Mechanism of action

Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to a distinct epitope encompassing both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage and on B cell tumours. The B cell tumours include CLL (generally associated with lower levels of CD20 expression) and non-Hodgkin's lymphomas (where > 90% tumours have high levels of CD20 expression). The CD20 molecule is not shed from the cell surface and is not internalised following antibody binding.

The binding of ofatumumab to the membrane-proximal epitope of the CD20 molecule induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of tumour cells. Ofatumumab has been shown to induce appreciable lysis of cells with high expression levels of complement defence molecules. Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells and in rituximab-resistant cells. In addition, the binding of ofatumumab allows the recruitment of natural killer cells allowing the induction of cell death through antibody-dependent cell-mediated cytotoxicity.

Pharmacodynamic effects

Peripheral B cells counts decreased after the first ofatumumab infusion in patients with haematologic malignancies. In patients with refractory CLL, the median decrease in B cell counts was 23% after the first infusion and 92% after the eighth infusion. Peripheral B cell counts remained low throughout the remainder of therapy in most patients, then gradually recovered (median decrease in B cell counts was 68% below baseline 3 months after the end of ofatumumab therapy).

Immunogenicity

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab; however the formation of anti-ofatumumab antibodies may be decreased because ofatumumab is a human antibody that depletes B cells in patients already immunocompromised by CLL.

In the pivotal clinical study (Hx-CD20-406), serum samples from 154 CLL patients treated with ofatumumab were tested for anti-ofatumumab antibodies. In the 46 patients who received at least 8 infusions and had serum ofatumumab concentrations that had decreased sufficiently to allow detection of anti-ofatumumab antibodies (33 of whom received all 12 infusions), all samples tested negative for anti-ofatumumab antibodies.

Clinical studies

The clinical efficacy of ofatumumab has been demonstrated in a planned interim analysis of an ongoing study Hx-CD20-406 (single-arm, open-label, multicentre), and one completed supportive study, Hx-CD20-402 (open-label, dose ranging, multicentre).

Hx-CD20-406

Arzerra was administered as a monotherapy to 154 patients with CLL. Patient median age was 63 years (range: 41 to 86 years), and the majority were male (72%) and white (97%). Patients received a median of 5 prior therapies, including rituximab (57%). Of these 154 patients, 59 patients were refractory to fludarabine and alemtuzumab therapy (defined as failure to achieve at least a partial response with fludarabine or alemtuzumab treatment or disease progression within 6 months of the last dose of fluda