Deimmunisation Case Studies
Many novel protein-based therapeutics (biologics) are not naturally occurring proteins. They may be enhanced by engineered mutations or fused to other functional entities. In either case they may be recognised as “non-self” by the immune system. Immunitrack’s technology can be used to determine whether a biologic will be perceived as non-self by the immune system.
Immunitrack is involved in several ongoing projects aimed at deimmunising antibodies for therapeutic use. We will provide updates on these studies when possible.
The following case study describes a retrospective analysis of a drug that failed in a clinical phase III.
Vatreptacog alfa Retrospective Case Study
In 2012 Novo Nordisk discontinued a phase 3 clinical trial on vatreptacog alfa, an optimised variant of their blockbuster Novoseven® containing 3 mutations (Figure 1). Vatreptacog alfa was designed to be a fast-acting recombinant factor VIIa analogue for certain groups of haemophilia patients. A few patients developed antibodies against the biologic during the trial and the program was cancelled, resulting in the loss of 3 billion Danish Krone.
Immunitrack conducted a retrospective analysis using our NeoScreen® platform, and this revealed that the M to Q mutation in vatreptacog alfa gave rise to a “non-self” peptide that bound to at least one particular MHC molecule (Figure 1). This knowledge could have allowed Novo Nordisk to conduct a more thorough risk assessment at an earlier point in the project.
Figure 1. Left: partial amino acid sequence of Novoseven® and its derivative vatreptacog alfa. Two of the 3 mutations in vatreptacog alfa are indicated with arrows. Right: Affinity assessment of 3 peptides, each containing one of the 3 mutations present in vatreptacog alfa. Peptides were assessed for binding to MHC II allele DRB5*0101. The M to Q mutation in vatreptacog alfa resulted in self-recognition and MHC binding as indicated arrow. Neither the original NovoSeven® sequence nor the E>V mutation resulted in MHC binding (flat lines on graph).