Trends in Pharmacological Sciences
OpinionImmunological mechanism underlying the immune response to recombinant human protein therapeutics
Introduction
One of the reasons for developing therapeutic proteins that are as identical as possible to their endogenous counterparts was to avoid recognition and activation of the immune system. Owing to their similarity to endogenous proteins, recombinant human (rhu) protein therapeutics were not expected to cause formation of anti-drug antibodies (ADAs). Nevertheless, the formation of antibodies against human homolog protein therapeutics in patients was recognized when reports appeared about the loss of efficacy of the therapeutic drug because of ADAs 1, 2. ADAs were also implied in severe side effects owing to cross-reactivity with the endogenous protein, leading to life-threatening conditions [3]. Taking into account the large number of rhu protein therapeutics in the production pipeline, the formation of ADAs needs to be prevented. But by what measures (e.g. epitope deleting, formulation adjustments, etc.) depends on the underlying immunological mechanisms.
In general, the immunogenicity of a therapeutic protein is categorized into two broad mechanisms: (a) low or non-existing tolerance with induction of a classical response dependent on T cells and (b) breakage of B cell tolerance. Immunological tolerance is defined as the capability of the immune system to precisely discriminate between self/tolerant and non-self/non-tolerant. Therapeutics of non-human origin (e.g. streptokinase) is recognized as non-self/non-tolerant and the classical T cell-dependent B cell activation is initiated leading to xenoantibodies [1]. In the case of rhu proteins functioning as a replacement therapy (e.g. rhu Factor VIII) for patients carrying genetic defects in the endogenous protein, it is most probably the low-tolerance that will activate the immune system [4]. Nevertheless, even immune tolerant patients develop ADAs against human homologs, and therefore an explanation other than a lack of tolerance needs to be considered. In recent years, the dogma of immunological tolerance has been refined by the ‘danger theory’. The danger theory states that the immune system has maturated to not only distinguish between self and non-self but also to raise an immune response against danger signals which can originate from both self and non-self proteins.
How the tolerance in patients is broken and the exact mechanism leading to the breakage of tolerance is not well understood, and both the tolerance as well as the danger theory need to be considered. This article focuses on the influence of presenting the rhu self-protein in a repetitive pattern (as in aggregates) and thereby confusing the immune system into believing that the aggregated rhu protein is a foreign antigen. Current immunological findings, such as the human marginal zone (MZ) B cells, are incorporated into the possible mechanism involved in breakage of tolerance against aggregated rhu therapeutics. It is well accepted that aggregation is a major key factor in immunogenicity and reducing aggregation levels also lowers immunogenicity [5]. Understanding the immunological mechanism behind the breakage of tolerance will provide profound insights into the problem of immunogenicity of rhu proteins and can help to develop reliable preclinical screening tools leading to safer and more efficient drugs.
Section snippets
Immunological mechanisms leading to the production of antibodies
The classical immune response against foreign antigens is dependent on T cell/B cell interaction to produce effective antibodies. Because rhu therapeutics is not supposed to be recognized as foreign by the immune cells the classical activation of T cell/B cell interaction is not sufficient to explain the formation of ADAs. This paper describes the mechanisms of inducing B cell activation and maturation into antibody-secreting plasma cells.
Case studies supporting the formation of ADAs against rhu proteins
There are many well-documented cases of immunogenicity of rhu therapeutic products. A few case studies will be presented here.
Can aggregation be the key?
Many product-related factors are considered to contribute to the immunogenicity of human therapeutic proteins, including primary structure, impurities (in particular protein aggregates), and protein modification such as PEGylation 1, 34. Clinical data suggests that aggregation is a major contributor to the immunogenicity of rhu therapeutics [35] (Table 2). Furthermore, studies conducted in animal models immune-tolerant for the human protein have provided convincing results that aggregates
Conclusion: The ‘waters’ of immunogenicity of rhu protein therapeutics run deep and need further exploration – animal models as appropriate models
Immunogenicity of therapeutic proteins is an increasing problem with serious clinical consequences and safety concerns from time to time. The rejection of human homologs has challenged the widely accepted view that the immune system can precisely distinguish between foreign and non-foreign proteins. Other theories, such as the danger theory, need to be explored further. So far, much information and insight have been obtained by using mouse models. Because breakage of tolerance seems to be a
Glossary
- Autoantibodies
- antibodies produced against self-proteins.
- B cell activating factor
- crucial cytokine involved in survival of peripheral B cells, keeping a steady B cell pool; it is also suspected to have a pivotal role in autoimmune diseases by favoring the survival of low-affinity autoreactive B cell.
- Erythropoiesis
- production of red blood cells from precursor cells in the bone marrow.
- Human leukocyte antigen (HLA)
- the HLA system in humans encodes for the major histocompatibility complex (MHC). The
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