The power of fresh human tissue studies in your R&D programmes. By Dr Keith Bowers
A successful Pharmaceutical industry, as a whole, is required if we are to improve the health and well being of our population. We can debate at length which new working models are best to achieve these lofty goals but one thing I do believe; that with such goals, this is a fulfilling and good career to be involved in. So when people ask me about whether I am comfortable with my recent move from Big Pharma (nearly 20 years with AstraZeneca in its various guises) to Biopta, a small, vibrant CRO, expert at delivering fresh human tissue programs it is easy for me to say… yes.
The basic elements of high scientific standards and the generation of decision-making data aligned to defined business needs, is common. What really attracted me to Biopta was that this alignment was evident immediately. When visiting I found the labs were professional and purposeful, stocked with well-maintained, pristine equipment, and populated with informed, energetic scientists- all evidence that scientific quality was high. On talking further, I found a real sense of purpose to the discussions. The science had to be value adding, whether for the internal R&D of Biopta, generating new tissue models, or for the operational delivery of data for contracted programs.
From a personal point of view the specialist area that Biopta operates so successfully in, the provision of fresh human tissue studies, is an attractive prospect. It is a well-defined area to delve into the scientific detail yet its application fits across the whole discovery and early development pipeline; from early target validation, through lead identification and optimisation phases and of course into development. It covers aspects of efficacy, drug pharmacokinetics and safety pharmacology. Since I have experience with all aspects of these phases I could see the value I could bring. This is important to me. I have been struck immediately by one difference in working in a smaller company, the impact that you have on the business is more transparent.
The use of fresh human tissue studies for both early target validation and confirmation of compound activity has been a common factor in every Discovery project I have worked upon; quite a number in the near 20 years I spent in large Pharma. So much so that I virtually take it for granted that human tissue data is a prerequisite if a compound is to progress into the early Development phases. What I never took for granted is the challenge this was to achieve, both in terms of sourcing the human tissue and the quality and the dedication of the scientists needed to work with an innately more variable tissue. The very nature of its source means that human tissue delivery to the laboratories is usually during unsociable hours, and this is when the day starts for tissue preparation and experimentation. Tissue dissection and manipulation needs technical expertise not easy to source for bespoke studies especially in an age where screening in clonal cell lines is the norm.
All of these challenges are offset against the power of that one graph in your slide pack showing your compound has the desired activity against the relevant tissue using a relevant end-point; Compound X blocks contraction of human COPD bronchus for >24 hours after washout, compound Y inhibits etc.
And why is that so powerful to your audience? Possibly because many of them have witnessed what I have seen; across numerous target classes and disease areas, the expression of your target can differ between animals and humans, not just in relative expression levels but also in which cells types they are expressed. This knowledge should at the very least guide your choice of animal model to mimic human mechanistic concepts; a strong argument for gaining that relevant human tissue data prior to choice animal models, if not indeed to replace it altogether.
Even within human target studies, access to an intracellular compartment required for efficacy can vary between cell lines and native tissue, presumably because of transporter expression. So profound can this difference be on a compound activity, especially in relationship to time, that it can or should change your dosing regimen for early pharmacodynamic readouts in Phase I and II clinical trials.
We can go further and talk about allosteric modulation and the concept of pathway selection by receptors depending upon the agonist. There are known examples of synthetic compounds that differentially stimulate or inhibit some cellular pathways, leaving others intact; biased agonism or antagonism. Such complexity, the balance of pathway activation/inhibition and the effect of background cell type, shows itself as altered compound activity in different models. Native human tissue, and possibly even disease tissue, would recapitulate this complexity in a clinically relevant manner and so should be the assay of choice for confirmation of compound activity. Indeed, I predict that the relevance of this argument will become greater as more high-throughput screening systems move towards label-free technologies. In this instance, the deliberate choice not to measure a distinct second messenger pathway to define a compound activity, but more to identify direct compound/target interaction, will lead to a greater need for deconvolution of the mechanism of action. Data from the use of native human tissue must be high in the pecking order for defining which compound/pathway interaction will be ultimately efficacious, or even more attractive, efficacious and differentiated from competitor molecules.
Of course these, and many other related concepts fall under the broad umbrella of translational science/medicine. Such a focus on the issues of translatability of preclinical data to the clinical setting is only correct given the attrition the Pharma industry experiences in phase II and III clinical trials. The use of native human tissue is a powerful tool in strengthening the predictive nature of preclinical data and I can only see its use increasing. Biopta has just opened new laboratories in Maryland, USA to meet this challenge and so it is exciting times indeed. I am looking forward to bringing together the expertise of Biopta with the needs of the Pharma/Biotechnology industry.