Biotherapeutics - The promise of biological innovation

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By Mike Pettapiece

Biotherapeutic therapies are sometimes referred to as biological smart bombs.
Such treatments are organic molecules that can zero in on a diseased area without harming normal, healthy tissues. That makes them more patient-friendly than a more invasive treatment regimen, such as that provided by radiotherapy or chemotherapy.

“Biotherapeutics are more targeted and potentially much more powerful,” says Dr. John Bell, senior scientist in cancer therapeutics at the Ottawa Hospital Research Institute. But they’re “not a single magic bullet”, he adds, rather “a suite of new biological therapies.”

So, for example, immunocentric-oriented researchers might arm an oncolytic virus with stimulatory cytokines or similar agents. Induced immune effector cells then act as surveillance guards on patrol and destroy disseminated tumour cells that may not be in reach of the oncolytic virus.

“These strategies work best in conjunction with other treatments,” said Jonathan Bramson, director of the Centre for Gene Therapeutics at McMaster University. “So I don’t believe for a second that they’ll work by themselves. The idea is that it will be used largely as an adjuvant (to augment the impact of a therapeutic treatment, such as a virus).”

Cancer gets most of the attention from biotherapeutic researchers these days. But investigators are also looking at the use of bio-strategies to go after other diseases and afflictions, such as tuberculosis, allergies, diabetes, and arthritis. Their therapies involve natural biologics, such as stem cells, antibodies, genes and viruses.

The use of natural substances as a weapon to combat diseases has a long history.

Hippocrates, the father of medicine, thought that garlic could be used to treat tumours. English country doctor Edward Jenner used a cowpox virus to vaccinate people against the scourge of smallpox in the late 18th century.

Jenner had observed that milkmaids seemingly did not contract smallpox, a disfiguring and often fatal disease in the 1700s and 1800s. He discovered that they were being “vaccinated” with a bovine virus (cowpox), a disease similar to smallpox but much less virulent, during their milking duties.

Two centuries later, astonishing technology gains in several areas – including molecular genomics and proteomics, and in infrastructure equipment, such as high-throughput screening – have shifted historic hunches into highly advanced scientific strategies.

Biotherapeutics are part of personalized medicine in which targeted therapies, based on a patient’s genetics, are used to cure diseases. So, researchers studying a patient’s cancer tumour tissues before treatment might learn which oncolytic viral product the cancer cells are most susceptible to. The virus might then be used as a clinical treatment.

As researchers gain greater understanding of gene expression, signalling pathways, immunoprotective function, and other processes – not every person with the same disease responds to a drug in the same way – they can predict the efficacy of various treatments, correct dosage levels, and likely side-effects on individual patients.

The use of oncolytic viruses that replicate within the body – allowing a small dose to be amplified – allows doctors to key on certain genetic pathways critical to cancer cell function and growth. Once a virus has invaded a cancer cell, it can multiply and destroy cellular elements, such as the vasculature network that feeds the cell.

Despite the gains seen from biotherapeutic strategies, many big pharma houses are moving cautiously in pursuing biotherapeutic research. But one impetus for their pursuit is the fact that huge-selling small-molecule drugs, such as Lipitor, are set to go off patent.

Sometimes the pharma firms end up buying biotherapeutic firms outright.

UK-based analyst firm, EvaluatePharma, estimates that seven of the top 10 drugs will be biotherapeutics by 2014, many of them anti-cancer antibody drugs. Back in 2000, only one of the top 10 best sellers was a biotherapeutic offering (Amgen’s Epogen).

As a whole, says Dr. Bell, the biotherapeutic field “has not really been fully embraced by pharma as yet.” But in the biotherapeutic community, researchers “who believe in the platform” often band together to take this approach in going after diseases, he says.

This co-operation frequently takes in scientists on more than one continent. One example is work on a recombinant adenovirus-vectored (Ad) vaccine against pulmonary tuberculosis. It has featured scientists from several countries and institutes, including McMaster, Texas A & M, the Institut Pasteur in Paris, and the Hannover School of Medicine in Germany.

