IgA antibodies for cancer therapy

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Abstract

Antibody-based therapy is a new treatment option for selected tumor patients. Today, human IgG1 is the most widely used isotype, because it effectively activates human complement, recruits NK cells for ADCC, and has an extended plasma half life. In recent work, however, neutrophils — the most populous cytotoxic cells in humans — were more effectively recruited by human IgA than by IgG antibodies. IgA antibodies may have the additional advantages of forming natural dimers with improved signaling capacity on tumor cells, and being actively transported into mucosal secretions with the potential for improved targeting of certain carcinomas from the luminal surface.

Section snippets

Introduction and rationale for the use of IgA antibodies in oncology

In addition to surgery, chemotherapy and radiotherapy, antibody-based immunotherapy seems to become a new treatment option for selected oncological patients [1], [2]. Based on documented efficacy in clinical trials, three antibodies — 17-1A against EpCAM, C2B8 against CD20 and 4D5 against HER-2/neu — have been approved for therapeutic application in tumor patients — others are expected to follow. In order to further improve the efficacy of unconjugated antibodies, it would be helpful to

Structure of IgA and its three different isoforms

Compared with other immunoglobulin isotypes, IgA is the most abundantly generated antibody isotype with a production of approx. 3–5 g/ day [9]. IgA is critically involved in the host defense at mucosal surfaces [10]. This important function in immune surveillance is underlined by clinical observations in genetically IgA-deficient patients, who suffer from recurrent bacterial infections — especially of the upper respiratory tract. In man, two isoforms of IgA — named IgA1 and IgA2 — are

Production of recombinant IgA

While early studies with IgA mainly used purified myeloma proteins, progress in antibody engineering recently allowed generation of recombinant IgA. This progress offers the chance to produce sufficient amounts of IgA antibodies with well-defined specificity for preclinical — and potentially also clinical — testing. Thus, human IgA antibodies against potential tumor target antigens such as CEA, EpCAM, HLA class II and CD20 were generated [16], [17], [18]. In vivo, the components of secretory

IgA receptors

Although IgG and IgA antibodies do not interact with receptors for the other respective isotype, the receptor system has some aspects in parallel. Thus, comparable to IgG receptors on endothelial cells [23] and on leukocytes [24], cellular IgA receptors can be divided into molecules which determine the pharmacokinetic profile of IgA, and those which mediate IgA effector functions on phagocytes. For IgA, the main pharmacokinetic receptor is the polymeric immunoglobulin receptor (pIgR), which

Pharmacokinetics of IgA

The pharmacokinetic properties of IgA are fundamentally different from those of IgG. In contrast to IgG, IgA does not bind to the neonatal Fc receptor (FcRn), and is — therefore — not protected from degradation, and has a significantly shorter half life than IgG [23]. On the other hand, dimeric IgA — but not IgG — binds to the polymeric immunoglobulin receptor, and is, therefore, actively transported into secretions [13]. Today, the best evidence for the active secretion of IgA comes from

Effector functions of IgA

Antibody-mediated effector mechanisms can be divided into direct effects, which are mediated by their variable F(ab′) regions, and indirect mechanisms, which require interaction of antibodies’ constant regions with complement proteins or Fc receptors on effector cells [3]. For a long time, IgA was considered an anti-inflammatory, the immune response down-modulating antibody isotype and not effective in activating host defense mechanisms. Therefore, research in oncology and in infectious

Therapeutic application of IgA antibodies

In infectious models, several animal studies showed the protective effects of therapeutic IgA antibodies — further establishing the importance of IgA antibodies for the mucosal immune defense [10]. Therefore, induction of a specific IgA response is considered a valuable goal in many vaccination studies for infectious diseases [59]. However, the function of IgA receptors was difficult to address in animal models, because no IgA receptor on effector cells has been molecularly defined in mice.

Conclusions

In summary, human IgA may have several advantages over human IgG1 — the currently most widely used antibody isotype for tumor therapy (Fig. 3). For example, increased valency of dimeric IgA may improve the signaling capacity of therapeutic antibodies — as demonstrated for artificial IgG dimers [46]. In addition, immunotherapy with IgA antibodies offers the potential to attack certain common tumors — such as lung or colon cancers — from the luminal surface. Furthermore, IgA antibodies are

Michael Dechant studied Medicine at the University of Erlangen-Nürnberg, Germany. Since 1999 he is working in the Division of Hematology/Oncology at the Department of Internal Medicine III (chaired by Prof. J.R. Kalden).

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    Michael Dechant studied Medicine at the University of Erlangen-Nürnberg, Germany. Since 1999 he is working in the Division of Hematology/Oncology at the Department of Internal Medicine III (chaired by Prof. J.R. Kalden).

    Thomas Valerius studied Medicine at the University of Erlangen-Nürnberg, Germany. Since his Board Certification for Internal Medicine in 1996, he is working in the Division of Hematology/Oncology at the Department of Internal Medicine. Since 1998, Thomas Valerius is Assistant Professor for Internal Medicine at the Medical Faculty of the University of Erlangen-Nürnberg.

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