Structure and function of antibodies

Introduction

Antibodies represent the quintessential effector molecules of the adaptive immune system. They display tremendous variation in structure, allowing the immune system to quickly adapt to invading pathogens, recognizing a virtually unlimited number of structures, and combining this with a large variety of functional traits in a modular fashion. Antibodies have also been exploited successfully as therapeutic agents, resulting in highly selective and powerful treatments that dramatically changed the lives of millions of patients treated with e.g. TNF inhibitors. An ever increasing list of approved therapeutic antibodies emphasizes not only the versatility of antibodies as therapeutic agents, but also the continued need to investigate antibody structure and function in its various facets. Although intensively studied, the basic biology of immunoglobulins is still incompletely understood, precisely because of their large structural variation and the potential to interact with so many other parts of the immune system.

Interestingly, besides key players in fighting infections, antibodies also contribute to immunopathology, and can regulate/modulate immune responses in various ways. Thus, many autoimmune disorders are characterized by autoantibodies. At the same time, autoreactive antibodies may also be essential to homeostasis, and self-reactive natural antibodies have been implied to contribute to clearance of e.g. degraded proteins. Antibodies are also produced in response to food & environmental (non-infectious) antigens, which may cause allergy. However, often no apparent effects develop, in part because of a response that is skewed towards IgG4, a poor trigger of effector functions. Therapeutic proteins can also elicit an immune response that often includes IgG4 antibodies, which usually does not result in hypersensitivity reactions, but can result in neutralization of the drug. Notably, in case of therapeutic antibodies, the resulting anti-drug antibodies are anti-idiotype antibodies, which can also develop naturally and have been implied in regulation of B cell responses. Thus, the spectrum of specificities and activities that antibodies display in situations of health and disease, unrelated to infection, is broad.

We investigate the development of antibody responses in these situations, how antibodies initiate and regulate these responses and may lead to pathology or loss of efficacy, and generate knowledge that may result in improved treatment options using therapeutic antibodies in the clinic. Our research addresses one central aim: unraveling the mechanisms of (lack of) regulation by antibodies in pathological and clinical setting. In this context, we focus in particular on non-infectious antigens. In order to achieve this, we develop biophysical and immunochemical methodology to investigate structure-function relationships of antibodies in a basic and clinical setting.

Medical needs

Funding

  • MODIRA (ZonMw, Netherlands Research Council)
  • PSORT (MRC)
  • Hersenstichting (Brain foundation of the Netherlands, together with VUMC)
  • Product and Process Development Plasma Products (PPOP; internal funding obtained in competition)
  • Product and Process Development Diagnostic Services/Reagents (PPODR, internal funding in competition)
  • Genmab

Our research