Calithera Pharma In Focus, Part 3 - Arginase Inhibitor And Acquisition Target

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<< Read More: Calithera In Focus, Part 2 - Upcoming Catalysts In TNBC And RCC

In the last part of our series on Calithera Biosciences (Nasdaq: CALA), we will be examining the company's second clinical asset,first-in-class arginase inhibitor CB-1158 and the company’s acquisition chances sometime this year or early 2018.  

CB-1158 therapy targets depletion of Arginine in the tumor microenvironment (TME) and has the potential to function as a novel metabolic checkpoint inhibitor to potentiate immune response. This amino acid regulates the proliferation and cytotoxicity of immune cells from both the innate and adaptive compartment.We believe that this modality can potentially serve as the backbone for a number of up and coming immunoncology (IO) approaches as the field attempts to achieve meaningful efficacies in solid tumors.

As we have discussed in our previous articles, tumor cells escape the immune surveillance system of the host through a number of pathways that contribute to a processes called immune tolerance. Myeloid derived suppressor cells (MDSC) represent one of the most powerful mechanisms used by tumors to evade this immune response. Once activated in the tumor mass, MDSCs produce a host of immunosuppressive compounds such as arginase, nitric oxide synthase, immunosuppressive cytokines, and indoleamine 2, 3-dioxygenase (IDO). These cells are most commonly found in Head & Neck Cancer, Colorectal Cancer (CRC), Mesothelioma, Renal Cell Carcinoma (RCC), Non-Small Cell Lung Cancer (NSCLC), among other tumor types.

Bristol-Myers-Squibb (NYSE: BMY) in particular seems keen on targeting these MDSCs in order to gain a meaningful edge in the IO space. The company has acquired or partnered a host of assets in the past few years to address the primary modalities of MDSC derived immune suppression.

In February of 2015 BMY acquired the private firm Flexus Biosciences for $1.25 Billion, which included an upfront payment of $800 Million in cash. Flexus was a relatively young company developing two preclinical therapies targeting IDO and the related molecule Tryptophan 2, 3-dioxygenase (TDO). The valuation does appear rather rich on the surface, but when one considers just how crucial MDSCs are in regulating immune response as well as the target market size, it appears to be a well-placed bet.

Similar to how IDO inhibition blocks degradation of tryptophan thus restoring T-cell function in the tumor, arginase inhibition may also help restore immune function in the TME. These enzymes inhibit immune responses through the local depletion of amino acids that are essential for anabolic functions in lymphocytes. Multiple studies have narrowed down the primary mechanisms of arginase derived immune suppression to a few interesting and key domains. Primarily, the reduction of extracellular arginine results in the depletion of the CD3ζ chain of the T-cell receptor (TCR).  This pathway is crucial for T-cell activity, cytotoxicity, and proliferation at the tumor site.

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Disclosure: I am/we are long CALA, AFMD.

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