1st CNE Seminar, LEO Pharma, Copenhagen, 14th of June 2018


Dr. Maurice Cary:

“Preclinical Development and Safety Assessment of Biotherapeutic Proteins – New Diagnostics and Interpretation Challenges in Histopathology”

In 2010 only 1 of the top 10 selling drugs in the world was a biologic. However, in 2017 9 of the top 10 selling drugs in the world are biologics, denoting a major shift in development of one category of drug (small molecules/NCEs) to another, i.e. biologics.

To date biologics are typically understood to be a large molecular weight therapeutic protein, e.g. monoclonal antibody, recombinant protein. Accompanying this shift is a new range of histopathology lesions rarely observed (if at all) in NCE nonclinical safety evaluation studies. Though this range of lesions may be new additions to the list of routine findings observed by today’s pathologist evaluating safety studies, they are in fact pathognomonic for hypersensitivity reactions described in the classic pathology literature for decades. In a safety evaluation study of a large molecular weight protein, such hypersensitivity responses, mediated by anti-drug antibodies (ADA), are expected reactions precipitated by the administration of a foreign protein (albeit a monoclonal antibody or recombinant protein) to a normal immunocompetent animal.

This lecture will give a general description of the types of hypersensitivity reactions typically observed in such studies along with examples of the corresponding histopathology lesions. With regard to the impact on the safety evaluation and relevance to humans, it is critical for the pathologist to remember that such reactions are expected and that immune reactions in animals are not predictive of the same occurring in humans.


Dr. Barbara von Beust:

“Preclinical Studies with mAb - the Role of Clinical Pathology and the Importance of Developing a Solid Study Plan”

The role of Veterinary Clinical Pathology is not really much different between conventional study plans or study plans for a preclinical study with a large molecule including monoclonal antibodies. However, as clinical pathology still has to establish itself as an important expert discipline in many standard preclinical environments, potentially serious consequences can result in any study but especially in specialized studies including biologics.

What is often underestimated is that certain assays in clinical pathology require extra time for solid validations and the establishment of scientifically sound standard practices in different species, for instance for cytokine determinations or flow cytometric phenotyping, or other specialized assays, depending on the expected treatment effect including immune suppression und secondary changes due to infections or acute phase response. This is due to the fact that ready to use kits do not exist for every species and variable, and certain practices also require specialized technical skills and training in laboratory personnel, and the requirement for additional blood samples may have an influence on the overall study plan, including the number of animals required. Also, in many cases it is required to compare treatment related effects to predosing blood samples, especially in monkeys and dogs, and these need to be sampled in due time (i.e. prior to the treatment phase) and processed, stored and tested adequately, which all require advance planning in close collaboration with the clinical pathology expert and laboratory management.

Importantly, treatment related changes such as an acute phase response or even chronic inflammatory disease may often not be diagnosed histopathologically as the acute phase proteins are increased mainly in blood, and subtle indicators for chronic disease such as anemia of chronic disease may also not be identified histologically but only in hematology. In addition, because such variables can show an important degree of biologic variation between individual animals each animal has to serve as its own control for comparison of potential treatment effects and the assessment, interpretation and reporting of such results requires experience, skills and often a solid background in functional and molecular immunology.

In this seminar I will illustrate some typical examples and provide some basic recommendations how to avoid pitfalls in preclinical studies with biologics.