Radio activity leads the way in treatment

Radioactive isotopes have a history of use in the drug industry, both as therapeutic agents and diagnostic aids.

Radioactive isotopes have a long history of use in the pharmaceutical industry, both as therapeutic agents to treat cancer, and as diagnostic aids.

But recently they have gained a whole new lease of life as biopharmaceuticals companies have realised that radio-nuclides have great potential in making their targeting molecules more effective.

While very many monoclonal antibodies and other biological agents have been developed that are extremely effective at targeting cells, receptors or enzymes, all too often their therapeutic efficacy is not good and there have been numerous high profile failures in the late stages of clinical trials.

So while the drug reaches its target in the body, it has insufficient effect once it gets there. One way to get around this is to attach a payload such as a radioactive isotope to the antibody; the antibody will do its job in targeting the active site, delivering the isotope very precisely to where it is needed.

stable complexes

This may sound a simple prospect, but there is another challenge when the radioactive isotope is a radiometal - how to attach the radiometal to the antibody. This is not a trivial operation, as some form of chelator has to be attached to the antibody itself, and then form a complex between the radio-nuclide and the chelator.

Dowpharma's ChelaMed radiopharmaceutical services specialises in just this sort of chemistry. 'A pharma company is unlikely to have the expertise in house to create a new radiopharmaceutical entity,' explains Dowpharma's business director Nick Hyde. 'We offer a complete service package based on our experience to help guide them through the process. So, for example, we have chelants that form stable radiometal complexes, we know how to produce the complexes, we know how to characterise them, and we can do proof of concept studies. It's not just about supplying chelants - it's about the whole package that helps the company produce an effective therapeutic.'

Hyde adds that the company is seeing increasing interest in the area. 'It goes back to the fact that there have been a number of well publicised failures in the antibody field,' he says. 'Biopharmaceuticals tend to get through Phase I and toxicity trials quite easily, but the problems occur at Phase III where the desired efficacy is all too often not seen. But as more products containing radioisotopes reach the market, demonstrating that they can be effective, this stimulates other companies to try.'

He says that the number of pharma companies now exploring this area to make therapeutics is increasing, and a whole session at the recent BIO 2004 show in San Francisco was devoted to the area. 'Many of these companies are trying to expand their therapeutic options, or trying to find new applications for their targeting molecule,' Hyde explains.

manufacturing challenges

'And we are providing them with one option for a therapeutic effect. Maybe they have a very effective targeting molecule which needs to have some other agent attached to it to get effective treatment. Or it's a product that's been around for a while, and they want to extend the product's life cycle by using it in a different way.

'We can help them tailor the chelant's chemical structure, help them design their molecule and even do some of the preclinical work to support them. It's a whole service offering that makes it possible for an antibody company to get into radiopharmaceuticals.'

There are a number of other challenges involved in the manufacture and supply of radiopharmaceuticals, not least the fact that close attention needs to be paid to the whole delivery chain by which a product reaches the patient. The antibody-chelant conjugate comes from one source, the isotope is likely to come from another, and the two have to be put together before the product can be used in a patient.

'The main issues are stability and half life,' Hyde says. 'There is the half life of the radioisotope, and also the stability of the metal complex, so it's important that very stable metal complexing agents are used to ensure the metal stays attached to the antibody as it moves through the body to the delivery site.

appropiate therapy

Hyde adds that a further challenge is having a facility that is able to cope with radioisotopes, as well as pharmaceuticals, which require different forms of licensing. 'Being able to handle radioisotopes and also being able to evaluate their performance clinically is a combination that most companies don't have - if they can handle radioisotopes, they are rarely able to work with pharmaceuticals too,' he says.

And a third challenge is being able to match the appropriate radioisotope to the therapeutic. 'Coming up with the total product isn't simple,' Hyde claims. 'There is a protein, with all the attendant difficulties that poses for analysis. Then there is the chelant, which is a complex molecule in its own right. And then you've got the radiometal. Each of these on its own can be difficult to handle and analyse, but there are very few companies who, unlike us, can help with all three.'

The first of the new generation of radiopharmaceuticals to gain approval was Zevalin (ibritumomab tiuxetan) from Biogen Idec. It is licensed to treat patients with relapsed or refractory low grade (slow-growing) non-Hodgkin's lymphoma (NHL). Traditional therapies for NHL include external beam radiation, which is particularly useful in the early stages of the disease when there are few, localised tumours.

Other treatments include conventional chemotherapy, and the monoclonal antibody Rituxan (rituximab). However, most patients initially exhibit a response, but then relapse, and experience progressively shorter remissions between each treatment regimen.

Zevalin provides an alternative. It comprises the murine monoclonal antibody ibritumomab, attached to the radioactive isotope yttrium-90 by the chelating agent tiuxetan. The drug targets the CD20 antigen on the surface of mature B cells and B cell tumours, inducing cellular damage in the target and neighbouring cells. Normal cells are regenerated, within six to nine months.

The yttrium-90 produces beta radiation with a path length of around 5mm, so 90% of the radiation is absorbed within 5mm of the isotope. This relatively long path length is thought to allow the emitted radiation to penetrate deeply into tumours and neighbouring cancer cells, minimising damage to healthy tissue. This also means that Zevalin has few of the side-effects normally associated with cancer therapies, such as nausea, vomiting and hair loss.

Also licensed to treat NHL is Bexxar (iodine-131 tositumomab), which was developed by Corixa and commercialised with GlaxoSmithKline and approved in 2003. Again, it is indicated for patients with CD20 positive follicular NHL that has relapsed and is resistant to rituximab. The monoclonal antibody, tositumomab, also targets a protein on the surface of the B cells, and the attached radioisotope kills them. Biogen Idec and Corixa are locked in a battle over the validity of Bexxar's patents. A court ruling that several key patents were invalid was recently overturned, and the case continues.

