Pacmab aims for multiply myeloma therapy

Sydney blood-cancer therapeutics developer Pacmab is due to present details of its prospective monoclonal antibody therapy for the multiple myeloma to the International Myeloma Conference in Sydney next week.

Experiments in SCID (severe combined immune deficiency) mice have shown that the monoclonal antibody, developed by Professor Bob Raison, of the University of Technology, Sydney, kills cancerous cells with very high specificity, strongly suppressing the growth of multiple myeloma tumours xenografts from humans.

Pacmab chief executive Alan Liddle said today that the company is now gearing up to produce a chimaeric, humanised version of the monoclonal antibody in sufficient quantities for a Phase I/IIa clinical trials early next year.

By binding to a mutant antigen expressed only on the surface of the cancerous cells, the antibody molecules mark the cancerous cells for elimination by natural killer T-cells.

PacMab announced recently raising AUD$700,000 in equity funding from venture capital company Symbion and sophisticated professional investors to develop its portfolio of monoclonal antibody for blood cancer. However, it kept the basis of the monoclonal antibody's specificity a commercial secret.

Liddle said the company will exhibit a poster at next week's conference describing Raison's work in identifying a peptide sequence in the light-chain or kappa 'stem' of the Y-shaped immunoglobulin molecule as a unique target for a monoclonal antibody.

Although the kappa chain is a natural component of normal antibody molecules, the monoclonal antibody does not recognise it in its native configuration. Raison suspects this could be because the free or membrane-bound form of the epitope has a different configuration when expressed by malignant cells, or the binding side is occluded by its proximity to the heavy, lambda chain.

Multiple myeloma can involve malignant cells expressing either the kappa antigen alone, or a combination of the kappa antigen and the lambda heavy-chain antigen. Because the kappa antigen is common to both forms, the Pacmab monoclonal antibody therapy, if successful, could be used to treat both forms.

Melbourne immunologist Dr Malcolm Simons, founder of the Melbourne genetics company Haplomics, and originator of the Genetic Technology's (GTG) broad patent on the use of non-coding DNA for diagnosing genetic disorders, is an interested and expert observer of the project.

Simons was diagnosed with multiple myeloma in 2003, but his cancer is now in a stable 'plateau phase' after he underwent a bone-marrow transplant and chemotherapy with thalidomide, which helps confine the cancerous cells to the bone marrow.

The disease causes the cancerous cells to clump together, and if they break out of the bone marrow, they can form scores of small tumours throughout the body.

The median survival time of multiple myeloma has been rising steadily around three years half a decade ago, to as much as seven years today.

Simons, who has declined maintenance chemotherapy because of the risk of infection while he is in an immunosuppressed state, said he plans to volunteer for next year's Phase I/IIa clinical trial.

He said current therapies employ a non-specific "blunderbuss" combination of chemotherapy and immunosuppressive steroids, sometimes with a matched bone marrow transplant from a donor, or a "self" graft.

The transplanted bone-marrow cells typically mount a rejection reaction against any residual myeloma cells, because the replacement bone marrow graft tends to recognise any the original cells of the immune system - including B-cells - as "non-self".

Simons said the disease disrupts the functioning of the patient's own bone-marrow stem cell population, and the process of haemopoiesis, resulting in leukaemia or anaemia.

The myeloma cells also clump together and transmit chemokines that cause osteoclasts to attack and erode bone, resulting in extensive pitting of bone, and eventually, brittleness and breakage.

Simons said the most attractive aspect of the prospective therapy was that it could become the first targeted therapy for the common forms of multiple myeloma. There are some 100,000 patients with multiple myeloma in industrialised nations, and around 35,000 new cases are diagnosed every year.

If the Phase I/II clinical trial is success, PacMab will seek to partner a big pharma company to take it to the clinic. Liddle said major pharmaceutical companies are taking an early interest in promising monoclonal antibody.