Science

Chemokines

Chemokines are small signaling proteins that play a critical role in orchestrating the movement of immune cells throughout the body. Such movement is required to maintain normal tissue development but also as part of the response to injury and inflammation. This process is mediated by interactions between the chemokines and their respective receptors which are variably expressed on a broad range of immune and non-immune cells. It is estimated that there are approximately 50 chemokines that bind to 20 receptors. There is growing interest in the ability of cancers to release chemokines and attract immunosuppressive cells to the tumor microenvironment where they may facilitate tumor growth and metastasis. Consequently, drugs that block the interactions between chemokines and their receptors have the potential to treat a broad range of diseases including cancer and autoimmune disorders.

Orion Biotechnology is developing novel recombinant chemokine analogues. The goal of this process is to identify molecules that bind to their chemokine receptor with higher affinity than the natural chemokine resulting in the generation of highly potent molecules with minimal potential for off-target toxicity. Orion’s lead chemokine analogue is OB-002 which is a CCR5 receptor antagonist with preclinical activity in cancer, neuroinflammation, and HIV infection. Orion also has a proprietary discovery platform that allows the rapid identification and optimization of other chemokine analogues.  

CCR5 antagonism in Cancer

A fundamental role of chemokines is to orchestrate the movement of immune cells around the body in response to inflammation and injury. However, the interaction of chemokines and their receptors may also play an important role in cancer. Chemokines secreted by tumour cells or by normal cells recruited to tumour sites can behave as growth factors, increase metastasis and angiogenesis, or contribute to the creation of an immunosuppressive environment that supports tumour growth. There is increasing interest in modulation of the CCL5 (RANTES) ligand/CCR5 receptor axis as a strategy to treat cancer. Cancer cells can secrete CCL5 or induce fibroblasts to secrete CCL5, which sustain the proliferation of CCR5-positive tumour cells, recruit T-regulatory cells and monocytes with suppressive functions, cause osteoclast activation; and favor bone metastasis, neo-angiogenesis, and dissemination of cancer cells to distant organs. CCL5 has been reported to provide anti-tumour activity or, conversely, to promote carcinogenesis, depending on the tumour environment. These opposite effects appear to be influenced by the type of cancer, CCR5 expression by cancer cells, and localization of CCL5 expression. Despite this apparent divergence, there is increasing preclinical and clinical evidence that CCR5 antagonism, given as monotherapy or in combination with other immunotherapeutic agents, can inhibit tumour growth and metastasis.

OB002-mechanism_Margot

CCR5 antagonism in Neuroinflammation

The CCR5 receptor is expressed on a range of cells within the central nervous system including microglia, neurons, and astrocytes. During infection or autoimmune reactions, these same cell populations express ligands to CCR5 (CCL3, CCL4, and CCL5). Consequently, the CCR5/CCL5 axis is thought to play an important role in a range of neurological diseases including multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome, cerebral malaria, HIV-associated neurocognitive disorders, and stroke recovery. In animal models, exposure to CCR5 antagonists appears to partially reverse CNS inflammation and OB-002 has had a similar effect in a mouse model of autoimmune brain inflammation.

CCR5 antagonism in HIV prevention

CCR5 is one of the two co-receptors that HIV uses to infect target cells. Individuals who carry a genetic defect that results in a truncated non-functioning CCR5 receptor are highly protected from HIV infection as initial HIV infection is usually mediated by viruses that selectively target CCR5. Because of this finding, CCR5 antagonists have been developed for the treatment of HIV infection and are being evaluated for HIV prevention. Among the currently available CCR5 antagonists, OB-002 has best-in-class in vitro potency and was able to completely prevent infection in a non-human primate model of HIV infection. A Phase 1 safety and acceptability study of a topical formulation of OB-002 will start in Poland in Q4 2019.

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contact us

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ORION Logo Pantone(375x133)

Our Headquarters

343 Preston Street

11th floor,

Ottawa, ON K1S 1N4

CANADA

info@orionbiotechnology.com