Complement Testing for Drug Development: Immunotoxicology, Efficacy, Pharmacodynamics
Leadership of IND Support Laboratory:
Dr. Frazer-Abel brings a decade of experience in clinical and pre-clinical complement and immunoinflammatory testing to the leadership of this laboratory. To prevent conflict of interest, Dr. Holers is not part of the leadership of the laboratory within Exsera and do not have any responsibility for the work pursued in our pharmaceutical and biotechnology support area.
What is the role of complement in immunogenicity and immunotox testing or “Why should I to add complement testing to my clinical trial?”
What is complement: Complement is an ancient part of the body’s innate immune defense system. The proteins of the complement cascade can recognize invading microbes based on charge or structure alone, even if that immune system has never been exposed to the microbe before. Similarly, complement can recognize debris from the destruction of the invaders and debris from the host that needs to be cleared, such as excess immune-complexes. Once complement has recognized invaders or debris it can initiate a powerful proinflammatory process. Still, what can be a great benefit in fighting infection locally, can be very detrimental if it happens systemically.
Complement and novel drugs: Complement often recognizes a novel biologic test article as foreign and the outcome can be an anaphylactoid- type response or an increased rate of clearance, for example. If the test article is an antibody or an engineered antibody type molecule, complement may recognize that as well. While this may be a desirable outcome in the case of CDC for cancer therapy, it can lead to adverse sequelae in other situations. Even if the biologic is not an antibody itself, but anti-drug antibodies are present, or develop, complement can be the mediator of resulting anaphylactoid responses.
The good news is that while complement can have these negative impacts on a test article profile, it is possible to determine if complement is involved and which pathway or activation mechanism is involved. Because complement reacts well to IgM and IgG antibody complexes, complement measurements can help elucidate the presence of anti-drug antibodies even where ADA assays are unavailable. Though complement testing has been around for decades, it has proven a difficult area to tackle. From the arcane nomenclature, to the tricky pre-analytic to post-analytic considerations, to the simple difficulties of functional tests, poor complement analysis is unfortunately too easy to find, but not to recognize. With an average of 15 years of experience in complement testing, the Exsera BioLabs team has a proven record of supplying quality complement results.
DownLoads & FORMS:
expertise:
Ashley Frazer-Abel, PhD, D(ABMLI)
Director, Exsera BioLabs
Dr. Frazer-Abel is the Director of the Exsera BioLabs and Assistant Professor. She brings a strong background in complement and autoimmune testing for both patient diagnostics and clinical trials, having served as Principal Investigator or Contributing Scientist for the complement and cytokine analysis for more than a hundred non-clinical and clinical trials. In addition she has a strong interest in the development and validation of novel assays to fill diagnostics gaps. Dr. Frazer-Abel brings with her experience of the regulatory landscape and requirements for diagnostics testing, as well as the requirements for compliance with the US FDA GLP and GCP regulations.
Publications:
DEHP Nanodroplets Leached from Polyvinyl Chloride IV Bags Promote Aggregation of IVIG and Activate Complement in Human Serum.Snell JR, Monticello CR, Her C, Ross EL, Frazer-Abel AA, Carpenter JF, Randolph TW. J Pharm Sci. 2019 Jun 20.
Mechanistic understanding for the greater sensitivity of monkeys to antisense oligonucleotide-mediated complement activation compared with humans. Shen L, Frazer-Abel A, Reynolds PR, Giclas PC, Chappell A, Pangburn MK, Younis H, Henry SP. J Pharmacol Exp Ther. 2014 Dec;351(3):709-17. doi: 10.1124/jpet.114.219378. Epub 2014 Oct 9.
PMID: 25301170