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Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells

Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells

Published on: February 15, 2019

Primate testing of TGN1412: right target, wrong cell.

M Pallardy¹, T Hünig

¹Universud, Faculty of Pharmacy, INSERM UMR 996, Chatenay-Malabry, France. huenig@vim.uni-wuerzburg.de

British Journal of Pharmacology

|October 1, 2010

Summary

Toxicity studies failed to predict adverse reactions to the CD28-specific antibody TGN1412. This was because the specific T-lymphocyte subset responsible for cytokine release in humans lacks the CD28 target molecule in cynomolgus monkeys.

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Area of Science:

Immunology
Pharmacology
Toxicology

Background:

The first-in-human study of TGN1412, a CD28-specific monoclonal antibody, resulted in severe cytokine release syndrome.
Preclinical toxicity studies in non-human primates failed to predict this adverse event, leaving the cause unexplained.

Purpose of the Study:

To identify the specific subset of human T-lymphocytes responsible for cytokine release syndrome during TGN1412 administration.
To investigate the presence of the CD28 target molecule on this T-lymphocyte subset in cynomolgus monkeys.

Main Methods:

Flow cytometry and cytokine analysis were used to characterize human T-lymphocyte subsets.
Immunohistochemistry and flow cytometry were employed to assess CD28 expression on cynomolgus monkey T-lymphocytes.

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Main Results:

The effector memory subset of human T-lymphocytes was identified as the primary source of pro-inflammatory cytokines.
This critical T-lymphocyte subset was found to lack CD28 expression in cynomolgus monkeys.

Conclusions:

The absence of CD28 on the relevant T-lymphocyte subset in cynomolgus monkeys explains the failure of preclinical models to predict TGN1412 toxicity.
This finding has significant implications for the preclinical evaluation of biological drugs, particularly monoclonal antibodies targeting T-cell co-stimulatory molecules.