Magic bullets - the biologics revolution
Immunotherapies are pervading many corners of medicine and there will be many more to come.
These biologics typically have unpronounceable names, unintelligible modes of action, cost a lot of money and lead many to espouse the miracles they can achieve.
Some GPs may feel they need help to navigate a path through the biologic maze.
A way through the maze
The science-within-a-science of immunotherapy has come about as a direct result of the immune system’s exceptional capacity for specificity.
As part of his Nobel Prize-winning work in 1906, Professor Paul Ehrlich predicted the development of ‘magic bullets’ that would identify and remove damaged or diseased tissue.1
It was not until the 1970s that more Nobel Prize-winning work resulted in our ability to readily produce highly specific antibodies directed against almost any peptide or protein.2
Biologics are developed from a range of natural sources that are human, animal or micro-organism in origin.
Although the array of therapies can seem confusing, there are some basic rules for the approved names, based on the original source of the protein/s contained in the biologic (see table — adapted from reference 3).3,4
|Rules for biologic names|
|Monoclonal totally murine protein||-momab||Tositumomab|
|Monoclonal humanised containing minimal murine protein||-zumab||Tocilizumab|
|Monoclonal fully human protein||-umab||Adalimumab|
|Chimeric, a mixture of types of protein||-iximab||Infliximab|
|Tyrosine or Janus kinase inhibitors, small molecule agents||-nib||Tofacitinib|
Monoclonals are antibodies derived against a target that is usually a peptide of some description.
The ‘chimeric’ description describes a therapeutic agent which contains elements of two different monoclonal species.
A fusion protein is chimeric by definition because it consists of Fragment crystallisable (Fc) and Fragment antigen-binding (Fab) antibody segments which have been derived separately then fused together.
Molecules containing murine (mouse) protein were developed first and have inherent problems with allergic reactions.
These reactions are much less common with molecules of purely human origin.
Finding a target
Identifying a target for therapy is central to the whole concept. This is an area of scientific wizardry that requires a mix of inspiration, trial and error, and good fortune.
In rheumatology, research into the origins of inflammation led to understanding the function of tumour necrosis factor alpha (TNF alpha).
The production of a monoclonal antibody directed against TNF alpha showed immediate therapeutic benefit in rheumatoid arthritis and subsequently, different cytokines have been targeted with important effects in other rheumatic conditions.
Biologics have been used to treat rheumatoid arthritis.
In oncology, potential targets for immune therapy are the processes controlling cell division, growth factors, the immune response (which is diminished in some tumours) and angiogenesis. Blocking this last process can deplete a tumour of its blood supply.
There are also ways to target abnormal cellular function. A cytokine such as TNF alpha can be targeted directly or its cellular receptors can be blocked with a fusion protein such as etanercept. A specific tumour receptor can be blocked directly by some agents, including trastuzimab.
A different cellular receptor could also be altered to increase removal of the targeted cell by triggering antibody-dependent cell-mediated cytotoxicity (ADCC) cells, which is how rituximab works.
Alternatively, the complex interactions between immune cells can be targeted. The cytotoxic T-lymphocyte-associated protein 4 complex (CTLA-4), which is involved in conversations between antigen-presenting cells and T-cells, can be blocked by belatacept for control of organ rejection or by abatacept for control of inflammation in rheumatoid arthritis.
The same pathway can be altered by ipilimumab, which enhances the immune response to melanoma cells.
Specific fusion proteins can be attached to a therapeutic ligand.
For example, a human Fc fragment (the tail region of an antibody) can be fused to a protein directed against colon cancer cells.
A radioactive isotope, such as Yttrium 90, can then be attached, which has a local targeted effect.
Altering the configuration of a fusion protein or monoclonal biologic by using Fc fragments from different immunoglobulin G (IgG) subgroups can alter or prolong the biological effect without changing the antigen-binding (Fab) fragment of a monoclonal antibody or the interactive component of a fusion protein.
