Chimeric IgA antibodies for lymphoma therapy

Dechant, Michael; Vidarsson, Gestur; Stockmeyer, Bernhard; Repp, Roland; Glennie, Martin J.; Gramatzki, Martin; Winkel, Jan G. J. van de; Valerius, T.

doi:10.1016/s0959-8049(01)80416-0

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“…Indeed, one of the cytotoxic effects expected from the IgA class in humans would be its strong ability to recruit and activate PMN via the FcαRI receptor, as was highlighted by several previous studies with tumor cells. 18,19,41 We showed that monomeric anti-CD20-IgA was better than IgG1 at recruiting human effector cells on target cells. While it is known that the affinity of FcαRI is identical for both mIgA and pIgA, 42 in our aggregation assays, polymeric anti-CD20-IgA showed a restricted capacity for effector recruitment compared to that observed with the monomeric form ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…In this context, new strategies could emerge from a better understanding of how other antibodies work and could potentially enable new effector activities and different pharmacokinetics to be exploited. The IgA class stands out as an interesting candidate for numerous reasons including its potential to recruit PMN 18 and its specific ability to target mucosal surfaces. The anti-viral and anti-bacterial properties of IgA have been widely studied and may lead to the emergence of new therapeutic candidates.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 In several in vitro models, human IgA effectively triggered PMN-mediated lysis of target cells. [16][17][18] Moreover, studies with anti-EGF-R monoclonal antibodies showed a significantly stronger activity of IgA than IgG1 in recruiting PMN for antibody-dependent cellular cytotoxicity (ADCC), which resulted in greater tumor cell killing in whole blood assays. 19,20 Beyond these in vitro studies, in vivo antitumor effects of IgA are still unexplored because of the difficulties in developing relevant animal models, especially because mice do not express FcαRI.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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.

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