Development of an assay to predict immunogenicity for an analogue of an endogenous protein

Development of an assay to predict immunogenicity for an analogue of an endogenous protein

Case study

A highly promising analogue of an endogenous protein was identified as a drug candidate in preclinical studies in rats and monkeys. The sponsor decided to proceed with clinical studies in humans within 10 months, which was a major challenge as the data on immunogenicity required for the regulatory IND filing had to be generated. Due to this ambitious goal, the sponsor decided to partner with Ardena to develop a rational scientific immunogenicity assay according to the regulatory guidelines.

In the first step, an immunogenicity risk assessment was performed. As the compound was an analogue of an endogenous protein, the therapeutic protein was classified as a high-risk molecule for immunogenicity. This risk classification was based on the assumption that any antibodies generated and directed against the protein analogue may also be directed against the endogenous protein causing serious adverse reactions.

The most important basis for an immunogenicity assay is the development of a positive control and its production in sufficient quality and quantity to cover the assay development and immunogenicity screening. These positive control antidrug antibodies (ADA) are required for evaluation of the key parameters in the immunogenicity assay: assay sensitivity and drug tolerance. For this purpose, rabbits were immunized with the analogue protein to induce polyclonal antibodies against the drug. After 87 days, sufficient immune response was observed and the final bleed was harvested. After affinity purification of the final bleed, a quantity of approximately 35 mg of ADAs was obtained.

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