• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Scientific Publications by FDA Staff

  • Print
  • Share
  • E-mail
-

Search Publications



Fields



Centers











Starting Date


Ending Date


Order by

Entry Details

J Pharm Sci 2017 Mar;106(3):751-60

In vivo effect of innate immune response modulating impurities on the skin milieu using a macaque model: impact on product immunogenicity.

Haile LA, Puig M, Polumuri SK, Ascher J, Verthelyi D

Abstract

Unwanted immune responses to therapeutic proteins can severely impact their safety and efficacy. Studies show that the presence of trace amounts of host cells and process-related impurities that stimulate pattern recognition receptors (PRR) can cause local inflammation and enhance product immunogenicity. Here we used purified PRR agonists as model impurities to assess the minimal level of individual innate immune response modulating impurities (IIRMIs) that could activate a local immune response. We show that levels of endotoxin as low as 10 pg (0.01 EU), 1 ng for polyinosinic:polycytidylic acid (PolyI:C), 100 ng for synthetic diacylated liopprotein, thiazoloquinolone compound, or muramyl dipeptide, 1 mug for flagellin or beta-glucan, or 5 mug for CpG-oligodeoxynucleotide increased expression of genes linked to innate immune activation and inflammatory processes in the skin of rhesus macaques. Furthermore, spiking studies using rasburicase as a model therapeutic showed that the levels of PRR agonists that induced detectable gene upregulation in the skin were associated with increased immunogenicity for rasburicase. This study underscores the need for testing multiple IIRMIs in biologics, strengthening the connection between the local mRNA induction in skin, innate immune activation, and antibody development in primates, and provides an indication of the levels of IIRMI in therapeutic products that could impact product immunogenicity.


Category: Journal Article
PubMed ID: #27923493 DOI: 10.1016/j.xphs.2016.11.001
Includes FDA Authors from Scientific Area(s): Biologics Drugs
Entry Created: 2016-12-08 Entry Last Modified: 2017-12-10
Feedback
-
-