Combating cancer: Apexigen and rabbit antibodies

There’s no shortage of drugs formulated with antibodies derived from people or from mice. But California-based Apexigen has turned elsewhere, developing treatments with antibodies derived from rabbits.

Rituxan (rituximab) and Herceptin (trastuzumab) are just two examples of drugs that use antibodies derived from mice or humans, or humanised antibodies derived from mice. However, rabbits can generate a much broader diversity of antibodies for a target than a mouse, a human or many other species, says Mark Nevins, vice president of business development at Apexigen.

Using a process called gene conversion, rabbits’ immune systems can create antibodies that are generally of a higher quality, and have greater affinity, creating a stronger bond between the antibody and the antigen.

Rabbit-derived antibodies are also effective against targets that many other therapies cannot see, and therefore bind to.

Against this background, Apexigen is currently working on seven different programmes and is “aggressively” pushing forward its lead cancer programme APX005, a humanised monoclonal antibody that received $20 million in financing in August.

Apexigen has a variety of related patents and Nevins says that thanks to the novelty of its products it doesn’t expect many difficulties getting claims for its antibody programmes.

First isolated in the 1970s, monoclonal antibodies have been heralded as a new hope for cancer therapy. With the capacity to be grown indefinitely, monoclonal antibodies mimic antibodies the body uses in immune response.

Many monoclonal antibodies work by binding to specific antigens and making them more visible to the immune system, while some can slow or stop the growth of a tumour by blocking growth signals from proteins, which attach to receptors on the surface of normal cells.

Other monoclonal antibody-based treatments deliver radiation or chemotherapy to cancer cells, for targeted therapy.

According to the Mayo Clinic, treatments using monoclonal antibodies generally have fewer side effects than traditional chemotherapy treatments.

The US Food and Drug Administration approved the first monoclonal antibody, muromonab, for human use in 1986. Muromonab is indicated to reduce acute rejection in patients who have undergone organ transplants. There have since been around 30 more monoclonal antibody therapies approved, many as cancer treatments, with hundreds more in clinical trials.

History

Apexigen was established as an independent company in July 2010 after being spun off from Epitomics, a firm that makes and uses rabbit antibodies in research. Epitomics was subsequently acquired by Abcam.

It has an exclusive licence from Epitomics to use the antibodies as therapeutic agents, and develops technologies in two main areas: rabbit hybridoma, the process of creating hybrid cell lines to culture monoclonal antibodies, and the rabbit antibody humanisation process, which makes the antibodies suitable for use in humans.

Epitomics continues to use the technology for its service business. But “we own all the rights to therapeutic use and we use them as a service provider,” Nevins says.

“We employ Epitomics to do a lot of our lab work, such as antibody discovery work. We’re operating on a virtual model, and rely both on them and other contract labs."

"Apexigen's patents cover the rabbit hybridoma fusion partner technology and the antibody humanisation process."

Apexigen’s seven humanised monoclonal antibody programmes are aimed at developing treatments in oncology, inflammatory disease and ophthalmology. For four of these programmes, it is collaborating with Chinese biotech firms Simcere Pharmaceutical Group, 3SBio, Jiangsu T-mab Biotechnology and Shanghai Duyiwei Biotechnology.

“The Chinese partners have responsibility to develop and commercialise the product in China—we lend them assistance as they need it,” Nevins says. Apexigen is also licensing out the use of its antibody platform. It has three partnerships in place: one with Janssen Biotech, another with Alcon, Novartis’ eye-care unit, and another with an undisclosed pharmaceutical company. These are using Apexigen’s technologies to develop their own treatments: “We are always interested in doing more antibody technology deals,” Nevins says.

Competition

Apexigen’s patents cover the rabbit hybridoma fusion partner technology and the antibody humanisation process. Has it been challenging securing patents on these technologies?

“It’s certainly become a more crowded field over the last number of years,” Nevins says. However the novelty of the product has certainly worked in Apexigen’s favour.

“Since we are one of the few using rabbit-derived humanised antibodies, we haven’t seen and don’t expect to see a lot of difficulties for getting claims for our antibody programmes.”

According to IMS Health, by 2016 global spending on biologic medicines will reach $200 billion, up from $157 billion in 2011. Spending on biosimilars will account for two percent of this figure, a five-fold increase in the same time period.

In addition, with the introduction of the Patient Protection and Affordable Healthcare Act in the US, the use of biosimilars is being actively encouraged.

But with so little clinical experience with rabbitderived antibodies in the literature, Nevins isn’t concerned about emerging biosimilar competition affecting Apexigen’s work.

“There is not a long clinical track record for the performance of rabbit antibodies compared with others,” he says.

In addition, the method of scaling up the production has been tried and tested: “The CMC [chemistry, manufacturing and control] processes for scaling up are very similar to those for other antibodies, so there are no difficulties there,” Nevins says.

There are enough data to show that there aren’t any toxicities or untoward effects caused by rabbit-derived antibodies, as opposed to mouse- or human-derived antibodies, he adds.

However, information about the different antibodies’ performance in the human body, and what the body does to the drug after administration, is, for the time being, thin on the ground, leaving little for biosimilar firms to work with.

“In terms of trying to develop a biosimilar you want something that’s going to perform very similarly, so you would probably have to use a rabbit antibody to get a biosimilar, unless you want to spend an awful lot of time tweaking a mouse antibody to perform like a rabbit’s,” Nevins says.

Pipeline

Apexigen will file an Investigational New Drug (IND) Application in the US on APX005 soon, and Nevins expects clinical trials to start in the near future. The firm has hired Boehringer Ingelheim as its contract manufacturer for its clinical trials.

“APX005 is a CD40 agonist, so it activates an immune response against tumours—we’re very excited about it,” Nevins says.

As well as boosting the body’s immune system to fight cancers that are difficult to treat, such as pancreatic cancer, the drug has also shown the potential to kill tumours directly.

The other drugs in Apexigen’s pipeline are either partnered or due to be partnered with firms in China for development. “We believe the best use of our technology is going to be to go after some of the more difficult targets—targets that companies want to be able to develop antibodies against, but have been frustrated with using other technologies,” he says.

Some proteins are difficult to generate antibodies against because of their structure, Nevins explains. The GBCR class of receptor, for example, has small transmembrane loops that the antibody binds to, though “there’s not very much there for the antibody to see”.

So far Apexigen’s partners have filed four INDs for products using its proprietary technologies—two of which are currently in phase I testing by its partners.

Just two rabbit-derived antibodies are going through clinical trials at the moment, Nevins says, each created by companies that generate antibodies from other animals as well as rabbits. But given the potential of this new technology, he predicts more rabbit-derived antibodies going through the clinic in the near future, creating new options for patients suffering from the most difficult to treat cancers.