Elotuzumab – Anti-CS1 Antibody for Multiple Myeloma

Elotuzumab (HuLuc63) is an anti-CS1 humanised monoclonal antibody (MAb) developed by PDL Biopharma. It is being used as a treatment for multiple myeloma. In 2008, three phase I/II safety and tolerability studies of elotuzumab were initiated in patients with relapsed multiple myeloma. One study was initiated as a monotherapy, the second was in combination with velcade and the third was in combination with revlimid (lenalidomide).

In December 2009, Facet Biotech and Bristol-Myers Squibb presented potentially promising data from the phase I study, which tested elotuzumab in combination with revlimid. The preliminary data showed that if elotuzumab was administered in combination with revlimid, it might provide a potential treatment option for patients with multiple myeloma.

In January 2010, Facet Biotech announced that the company had enrolled the first patient in a randomised phase II study of the ongoing phase I study of elotuzumab in combination with revlimid. The study will recruit about 60 patients with relapsed multiple myeloma. In addition, Facet Biotech was awarded $15m milestone payment by Bristol-Myers.

Drug therapies for multiple myeloma

After non-Hodgkin's lymphoma, multiple myeloma is the second most common haematological malignancy. It arises from the over production of antibody-producing plasma cells leading to the formation of tumours in the bone marrow. As these abnormal malignant cells spread throughout the bone marrow, they disrupt normal production of red blood cells, platelets and white cells.

For decades, cytotoxic chemotherapy has been the mainstay of treatment of multiple myeloma in symptomatic patients, usually augmented with steroids. Melphalan, vincristine, cyclophosphamide, doxorubicin, idrarubicin and carmustine are some of the most commonly used cytotoxic drugs.

More recently, a number of newly introduced biological therapies have expanded treatment options, especially for patients who are refractory to conventional chemotherapy and whose disease has progressed.

These newer therapies include interferon, thalidomide, and lenalinomide, in addition to bortezomib, the first-in-class proteasome inhibitor.

Although there have been some important advances in the treatment of multiple myeloma with the advent of biological therapies, it remains a disease for which new treatments are still urgently needed.

This is highlighted by average five-year survival rates of about 30% and ten-year survival rates of only 3%.

CS1 – a novel target for multiple myeloma

PDL Biopharma's elotuzumab is directed against CS1, a cell surface glycoprotein that appears highly expressed on myeloma cells but minimally expressed on normal cells. It represents an entirely new therapeutic target with the potential to provide a new form of treatment for multiple myeloma patients.

Preclinical in vitro studies have shown that in the presence of elotuzumab, myeloma cells undergo lysis and death. Researchers suggest that elotuzumab may exert its anti-tumour effects via antibody-dependent cell cytotoxicity in which natural killer (NK) cells play an important role.

Positive findings in preclinical studies have seen elotuzumab advance to clinical development with phase I studies now underway. The trials, which are taking place in the US, will investigate the safety of elotuzumab in patients who have relapsed on prior therapy or become refractory to treatment.

These patients have incurable diseases and therefore represent those with the greatest unmet clinical need.

BMS to co-develop elotuzumab

In August 2008, PDL Biopharma announced that it had signed a co-development and marketing agreement with Bristol-Myers Squibb, in which BMS would lead global development activities for elotuzumab, while PDL Biopharma would focus on completion of the phase I programme and support phase II studies.

The agreement between the two companies may also extend to PDL241 and another anti-CS1 antibody, which are still at the preclinical stage of development.

BMS is a leading player in the market for anti-cancer drugs. Its portfolio of anti-cancer drugs includes Erbitux (cetuximab), a therapeutic MAb that is approved for the treatment of metastatic colorectal cancer and locally advanced squamous cell carcinoma of the head and neck.

Marketing commentary

Despite an expanded range of treatment options for patients with multiple myeloma, there is still urgent unmet need for drugs to improve survival rates. Biological therapies are seen as an important new avenue of research with the potential to generate completely new therapeutic targets for haematological malignancies.

Elotuzumab represents one such example and its progress through clinical trials in multiple myeloma patients will be watched with interest.