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TFRI-funded Core team working to battle most lethal brain cancer

Core platforms are an important element of TFRI’s New Frontiers Program Project Grant (PPG) teams. This blog features the Toronto Recombinant Antibody Centre (TRAC) at the University of Toronto, which is the most advanced of the three cores integral to the newly approved TFRI glioblastoma multiforme (GMB) project launched in 2016 with $2.25 million in funding.

View the PPG funding announcement here

Here Christine Misquitta, TRAC program manager, explains how this core is working with its partner cores to find new treatment options.

Our team of three research groups, including University of Toronto investigators Drs. Jason Moffat and Sachdev (Dev) Sidhu and TFRI PPG leader, Dr. Sheila Singh (McMaster University), combines different areas of expertise to tackle GBM, the most lethal and aggressive brain tumour in adults. Approximately two to three people per 100,000 are diagnosed with GBM each year, with less than five per cent of these patients surviving beyond five years.

Dr. Moffat’s group and core platform identifies new targets against which GBM therapeutics can be developed. Their discovery data identifies tumour-associated antigens for immuno-targeting (an antigen is
a molecule the body doesn’t recognize, thus evoking an immune response).

Dr. Sidhu and the TRAC group then engineer antibodies, protein molecules normally produced by the body as a primary immune defense but that can now be produced in a test tube. These antibodies recognize the identified targets in cellular models of GBM, binding to cancer cells and ultimately killing them. The antibodies and their therapeutic variations are then tested in GBM in vivomodels by Dr. Singh’s group and her core platform.
TRAC Lab

Drs. Jarrett Adams and Levi Blazer in the TRAC lab.

The TRAC is an integrated laboratory with a research platform generating therapeutic-grade antibodies against virtually any antigen. It functions as a pipeline, with three divisions that specialize in particular workflows of antibody discovery and development:

>The first division identifies antibodies that recognize target antigens by screening billions of unique synthetic antibodies using in vitro high throughput selections;

>The second division produces and characterizes antibody fragments (called Fabs) from bacteria and functionally characterizes how tightly and specifically they bind the antigens using biochemical and cellular assays;

>The third division – which has now moved to our commercial partner, the Centre for the Commercialization of Antibodies and Biologics (CCAB) – harvests full- length antibodies (IgGs) and other antibody formats from mammalian tissue culture. The focus of this team is to achieve production quality and amounts required for pre-clinical testing.

At the end of the TRAC/CCAB pipeline, the antibodies are in a therapeutic format and ready for use in animal studies and further pre-clinical assessment. Importantly, the pipeline acts like a funnel: it starts from large pools of antibodies and becomes more and more focused on lead molecules as the project progresses.

TRAC

Drs. Jarrett Adams and Lia Cardarelli in the TRAC lab.

Once antibodies are selected, they are sequenced to establish the genetic basis for antigen recognition. TRAC now has more than 9,000 characterized antibodies in our catalogue, targeting more than 600 different human proteins. We benefit from having dedicated staff in each portion of the pipeline who are supported by the TFRI, as well as additional grants and industrial partnerships. Our core is built to produce custom biologics (molecules produced from recombinant DNA, as opposed to chemically manufactured drugs) that enable the study of cellular processes so that, ultimately, we create lead candidate therapeutics that can have a real impact on the health of cancer patients.

I think it’s incredible how many of today’s diseases our group is working on – including cancer, infectious diseases and chronic diseases. We have many talented collaborators and we’re looking to solve a wide range of health problems with antibody therapeutics. With this TFRI grant, we have an opportunity to use our technologies to help patients with GBM, who have very few therapeutic options. We are also working on cancers such as lung, pancreatic, breast, and others that are hard-to-treat, and we now have lead molecules targeting each of these diseases that are progressing to pre-clinical assessment. Support from foundations like Terry Fox allows our team to do what we do. We consider ourselves very fortunate when our efforts are recognized and funded in this way.

Christine Misquitta

Christine Misquitta, TRAC program manager


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