A report by scientists at the U.S. Food and Drug Administration (FDA) clarifies some of the approaches researchers can use to identify small changes introduced into bio-engineered proteins drugs that don’t exist in the natural protein and that might trigger production of anti-drug antibodies. The findings could also identify those patients most likely to be affected by those changes. Bio-engineering uses genetics and other technologies to design and manufacture proteins so they have characteristics not found in natural proteins.

The results of the FDA study are important because anti-drug antibodies (ADAs) can reduce both the safety and efficacy of drugs, thus derailing or delaying their development and availability to the public.

Hemophilia is a bleeding disorder that causes potentially life-threatening, excessive bleeding after an injury. The disease is caused by the lack—or low level-of—one of a class of proteins called clotting factors. Clotting factors are part of a biochemical chain reaction that forms a clot. A lack of any molecule in that chain will slow down or prevent the formation of a clot, a possibly life-threatening outcome. The only treatments available are replacement of the missing clotting factors that either are obtained from human plasma or manufactured by genetic engineering.

A potential advantage to the use of genetically engineering clotting factors is the ability to design molecules that can last longer in the body than natural factors, or have other characteristics that make them safer and more effective. However, while all new changes in a bio-engineered protein drug, called neo-sequences, have the potential to trigger ADAs, not all do so. Therefore, it would be extremely useful during drug development to have a way to predict whether there is a high risk that a specific neo-sequence will trigger ADA production.

Specifically, the techniques used in the study could help future researchers to more accurately determine which new-sequences have the potential to trigger ADAs. This would also help researchers to identify which patients in a proposed clinical trial might be at increased risk for developing ADAs to protein drugs used to treat hemophilia or other diseases. In turn, that could enable researchers to design better clinical trials, reducing both the time and expense required to complete these studies.

The FDA scientists studied a particular bio-engineered drug called vatreptocog alfa, which was being developed as a “bypass” drug for factor VIII deficient patients for whom factor VIII infusions are no longer effective. A bypass drug enables a normal biochemical chain reaction to occur in the body even in the absence of a critical part of that chain.

The previous treatment—recombinant Factor VIIa--had been used for over 20 years without reports of patients developing ADAs. However, vetreptocog alfa--the bio-engineered version of Factor VIIa--had three minor changes engineered into its structure to improve its efficacy. Patients receiving this drug during a Phase 3 clinical trial did develop ADAs. (Phase 3 clinical trials are human studies in which a medical product’s efficacy is studied in patients.)

In a series of laboratory studies the FDA scientists performed studies to provide mechanistic evidence to determine how the small structural differences in vatreptocog alfa could trigger antibody production against the protein. Specifically, the scientists showed that these differences in the engineered protein were able to bind to certain molecules on the surface of immune system cells that are key to triggering an antibody response. These immune cell molecules, called HLA class II antigens, act like sentinels, scanning the body for foreign substances.

The scientists found that all 11 patients (100%) who had ADAs to vatreptacog alfa peptides also had at least one HLA class II antigen that binds tightly to one of the structural differences on the bio- engineered protein drug; however, only 44 percent of patients without ADAs to the drug had such an allele.

TITLE

Post hoc assessment of the immunogenicity of bioengineered factor VIIa demonstrates the use of preclinical tools

Science Translational Medicine 11 Jan 2017:
Vol. 9, Issue 372,
DOI: 10.1126/scitranslmed.aag1286

AUTHORS

Kasper Lamberth,^1* Stine Louise Reedtz-Runge,¹ Jonathan Simon,² Ksenia Klementyeva,²
Gouri Shankar Pandey,² Søren Berg Padkjær,¹ Véronique Pascal,¹ Ileana R. León,¹
AQ2 Charlotte Nini Gudme,¹ Søren Buus,³ Zuben E. Sauna^2*

¹Global Research, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
²Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapeutics, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
³Laboratory of Experimental Immunology, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.

*Corresponding author. Email: [email protected] (Z.E.S.); [email protected] (K.L.)