IgA antibodies for cancer therapy
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).
References (64)
- et al.
Signaling antibodies in cancer therapy
Curr. Opin. Immunol.
(1999) - et al.
Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies
Blood
(1998) - et al.
Therapeutic efficacy of FcγRI/CD64-directed bispecific antibodies in B-cell lymphoma
Blood
(2000) - et al.
The Fab and Fc fragments of IgA1 exhibit a different arrangement from that in IgG: a study by X-ray and neutron solution scattering and homology modelling
J. Mol. Biol.
(1999) - et al.
Dimeric recombinant IgA directed against carcino-embryonic antigen, a novel tool for carcinoma localization
Mol. Immunol.
(1994) - et al.
FcRn: the MHC class I- related receptor that is more than an IgG transporter
Immunol. Today
(1997) - et al.
Human immunoglobulin A receptor (FcαRI, CD89) function in transgenic mice requires both FcRγ-chain and CR3 (CD11b/CD18)
Blood
(1999) - et al.
Functional association between the human myeloid immunoglobulin A Fc receptor (CD89) and FcRγ-chain. Molecular basis for CD89/FcRγ-chain association
J. Biol. Chem.
(1995) - et al.
Role of Src in the modulation of multiple adaptor proteins in FcαRI oxidant signaling
Blood
(1999) - et al.
Identification of residues in the CH2/CH3 domain interface of IgA essential for interaction with the human Fcα-receptor (FcαR) CD89
J. Biol. Chem.
(1999)
A critical role for PI 3-kinase in cytokine-induced Fcα receptor activation
Blood
The major subunit of the asialoglycoprotein receptor is expressed on the hepatocellular surface in mice lacking the minor receptor subunit
J. Biol. Chem.
The human Fc receptor for IgA (FcαRI, CD89) on transgenic peritoneal macrophages triggers phagocytosis and tumor cell lysis
Immunol. Lett.
FcαRI (CD89) as a novel trigger molecule for bispecific antibody therapy
Blood
Bispecific antibodies in cancer therapy
Curr. Opin. Immunol.
HLA class II as potential target antigen on malignant B cells for therapy with bispecific antibodies in combination with granulocyte colony-stimulating factor
Blood
Cytokines, tumour-cell death and immunogenicity: a question of choice
Immunol. Today
Monoclonal antibody therapy of cancer
Semin. Oncol.
Monoclonal antibody therapies — a ‘constant’ threat to cancer
Nat. Med.
Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets
Nat. Med.
Human antibodies by design
Nat. Biotechnol.
The structure and function of human IgA
Biochem. J.
Intestinal IgA: novel views on its function in the defence of the largest mucosal surface
Gut
The joining (J) chain is present in invertebrates that do not express immunoglobulins
Proc. Natl. Acad. Sci. USA
Transepithelial transport of immunoglobulins
Annu. Rev. Immunol.
Lack of association of secretory component with IgA in J chain-deficient mice
J. Immunol.
Secretory component delays the conversion of secretory IgA into antigen-binding competent F(ab′)2: a possible implication for mucosal defense
J. Immunol.
A recombinant, fully human monoclonal antibody with antitumor activity constructed from phage-displayed antibody fragments
Nat. Biotechnol.
Human chimeric IgA antibodies mediate improved effector cell recruitment against B-cell lymphoma
Blood
In vitro comparsion of the antigen-binding and stability properties of the various molecular forms of IgA antibodies assembled and produced in CHO cells
Proc. Natl. Acad. Sci. USA
Recombinant expression of polymeric IgA: incorporation of J chain and secretory component of human origin
Eur. J. Immunol.
Cited by (69)
Therapeutic exploitation of neutrophils to fight cancer
2021, Seminars in ImmunologyCitation Excerpt :Tumor colonies grown in the presence of endothelial cells increased neutrophil recruitment through release of the neutrophil chemokine IL-8 by endothelial cells [96]. Moreover, FcαRI targeting on neutrophils induces more potent tumor cell killing compared to FcγR targeting [97,98]. The enhanced potency of FcαRI targeting has been shown in vitro for various tumor-associated antigens (TAA), including EGFR (epithelial carcinoma, colorectal carcinoma, renal cell carcinoma), Her-2/neu (breast carcinoma), CD20 and HLA class II (B cell lymphoma), CD30 (B cell lymphoma and T cell lymphoma), carcinoembryonic antigen (CEA) and EpCAM (colon carcinoma) [91,97,99–109].
C1q, antibodies and anti-C1q autoantibodies
2015, Molecular ImmunologyCitation Excerpt :Papp et al. demonstrated that the potential pathological impact of ICs is also dependent on the IC signature, the antibody classes and subclasses and the antigen to which the ICs are directed to (Papp et al., 2012). Whereas IgG1 and IgG3 are strong complement activators, IgG-mediated complement activation of the classical pathway can be silenced and be manipulated by specific antibody isotypes which do not bind C1q, for example, IgG4 or IgA (Davies et al., 2014; Dechant and Valerius, 2001; Kerr, 1990; Labrijn et al., 2008; van der Neut et al., 2007; Woof and Kerr, 2006). The IC signature might therefore also be dependent on the composition of IgG1, IgG4 or IgA competing for antigen and complement factors.
Complement in therapy and disease. Regulating the complement system with antibody-based therapeutics.
2015, Molecular ImmunologyCitation Excerpt :The length and flexibility of the hinge region as well as the heterogeneity of glycans in the CH2 domain are also factors that influence C1q binding and complement activation (Coloma et al., 1997; Dangl et al., 1988; Raju, 2008; Tan et al., 1990). Finally, IgG-mediated complement activation can be dampened by the presence of specific antibodies of other isotypes, such as human IgG4 or IgA, which are both impaired in their interaction with C1q (Davies et al., 2014; Dechant and Valerius, 2001; Kerr, 1990; Labrijn et al., 2008; van der Neut Kolfschoten et al., 2007; Woof and Kerr, 2006). Such dampening may result from competition for antigen binding and/or from steric interference of antigen-bound IgG4 or IgA with complement factors.
Fc Receptors in Mucosal Immunology
2015, Mucosal Immunology: Fourth EditionIgGA: A "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions
2014, Chemistry and BiologyCitation Excerpt :As expected, heat inactivation of the serum prior to use in these assays abrogated all CDC activity (Figure S3E). It is well established that engagement of the FcαRI receptor by IgA immune complexes elicits potent ADCC by activated neutrophils and eosinophils, as well as high phagocytic potency by macrophages (Dechant and Valerius, 2001; van Egmond et al., 2001). However, the challenges associated with IgA expression and purification and its inability to capitalize on the cytotoxic mechanisms that depend on FcγR or the activation of the classical complement pathway have limited the use of this antibody isotype as a therapeutic.
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.