Osteoporesis

Development of A humanized OPN blockade
antibody immunotherapy for Osteoporesis

A. Intellectual Property

US patent 62/944,777: Osteopontin Monoclonal Antibodies for Cancer and Osteoporosis Immunotherapy.

B. Osteoporesis

B1. Osteoporosis is the most common chronic metabolic bone disease in humans.
Osteoporosis is characterized by low bone mass and increased bone fragility. It occurs in all age groups, gender, and races 1, but is more frequently in postmenopausal women and increases with aging. It is estimated that 40% postmenopausal women and 20% men 50 years and older will experience an osteoporotic fracture at some point in their life 2, 3. With an aging population and longer life span, osteoporosis is increasingly becoming a public health risk.

B2. Neutralization antibody immunotherapy represents a new class of treatment for osteoporosis. Bone mineral density is determined by the dynamic metabolic balance: new bone mineral deposition by osteoblasts and existing bone resorption by osteoclasts. Dysregulation of this metabolic balance leads to osteoporosis 4. Bisphosphonates (e.g., alendronate and pamidronate) and selective estrogen receptor modulators (e.g., raloxifene), are the most commonly used drugs for osteoporosis 5. However, the mild to severe adverse effects limit their use in the clinic 1, 5. Neutralization antibodies have emerged as a new class of drugs for osteoporosis. RANKL-blockade monoclonal antibody Denosumab is effective in inhibiting osteoclast activation and can therefore prevent bone loss 6, 7. The FDA has recently approved Romosozumab, a humanized monoclonal antibody that neutralizes the bone regulator sclerostin, for osteoporosis in postmenopausal women with a high risk of fracture 8.

B3. Osteopontin (OPN) is a key regulator of osteoporosis. Osteopontin (OPN) is a secreted protein that binds to CD44 and integrin receptors to regulate various biological processes, including osteoporosis 9-13. In mouse models, it has been determined that OPN is essential for osteoclastic bone resorption and suppression of osteoblastic bone formation 10. Furthermore, OPN-deficient mice are resistant to ovariectomy-induced osteoporosis 9. In humans, high serum OPN levels are associated with low bone mineral density in postmenopausal women 14, 15. Studies with OPN-deficient mice indicate that osteoclast-expressed CD44 is essential for OPN function in osteoporosis 16. Recent studies determined that CD44 functions as a receptor for OPN 11, 13, 17, 18. These findings indicate that the OPN-CD44 axis plays an essential role in osteoporosis.

B4. The myeloid cell lineage transcription factor IRF8 represses OPN expression to prevent osteoporosis. IRF8 is an essential regulator of osteoclastogenesis 19-24 IRF8-deficient mice develop severe osteoporosis due to increased osteoclasts 19. It has been shown that IRF8 suppresses osteoclast differentiation from myeloid progenitor cells 22-24. Our recent study determined that IRF8 directly binds to the Irf8 promoter to repress OPN expression 13. Therefore, in addition to the IRF8-NFATc1 pathway 19, the IRF8-OPN axis also plays a key role in osteoporosis. Under pathological conditions, IRF8 is often silenced in myeloid cells by its promoter DNA methylation 21. Because IRF8 is an essential transcription factor for myelopoiesis 25, targeting OPN is potentially a more safe and effective approach to suppress osteoporosis. These findings indicate that OPN promotes osteoporosis and provide a strong rationale to block OPN-CD44 interactions to suppress osteoporosis.

C. Chemedimmune is developing the humanized OPN neutralization antibody h100D3 for osteoporosis immunotherapy.

In our cancer immunotherapy project, we have developed the humanized OPN neutralization antibody h100D3 that is effective in blocking OPN-CD44 interactions 13. The OPN-CD44 interaction is essential for osteoporesis 16. These scientific data provide strong scientific evidence that h100D3 is effective for suppression of osteoporesis. Chemedimmune is currently developing h100D3 for human osteoporesis in manopausal women and cancer patients with osteoporesis.

C1. Current development status
We have submitted a NIAMS Phase I SBIR grant application to test our OPN neutralization antibody h100D3 for osteoporosis immunotherapy.

References

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