In a Phase III trial in 40 patients who were given Bexxar intravenously once a week for two weeks, 63% responded to the drug with a median response time of 25 months, and 29% exhibited a complete response. Again, side-effects were lower than would be expected from more traditional treatments.

tumour metastasis

Dow has developed and licensed three separate radiopharmaceutical technologies: Quadramet, Iotrex and STR, or skeletal targeted radiotherapy. Licensed to Cytogen, Cis Bio and others, Quadramet is a cancer therapy designed to give pain relief in patients with metastatic bone lesions. It is a combination of the beta-emitting radioisotope samarium-153 with the chelating agent EDTMP, which targets the drug to sites where new bone is being formed.

When tumours metastasise to the bones, they continue growing and destroy nearby bone. As the bone is eroded, new bone formation is stimulated, which encircles the metastatic tumour. Quadramet targets the areas where bone is being formed, delivering the radiation precisely to the site, which can reduce pain levels significantly.

Quadramet's effects can last as long as four months from a single injection, and it has an early onset of action. It has a plasma half life of five to six hours, and exhibits little or no accumulation in soft tissue.

The agent is under development for further indications, notably the potential of higher doses of the agent to target and treat primary bone cancers. Cytogen is also looking at its use at an earlier stage of disease, and also in various cancers and in combination with other treatments such as standard chemotherapy and bisphosphonates.

Iotrex contains the radioisotope iodine-125, along with HBS. It is being used by Proxima Therapeutics as part of its GliaSite radiation therapy system to treat brain tumours. It combines the agent with a balloon catheter, to treat newly diagnosed, metastatic and recurrent brain rumours by delivering radiation from within the cavity that is created when the tumour is removed by surgery.

After surgery, the balloon catheter is placed in the space left behind, and the other end extends outside the skull, with Iotrex and saline injected to fill the balloon. The radiation is delivered to the edges of the tumour cavity, where it attacks any cancerous cells that may remain. The mixture remains in the balloon catheter for three to seven days, until sufficient radiation has been delivered. The mixture is then withdrawn, and the catheter removed by a quick surgical procedure.

In a multicentre clinical trial, 21 patients with recurrent malignant gliomas were treated with GliaSite, and had a median survival of 387 days, and a 52% survival rate after a year.

first line failure

Dow has licensed STR to NeoRx, which is developing the holmium-166-DOTMP system for use with high dose chemotherapy and autologous stem cell transplantation to treat patients suffering from multiple myeloma and other cancers of the bone and bone marrow, including leukaemias, lymphomas and bone metastases of breast, prostate and lung cancer.

STR contains the targeting molecule DOTMP in a stable complex with the beta emitting isotope holmium-166. When injected into the bloodstream, it binds rapidly to bone mineral to treat bone and marrow with a brief, intense dose of radiation to destroy cancer cells.

The normal first line therapy for multiple myeloma is chemotherapy, but around a third of newly diagnosed patients fail to respond to initial regimens. Patients who respond well may then be given high dose chemotherapy along with autologous stem cell transplantation, which is the standard of care for myeloma.

However, three year survival rates are only in the range 48-59%, and STR may help improve this. Myeloma cells are sensitive to radiation, but conventional methods of delivering radiation such as total body irradiation expose non-target tissues to radiation, and can cause serious side-effects. STR allows the myeloma cells to be targeted within the bone marrow, minimising the exposure of radiation to other tissues and organs.

Ten myeloma patients were given the combination in a Phase I/II clinical trial. They achieved a complete response rate of 40%, and a three year survival rate of 90%. A pivotal placebo -controlled Phase III trial began enrolling patients in March, and NeoRx hopes to file an NDA for multiple myeloma in mid-2007. It is seeking a strategic partnership to help commercialise the treatment, which has been granted orphan drug status by the FDA.

Dow is involved in a further collaboration with Avidex. The project, using Avidex's monoclonal T cell receptors, is currently focused on using the receptor EsoDex to treat lung and bladder cancer. EsoDex targets the NY-ESO antigen, which is a very specific marker of cancer cells. Because this is an internal antigen, it would not be detected by a therapeutic monoclonal antibody. EsoDex is designed to bind to fragments of the antigen on the surface of tumour cells, and the plan is to use a Dow chelator to attach a radionuclide such as yttrium-90 or lutetium-177.

novel diagnostics

It's not just therapeutics that are likely to benefit from chelator technology - they have great potential for creating novel diagnostics, too. Dow is involved in a multipartner collaboration with various partners. Funded by the US National Cancer Institute, the project is looking to create and evaluate contrast and therapeutic agents to seek out specific molecular targets to diagnose and, hopefully in the end, treat cancers.

The target is newly formed vasculature, which is an early sign of tumour development. If these blood vessels could be labelled with radioactive markers, a nuclear medicine camera of some form can be used to determine the nature and extent of tumour development.

To make the contrast agents, tiny perfluorocarbon nanoparticles are first suspended in an emulsion. A radionuclide such as technetium-99m is then attached to provide the contrast required for imaging. The nanoparticles are also labelled with a specific ligand that targets the newly formed blood vessels. In theory, anticancer drugs and therapeutic radionuclides could also be incorporated in the nanoparticles to deliver treatment selectively to developing tumours.

While it's still early days for targeted radiopharmaceuticals, the slow stream of products that is beginning to reach the market indicates that they have great potential as therapeutic agents that can be designed to act very specifically at tumour sites.