while inhibiting bone absorption. Hormonal drugs have more risks and are associated with venous thrombosis and cardiovascular disease. More importantly, bone anabolic drugs, in their true sense, not only improve bone mass, but also effectively improve the bone microstructure and promote osteogenesis. However, this is precisely what the existing anti-bone absorption drugs cannot do. In the past 15 years, various medical measures aiming at reducing fracture risk have been systematically investigated in clinical trials, while the actual available drugs are still quite limited. So far, only parathyroid hormone (PTH) drugs have been proven to stimulate osteogenesis. However, many disadvantages are known. For example, it is not a lasting solution for the purpose of bone remodeling and has little effect on fracture repair. It also needs to be percutaneously administered every day for more than one year, and only administered in a low-dose; is high cost and cannot be continuously used for more than two years; and its safety exposure resulted in a black-box warning from the US FDA, etc.
Sclerostin serves as a new biological target for drug development, and the principle is that osteoporosis could be treated by regulating anabolism of osteoblasts. Such a target fills a gap in the field of treating osteoporosis by regulating bone metabolism.
Sclerostin is a secretory glycoprotein expressed by the SOST gene, and its amino acid sequence is characterized by 190 residues and a hoop domain containing cysteine. It has been shown that it is mainly expressed in bone cells, with very low expression in osteoblasts, cartilage, liver, kidney, bone marrow, heart, pancreas and other locations.
Studies have shown that sclerotin can regulate osteogenesis through inhibiting the Wnt signaling pathway by binding to low-density lipoprotein receptor LRP5/6. At present, monoclonal antibody drugs against this target developed by several companies have entered phase III or II clinical trials, respectively. The indications of these antibodies are osteoporosis, bone damage/related osteopathy, and so on. Related patents include: WO2008133722, WO2010130830, WO2013063095, WO2014006100, WO2014081955, WO2005014650, WO2006119062, and WO2008115732. It is worth mentioning that some studies have shown that anti-sclerostin antibodies are not in conflict with treatment using traditional bisphosphonates, and these two drugs may be used in combination.
The present invention provides novel antibodies developed against a new target for the treatment of bone diseases such as osteoporosis, the antibody being characterized by high affinity, high efficacy, extended half-life and a reduced number of administrations. In addition, the novel molecules of the present invention have high solubility and good stability, which makes it easier to produce a preparation, thereby reducing production costs.