Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Sema4D’

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National Harbor, MD

Despite remarkable results with cancer immunotherapy to date, we do need to keep out feet on the ground and remember that response rates are relatively low to modest (10–30%) and the majority of patients do not respond or see a benefit with these approaches.

As we start moving beyond checkpoint monotherapy, the realisation has fast hit many researchers and companies that we really don’t know as much about the tumour microenvironment (TME) as we would like.

No doubt we will learn a lot more about it from the combinatory approaches, but be aware that this also means higher risk associated with such developments – we will likely see a lot of failures – and hopefully, some successes too.

This is where the little biotech companies have an opportunity to shine… they may have some intriguing IO compounds in development but not an anti-PD1/L1 backbone, meaning they can collaborate with a big pharma company to explore novel combinations in small phase 1/2 trials to determine what works or not. This is much lower risk (and R&D costs) for both parties and we get to see more quickly where things shake out.

At the annual Society for Immunotherapy of Cancer (SITC) meeting last week, there was a whole day devoted to New Immunotherapy Drug Development.  

Some of these agents look worthy of watching out for and following their progress.  A variety of data in different targets and MOA were presented from big and small companies alike.  We selected a few of the promising ones for further review and discussion.

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Bone is a tissue in constant state of remodeling by osteoclasts (cells responsible for bone resorption) and osteoblasts (cells responsible for new bone formation).

Osteoporosis is a disease of progressive bone loss that is associated with increase risk of fractures.  Particularly debilitating are hip fractures in the elderly that are costly to treat and also lead to increased death and reduction in quality of life.  It’s estimated that osteoporosis affects 44 million people in the United States over the age of 50.

Most treatments for osteoporosis inhibit bone resorption e.g. bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid).  By inhibiting or reducing bone resorption, there is a lower amount of bone loss.

Recent research published in the November 2011 issue of the journal Nature Medicine has highlighted a new potential target for osteoporosis drug development that acts on osteoblasts and promotes bone formation.

In a series of elegant experiments, Takako Negishi-Koga and colleagues found that osteoclast-derived Semaphorin 4D (Sema4D) inhibits bone formation.

They found that the transmembrane protein Sema4D is expressed by osteoclasts and inhibits osteoblastic bone formation. In other words, Sema4D is a critical mediator of osteclast-osteoblast communication. 

They reported that:

In osteoblastic cells, Sema4D stimulation decreased the expression of cadherin-11 at the cell-cell contact region suggesting that Sema4D stimulates cell motility through an impairment of cell-cell adhesion, which in turn results in the reduction in bone-forming activity.

Osteoclast-derived Sema4D inhibits bone formation: 

The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. 

The implication of these findings is that blocking Sema4D could promote osteoblastic bone formation without affecting osteoclastic bone resorption.  The researchers successfully tested this hypothesis using an antibody to Sema4D.

They concluded that:

These results suggest that the blocking Sema4D–Plexin-B1 interaction is a new and potentially effective strategy for increasing bone formation in humans.

This preclinical work using an animal model is highly promising and suggests that as we learn more about the bone microenvironment, new therapeutic and molecular targets for drug development may emerge.

ResearchBlogging.orgNegishi-Koga, T., Shinohara, M., Komatsu, N., Bito, H., Kodama, T., Friedel, R., & Takayanagi, H. (2011). Suppression of bone formation by osteoclastic expression of semaphorin 4D Nature Medicine, 17 (11), 1473-1480 DOI: 10.1038/nm.2489

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