Healthcare spotlight: Antibodies - applications and success

Antibodies are set to play an even bigger role in healthcare in the years to come, and private equity can support companies at the forefront of such innovation. Dee Athwal, a pharma and biotech adviser and  part of Inflexion’s Healthcare Advisory Board shares his insights on this niche area.

Where do you see the future clinical / therapeutic applications for antibodies?

In the coming years we’ll see antibodies used to modulate the immune system, turning the body’s innate defence systems on and off depending on the intervention for modulating the disease. Effectively it is utilising the antibody to actually change attributes and features of the immune system to either become active or suppress an overactive immune system. Cancer is a good example of how antibodies are being used to activate the immune system. Tumours are able to evade the body’s immune system by effectively keeping T cells responsible for destroying the tumour “switched off”, allowing cancer cells to grow and establish themselves. Antibodies are now being used to block the signal the tumour cell uses to keep T cells switched off, so they are effectively decloaking the tumour and allowing the T cell to become activated, thereby killing the tumour cell. This class of therapeutics are referred to as checkpoint inhibitors.

Similarly, using antibodies as agonists (activators) of the immune system is gaining traction. These antibodies typically bind to receptors on the surface of cells and in doing so trigger signals in those cells be it to activate immune cells or trigger a signal that results in cell death. Agonistic antibodies typically require two or more events to happen which is achieved by engineering multiple binding sites into the antibody producing so called bispecific / multispecifc antibodies.

Progress in the linking of cytotoxic drugs to antibodies, resulting in so called antibody drug conjugates (ADCs) addresses a significant issue with cytotoxic drugs, namely balancing the desired on target activity with the off target effects which frequently results in a small therapeutic window in which to use chemo therapeutic drugs. The drug when attached to the antibody has no activity, the antibody will bind to the target cell followed by the release of the drug which then becomes activated but at the desired site of action. Companies are now exploring an increasing array of potent cytotoxic drugs and ways in which these drugs can be coupled to antibodies.  In parallel to this, new technologies and assays are being developed to evaluate these complex drugs and ensure they are being manufactured in a consistent reproducible manner.

We are also starting to see antibodies being considered for intracellular targets, targets inside cells, with various technologies under development to achieve this. Currently the majority of antibody targets are found outside cells or on the surface of cells, but many disease targets are located inside the cell which are targeted through the use of traditional small molecule drugs.  By exploiting technologies used in gene therapy it is now possible to deliver the genetic information for producing antibodies, effectively making a cell factory for the antibody.

Why has this focus on immunomodulators come to the fore?

New technologies have given us a deeper understanding of diseases and this has resulted in new targets that were not historically known to be drivers of the disease. First generation anti-cancer antibodies targeted tumour cells directly by focusing on what was different in a tumour cell as compared to a normal cell. Whilst understanding the differences between normal and cancer cells remains an important area of research, the discovery of how tumours evade the immune system has provided novel and more effective approaches to treating disease with cures now being reported. We can now engineer antibodies to act in novel and more powerful ways than previously thought.  

What are the key challenges of getting a biologic therapy to market?

There are multiple:

Manufacturing the product remains a major challenge. Whilst technology such as single use bioreactors and new manufacturing providers has had a material impact in addressing historical global shortages of capacity for the manufacture of biological products including antibodies, the explosion in early discovery and Phase I/II antibody programmes means capacity is not always available. Advances have also been made in improving the manufacturability of antibodies. It is possible to make design changes to a potential therapeutic antibody that address challenges that would be encountered during manufacturing scale up. However, the design and complexity of therapeutic antibodies has increased, examples are bispecific / multispecific antibodies that are capable of binding two or more different targets. These increasingly complex antibodies can be challenging to manufacture at scale and at acceptable cost. Manufacturing processes have to be adapted for these newer molecular structures that adds to development timelines, yields and costs.

You then have the regulatory requirements, with drug development getting more expensive as science advances and the complexity of the molecules increase. It takes time to generate required data prior to the start of a clinical trials. This data needs to be reviewed by regulators who determine if a clinical trial is justified. Often, the regulators will stipulate that clinical studies are carried out is specific patient / subject cohorts, requiring substantial resource for recruiting into the study and the time for reaching the clinical endpoints.. For example dementia is typically a slow progressive disease resulting in cognitive decline in patients over several years. As such, if you start a trial aimed at demonstrating that cognitive decline is slowed by your therapeutic, you have to perform the study over several years, comparing patients on drug vs a control untreated group in order to demonstrate tangible benefit or not, at slowing the progress. Cancer is another example, with your drug outcome requiring five or 10 years before a possible benefit is clear over existing drugs which provide five- or 10-year extension of life. The longer the trial, the higher the cost as you need to show an improvement over existing therapy, so drug development becomes more expensive.

This touches on another major challenge: price. These drugs are expensive and there are increasing pressures on healthcare systems to make these drugs accessible. Affordability is a challenge with the industry exploring different models with payers including linking payment with patient outcomes . Pricing requires alignment of providers and payers, and that’s a complex evolving ecosystem.

How do you see these challenges being overcome?

For the industry to innovate, it needs to be able to make profits which in turn support fundamental R&D. This R&D is becoming more and more expensive, and the hurdles facing the industry are growing as regulators and patients are increasingly concerned with and aware of safety issues. People rightly want better and more efficacious drugs, but it means more research and that translates to more expensive. As the drugs become more complex, for example gene therapies, the cost increases exponentially.

From an industry perspective we can become more efficient, with technology driving down some of the costs associated with manufacturing. There are technologies coming to market that have already increased capacity in the industry, for example single-use bioreactors (disposable manufacturing platforms) which have not only expanded capacity but also driven down costs of establishing these facilities.

There are also increasingly tools available to help recruit the right types of patients we need for testing, with better stratification making for better trial design. Increasing understanding of why some drugs work in some patients and not others is enabling the selection and tailoring of medicines at the individual level, in effect personalised medicines. Personalised medicine is an emerging practice of medicine that uses an individual's genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease. Knowledge of a patient's genetic profile can help prescribers select the proper medication or therapy and administer it using the appropriate dose or regimen. 

Following several decades of producing complex biologicals like antibodies has increased in our understanding of how to produce and use biologicals and the development of more standardised platform manufacturing processes. You can essentially take the recipe off the shelf and make your drug – typically some “tinkering” is still required but the platform does create efficiency.

Importantly, regulators are standardising and aligning guidance globally, moving to common templates for submission of data for review so you don’t have to tailor documents for each country submission.

Where do you see the most innovation over the next five years?

The US and Asia will win this for three primary reasons: access to capital is significantly greater in the US and Asia, they are less risk-averse and so more prepared to invest in innovation combined with an established culture of entrepreneurship.

The UK and EU is too fragmented at the moment, with too many smaller companies lacking scale. The UK government is making attempts to redress this but as it stands today, there is a long way to go before it actually has a meaningful impact and support needs to be more co-ordinated. As an example, the recent proposed changes to R&D tax credits is but one example of an action that undermines innovation and investment in the UK.

Dee Athwal has been a pharma and biotech adviser for over 15 years, is CEO of Complement Therapeutics and previously held senior roles at Capella Bioscience and UCB.