The options are almost endless, the Holy Grail being a target that has absolute specificity to a given abnormal cell type or product and no other.
However, the biologic story is not about uniform success. SLE, the archetypal immune complex disease, is proving a most difficult target with some cases responding well to biologics and others failing totally. There may be many causes for this response.
Accurate diagnosis is essential to determining who will benefit from biologics, but this may not necessarily sit with conventional diagnostic approaches.
The use of clinical diagnostic criteria may help to define candidates for research purposes, but if we are to use a specific cytokine antagonist or cellular marker as treatment, then we should first ensure that our patient is suffering from the effects of an excess of that cytokine or possess that marker. This may not correlate with the clinical diagnostic criteria.
While it is possible to measure cytokine concentrations, it is an expensive exercise. However, bearing in mind the cost of treatment, this may become essential in the future.
Prior to treatment, patients with chronic inflammatory conditions should first be screened for latent tuberculosis, hepatitis B and HIV.
Vaccination against varicella prior to treatment is a consideration because live virus vaccinations are inadvisable once treatment has started. Hepatitis C status should be checked, but is not a bar to treatment.
Changes in immune status may result in alterations to immune surveillance and premature neoplasia. Patients with a diagnosis of cancer in the previous five years probably shouldn’t receive biologics for inflammatory disease.
Worldwide registries are being maintained to look for signals that might indicate increased future cancer risk. The significance of non-melanoma skin cancer, diagnosed both prior to and during therapy, may have been overlooked in the past.5
The availability of biologic drugs has meant that patients with inflammatory joint disease are experiencing symptom resolution and seeing disease progression halted.
Some cancers previously thought to be untreatable are suddenly resolving, with life expectancy now measured in months or years rather than days or weeks.
The economic benefits for many patients with chronic inflammatory diseases have been enormous.
Patients who once had a limited future are now living independent and fulfilling (and taxpaying) lives. However, the fact that responses are not uniform reminds us that neither our drugs nor our diagnoses are infallible.
These agents are capable of impressive effects, but there are downsides.
Suppressing an overactive immune system can result in infection and atypical neoplasia, while boosting the immune response to suppress tumour activity can result in autoimmune disease manifesting in the skin, gut and endocrine systems, to name a few.
Such problems can be predicted, but longer-term reactions might prove unexpected and profound.
Patients receiving these new medicines must be monitored closely to look for signals that might indicate the development of novel and severe complications.
While the production of each of these drugs is relatively cheap, the development and initial set-up is very expensive and potentially dangerous.
Some may recall the catastrophe when a novel anti-CD28 monoclonal antibody called TGN1412 was first given to healthy volunteers, leading to multiorgan failure in the trial subjects.6
A drug for a common problem may confer a similar cost to conventional treatments.
An example is denosumab — a monoclonal antibody directed against receptor activator of nuclear factor kappa-alpha ligand (RANKL), a molecule necessary for the maturation of osteoclasts — which is effective in controlling osteoporosis and involves a similar cost compared with conventional agents.
However, agents for orphan diseases may incur great cost. For example, eculizumab will control complement degradation and is used in atypical haemolytic uremic syndrome and other equally rare situations, but it costs hundreds of thousands of dollars per year, per patient.
The most expensive item for the PBS is adalimumab, which is used for inflammatory diseases of the skin, joints and gut.
This costs the taxpayer more than $330 million a year. Other biologs comprise five of the top 10 drugs by cost.7
Generic formulations normally replace conventional drugs, but this does not apply as readily to the biologics class, which are essentially unique and characterised by effect rather than a precise formula.
Biosimilars are emerging at a cost of perhaps 40-80% of the original. The Department of Health has published a fact sheet that explains the details.8
This new science of biological medicines and investigational tools will alter the way we think about and practice medicine, with unimaginable improvements in quality of life, prognosis and potential cures. The problem for governments will be managing their cost, availability and utilisation.
Professor Bossingham is a retired rheumatologist and associate professor at James Cook University College of Medicine and Dentistry, Queensland.
References on request.