McMaster researchers led by Zhou Xing developed the AdAg85A vaccine now in early-phase human trial. In pre-clinical trials with murine and guinea pig models, researchers found that immune boosting via an intranasal mucosal route with AdAg85A was able to prolong the lives of TB-afflicted guinea pigs that were primed with traditional BCG vaccine (Bacille Calmette-Guérin).

Collaboration and leveraging different strengths was the thinking behind ORBiT, the Ontario Regional Biotherapeutics program. Fully funded by the provincial government, ORBiT brings together researchers in Ottawa, Toronto, and Hamilton with expertise in oncolytic viruses, vaccine investigation, immunostimulatory agents and monitoring of immune function.

ORBiT scientists say they are seeing successes. One oncolytic virus in particular, labelled JX-594, is now in phase II trials with hepatocellular carcinoma (liver cancer) patients. The virus “actually strangles the tumour”, says Dr. Bell, cutting off the vasculature network that feeds the cancer cells. That was “an unexpected observation”, he adds.

JX-594 has also seen some efficacy and safety (not causing harm) provisions in early trials taking place in North America and South Korea, involving patients with such other cancers as non-small cell lung cancer, malignant melanoma, colorectal cancer, and breast cancer. Like similar viruses, JX-594 replicates within tumour cells but not within normal, healthy cells.

This biotherapeutic uses a poxvirus backbone, Vaccinia Virus, known for having all but stamped out smallpox worldwide. By deleting the vaccinia growth factor gene, scientists take advantage of the fact that VGF is a homolog of mammalian epidermal growth factor (EGF). The virus then naturally targets the EGF-Receptor pathway critical to many human cancers.

Further engineering enhances the cancer-selectivity by linking the virus with other genes expressed by cancer cells. In effect, the tumour cells complement the viral gene-deletions. JX-594 is also ‘armed’ with an immunostimulatory protein that leads to an anti-tumoural immune attack and eventual tumour necrosis.

McMaster University in Hamilton is one of the JX-594 trial sites. In addition, that university has the only clinical-grade facility in Ontario – in the Centre for Gene Therapeutics – capable of assessing and monitoring the anti-tumour, immune-level function of trial patients.

McMaster is looking at cancer vaccines as an adjuvant to existing therapies, taking advantage of immune cell hunter capacity to look for malignant cells within the body. Researchers have used genetically modified dendritic cells (protein-loaded specialized white blood cells that uniquely identify cancers) for immunization against cancer antigens.

Such immunogenicity is aimed at getting around the ability of cancer cells to avoid being ‘recognized’ by immune cells.

The microenvironment of a tumour, says Dr. Bramson, is immune-suppressive. So cancer cells effectively escape immunosurveillance.

In fact, some aspects of the immune system seem to promote formation of tumours. Researchers have long noted similarities between tumour promotion and the inflammatory sites of wound healing, he says. So they study “the mechanism of the healing process to see what we can flip around on a tumour.”

JX-594, heading to phase III clinical trials (that will take in China too) next year, is one of the most prominent biotherapeutics. It has sprung from a company, Jennerex Bioetherapeutics Inc. Dr. Bell is chief scientific officer for the enterprise, co-located in San Francisco and Ottawa. He believes it can be a leading example of growth in new jobs and industries.

“I think what we’re trying to do with Jennerex is really to build an international company between Canada and the U.S. . . . and the next step will be, Where do you manufacture them? . . . We’re trying to develop that infrastructure in Ontario.”

Even with all its promise, fundraising for biotherapeutic research and companies is a tough go, especially in this economic downturn. Many researchers must rely on governments to keep supplying grants and research monies. Trials take many years and exhaust investor patience.

“It’s always a struggle to raise funds, for sure,” said Dr. Bell. “I just think that they (biotherapeutic interventions) have so much potential because of their genetic diversity. . . . It’s (fundraising) the challenge we face because people can see a quicker return on their investment (in Canada) from other things, like natural resources.”

Mike Pettapiece writes and edits the newsletter for the Golden Horseshoe Biosciences Network, based at McMaster University in Hamilton. He can be reached at: mikepettapiece@cogeco.ca