Anti-CD20 IgA can protect mice against lymphoma development: evaluation of the direct impact of IgA and cytotoxic effector recruitment on CD20 target cells

Abstract

The online version of this article has a Supplementary Appendix. BackgroundWhile most antibody-based therapies use IgG because of their well-known biological properties, some functional limitations of these antibodies call for the development of derivatives with other therapeutic functions. Although less abundant than IgG in serum, IgA is the most abundantly produced Ig class in humans. Besides the specific targeting of its dimeric form to mucosal areas, IgA was shown to recruit polymorphonuclear neutrophils against certain targets more efficiently than does IgG1. Design and MethodsIn this study, we investigated the various pathways by which anti-tumor effects can be mediated by anti-CD20 IgA against lymphoma cells. ResultsWe found that polymeric human IgA was significantly more effective than human IgG1 in mediating direct killing or growth inhibition of target cells in the absence of complement. We also demonstrated that this direct killing was able to indirectly induce the classical pathway of the complement cascade although to a lesser extent than direct recruitment of complement by IgG. Recruitment of the alternative complement pathway by specific IgA was also observed. In addition to activating complement for lysis of lymphoma cell lines or primary cells from patients with lymphoma, we showed that monomeric anti-CD20 IgA can effectively protect mice against tumor development in a passive immunization strategy and we demonstrated that this protective effect may be enhanced in mice expressing the human FcαRI receptor on their neutrophils. ConclusionsWe show that anti-CD20 IgA antibodies have original therapeutic properties against lymphoma cells, with strong direct effects, ability to recruit neutrophils for cell cytotoxicity and even recruitment of complement, although largely through an indirect way.

An Anti-EGFR IgA That Displays Improved Pharmacokinetics and Myeloid Effector Cell Engagement In Vivo

“…However, in vitro studies documented that myeloid effector cells-and PMN in particular-were more effective in ADCC by IgA than by IgG1 antibodies (11)(12)(13). Human IgA antibodies demonstrated significant antitumor activity in huFcaRI-transgenic mice, which are required to investigate Fc-mediated effector functions of this antibody isotype in vivo, because mice do not express a functional FcaRI orthologue (30,44,45). However, the serum halflife of recombinant human IgA antibodies in mice was unexpectedly short-probably due to rapid clearance by the ASGPR (30,31) and the lack of binding to FcRn.…”

Effector mechanisms of IgA antibodies against CD20 include recruitment of myeloid cells for antibody‐dependent cell‐mediated cytotoxicity and complement‐dependent cytotoxicity

“…Bispecific antibodies simultaneously targeting CD20 and the myeloid receptor for IgA (FcαRI; CD89) demonstrated that polymorphonuclear cells (PMN) could effectively kill lymphoma cells by targeting CD20 (Stockmeyer et al , ). Subsequently, a CD20 antibody of human IgA isotype demonstrated in vitro and in vivo efficacy against lymphoma cells, but the mode of action of this antibody has not been fully characterised (Pascal et al , ). IgA antibodies constitute an important part of the mucosal immune system and differ from IgG in structure and function.…”

Glanzmann thrombasthenia platelets compete with transfused platelets, reducing the haemostatic impact of platelet transfusions

“…Bispecific antibodies simultaneously targeting CD20 and the myeloid receptor for IgA (FcaRI; CD89) demonstrated that polymorphonuclear cells (PMN) could effectively kill lymphoma cells by targeting CD20 (Stockmeyer et al, 2000). Subsequently, a CD20 antibody of human IgA isotype demonstrated in vitro and in vivo efficacy against lymphoma cells, but the mode of action of this antibody has not been fully characterised (Pascal et al, 2012). IgA antibodies constitute an important part of the mucosal immune system and differ from IgG in structure and function.…”