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Increased development of monoclonal antibodies could see more reaching the market

Antibodies are large proteins (immuno-globulins) produced by the body's immune system in response to the presence of foreign cells (antigens). Antibodies attach to antigens, thus marking them for destruction by other components of the immune system. They are highly specific for certain cells, and so can bind solely to one specific molecule, leaving other types untroubled.

Antibodies targeting specific cells can be made in the laboratory and are called monoclonal antibodies (MAbs) because they are identical clones of one single parent cell.

It is almost always possible to produce MAbs against a given cell and such technology is becoming an important tool in diagnostics and imaging, and, of course, in medicine.

By recognising and marking unwanted cells, MAbs induce the body's own immune system to raise a response against these target cells.

Globally, MAbs represent the largest group of medicines currently undergoing pipeline development.

MAbs against cancer
Epidermal growth factor receptor (EGFR), also referred to as ErbB1 or HER1, is associated with cell division and appears to be expressed abnormally in many solid tumour types.

CIMYM (a subsidiary of YM BioSciences) is developing nimotuzumab (TheraCIM h-R3, Theraloc), an EGFR antagonist with the intent of blocking epithelial growth factor and tumour growth factor from binding to EGFRs in order to prevent cancer cells from multiplying.

The drug is currently in clinical development for the treatment of glioma and head and neck cancer, and is given repeatedly in combination with radiation therapy.

The addition of nimotuzumab to radiotherapy was reported in December 2004 to improve complete response rates, compared with radiotherapy alone (91 per cent Vs 52 per cent) in patients with locally advanced nasopharyngeal cancer.

Some 130 patients were randomised to receive either radiotherapy alone, or in combination with nimotuzumab given at a dosage of 100 mg/week for an eightweek period. The results of this study also suggested that nimotuzumab is not associated with an acneiform rash.

Another media release from YM BioSciences, in February 2005, described the results of a 20-patient study in children with glioma who had failed all previous treatment options. Here, nimotuzumab was associated with disease control in 35 per cent of children; partial response was observed in 6 per cent and stable disease in 29 per cent.

Phase II and III clinical trials are currently ongoing in pancreatic cancer, head and neck cancer, nasopharyngeal cancer and brain cancer.


MAbs against sepsis
Sepsis is a very serious condition that is caused primarily by bacterial infections, but can also be a result of fungal, parasitic or viral infections.

It is the result of a systemic inflammatory over-reaction to infection, leading to organ dysfunction and, ultimately, death.

Tumour necrosis factor (TNF) has been recognised recently to be a major mediator in the sepsis cascade.

US company Abbott Laboratories' afelimomab (Segard) is a fragment of a murine monoclonal anti-TNF antibody that is currently in phase III development as a potential therapy for sepsis and septic shock (sepsis accompanied by persistent hypotension despite adequate fluid resuscitation, leading to inadequate tissue perfusion).

In the pivotal MONARCS (Monoclonal Anti-TNF: a Randomised Controlled Sepsis) study, some 2,634 patients with severe sepsis (sepsis with acute organ failure) were randomised to receive intravenous infusions of afelimomab 1 mg/kg three times daily for three days, or placebo.

It reduced the 28-day mortality rate in patients with elevated interleukin-6 (IL-6) levels, compared with placebo (43 per cent Vs 49 per cent; p < 0.05).

Afelimomab displayed a similar tolera-bility profile to placebo; adverse events were reported in approximately 100 per cent of patients, and serious adverse events in approximately 50 per cent.

Amgen is developing denosumab, a fully humanised monoclonal antibody against the receptor activator of NF kappa B ligand (RANKL), a cytokine that regulates the differentiation of osteoclasts.

Denosumab acts to inhibit bone destruction by decreasing the number of osteoclasts and slowing bone loss. It is, therefore, being developed for treating bone disorders, such as postmenopausal osteoporosis, treatment-induced bone loss, cancer-related bone diseases and rheumatoid arthritis.

A recent study, reported in February 2006, randomised 412 women with postmenopausal osteoporosis to receive treatment with subcutaneous denosumab at varying dosages, oral alendronic acid (a drug well-known to improve bone density), or placebo.

Women who received denosumab experienced significantly greater increases in bone mineral density (BMD) at the lumbar spine, total hip, femoral neck and distal third of the radius after one year, versus decreases seen with placebo.

Changes from baseline in BMD were at least as great with denosumab, as with alendronic acid. In this study, denosumab was well tolerated, as well as effective. No significant differences between the adverse event profile in denosumab recipients and placebo recipients were observed.

Treatment withdrawals due to adverse events occurred with an incidence of 2 per cent among recipients receiving denosumab or placebo.

Clinical trials are currently ongoing in the areas of rheumatoid arthritis, bone metastases and multiple myeloma.


FDA-approved MAbs
A number of MAbs are currently available on the market. Genentech and Biogen Idec's Rituxan (rituximab), marketed as MAbThera in Australia by Roche, is approved for the treatment of patients suffering from non-Hodgkin's lymphoma.

It is also undergoing development as a potential treatment for a number of other haematological cancers, as well as for rheumatoid arthritis and systemic lupus erythematosus.

Erbitux (cetuximab), originally developed by ImClone Systems, and licensed to Bristol-Myers Squibb and Merck KGaA, was approved for the treatment of colo-rectal cancer in 2004 and is currently undergoing registration for head and neck cancer.

Clinical development has also been reported in other types of solid tumours. An old-timer of the MAb market, Zenapax (daclizumab) was approved by the US FDA in 1997, for the prevention of renal transplant rejection.

Developed by Protein Design Labs, it is licensed worldwide to Roche; the drug is currently undergoing phase II development with PDL BioPharma for asthma and multiple sclerosis.

Looking forward
As the largest drug class undergoing development, the next 10-to-15 years will see a flood of monoclonal antibodies on the pharmaceutical market, adding to the armamentarium against immune-related disease currently available.


Generic name

Trade name (company)




Noxafil (Schering-Plough)

Treatment of serious refractory invasive fungal disease


Measles and rubella virus vaccine

Takeda Pharmaceutical

Prevention of measles and rubella infections



Avandaryl (GlaxoSmithKline)

Treatment of Type II diabetes mellitus


Tramadol extended-release

Ultram ER (Ortho-McNeil, Biovail Corporation)

Treatment of moderate-to-moderately-severe chronic pain


Insulin neutral protamine lispro/insulin lispro 50:50

Humalog Mix50:50 (Eli Lilly & Co)

Treatment of diabetes mellitus


Aripiprazole (2mg tablets and nonrefligerated oral solution)

Abilify (Bristol-Myers Squibb and Otsuka Pharmaceutical)

Treatment of schizophrenia, acute manic and mixed episodes
of bipolar disorders


Benzoyl peroxide (first to use Microsponge delivery technology)

NeoBenz (SkinMedica)

Treatment of acne vulgaris



Eligard (MediGene AG)

Treatment of advanced prostate cancer


Tacrolimus-eluting coronary stent

Janus Flex (Sorin Group)

Prevention of coronary artery restenosis


Pipeline is written by Anna Mett of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight. For more information on Adis services,

2nd September 2008


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