One of the big issues facing biotherapeutics is potential for generation of unwanted immune response. Biologicals have a propensity to elicit immune responses as a consequence of many factors including being protein-based macromolecules. Immunogenicity is relevant for both proteins and peptides including those generated by recombinant DNA technology as well as synthetic peptides. For example, insulin for use in the treatment of diabetes was originally derived from animal sources and was associated with anti-insulin antibodies. Recombinant insulin is significantly less immunogenic, however the potential still exists to elicit an unwanted immune response. Monoclonal antibodies have also been associated with the generation of unwanted immune responses.

An unwanted immune response can present in a variety of different ways:

  • An hyperimmune response which can result in potentially life-threatening anaphylactic reaction.
  • Formation of Anti-Drug Antibodies (ADA): can potentially lead to increased adverse events and reduced efficacy. For example, ADA can change the pharmacokinetics of the biological such that more frequent dosing is required. Alternatively the binding can result in acting as a carrier – thus effectively increasing the half-life of the circulating drug. ADA may cause significant clinical effects such as infusion reactions, and alter the products pharmacokinetic and/or pharmacodynamic profiles of the biological. Formation of ADA can also be a precursor to the development of neutralising antibodies.
  • Neutralising antibodies against the therapeutic protein: the formation of neutralising antibodies against the biological is problematic as it can result in a loss of efficacy.
  • Neutralising antibodies against endogenous counterpart: are even more problematic as it can result in a clinical deficiency syndrome when protein which are a constituent part of the patient are targeted.


Thus the major issues with the formation of unwanted immune response can be both immediate and long term clinical consequence. Additionally the formation of unwanted immune response is unpredictable. There are several factors which are associated with an increased risk of immunogenicity such as the route of administration and formation of aggregates. These are, however, not the only factors and changes to the manufacturing process can result in the generation of immune response which were not previously problematic. Consequently immunogenicity is a risk which needs to be investigated and managed.

The bottom line is that immunogenicity assessments are critical in the development and registration of proteins and peptides including biosimilars.