Boross, Peter

Nimmerjahn, Falk

Peipp, Matthias

Frontiers in Immunology

PubMed

OPEN FAU Online-Publikationssystem der Friedrich-Alexander-Universität Erlangen-Nürnberg

Frontiers in ImmunologyOPEN ACCESSEDITED AND REVIEWED BYHarry W Schroeder,University of Alabama at Birmingham,United States*CORRESPONDENCEPeter Borosspeterboross@gmail.comSPECIALTY SECTIONThis article was submitted toB Cell Biology,a section of the journalFrontiers in ImmunologyRECEIVED 18 December 2022ACCEPTED 21 December 2022PUBLISHED 12 January 2023CITATIONBoross P, Peipp M and Nimmerjahn F(2023) Editorial: Effector functions oftherapeutic antibodies.Front. Immunol. 13:1126966.doi: 10.3389/fimmu.2022.1126966COPYRIGHT© 2023 Boross, Peipp and Nimmerjahn.This is an open-access articledistributed under the terms of theCreative Commons Attribution License(CC BY). The use, distribution orreproduction in other forums ispermitted, provided the original author(s) and the copyright owner(s) arecredited and that the originalpublication in this journal is cited, inaccordance with accepted academicpractice. No use, distribution orreproduction is permitted which doesnot comply with these terms.TYPE EditorialPUBLISHED 12 January 2023DOI 10.3389/fimmu.2022.1126966Editorial: Effector functions oftherapeutic antibodiesPeter Boross1*, Matthias Peipp2 and Falk Nimmerjahn31Genmab BV, Utrecht, Netherlands, 2Stem Cell Transplantation and Immunotherapy, Division ofAntibody-Based Immunotherapy, Department of Medicine II, Christian Albrechts University Kiel andUniversity Medical Center Schleswig-Holstein, Kiel, Germany, 3Department of Biology, Institute ofGenetics, University of Erlangen-Nürnberg, Erlangen, GermanyKEYWORDSan t ibod ie s , g l ycosy l a t ion , I gA , e ff ec to r func t ions , Fc recepto r s ,complement, checkpointEditorial on the Research TopicEffector functions of therapeutic antibodiesTherapeutic antibodies are broadly used in both oncology and autoimmuneindications. Currently there are more than hundred antibodies approved by the FDAand many more are in development. Therapeutic antibodies of the human IgG1 subclasswith an unmodified Fc portion are increasingly being replaced with engineeredantibodies or novel antibody formats. In order to improve the therapeutic index ofantibodies, the Fc portion of IgG can be protein- or glyco-engineered (1). Other IgGsubclasses or antibody isotypes are also being explored. These modifications are aimed ataltering the natural interactions with immune effector functions, such as Fc receptors orthe complement system to ultimately improve the efficacy and safety oftherapeutic antibodies.The effector functions induced by the IgG Fc domain of therapeutic antibodies arecharacterized by complex interactions in vivo. The type and magnitude of theseinteractions depend on a number of factors. However it is not well understood how invitro results, and pre-clinical in vivo studies, translate into clinical efficacy and safety. Inin vitro assays, IgG effector functions are often studied in isolation and the effectorfunctions in pre-clinical mouse models differ from those available in humans. Thereforebridging data from these different model systems is important to enable the use ofpreclinical results to predict clinical efficacy.This Research Topic collates eleven articles focusing on the role of the IgG Fc domainfor the effector functions of antibodies and highlights different strategies to alter IgG Fc tomodify wanted and unwanted biological effects.In addition to immune checkpoints on adaptive immune cells, targeting similarcheckpoints on myeloid cells are also being explored. Chan et al. provides acomprehensive overview of the most prominent example of these, the CD47-SIRPaaxis, and describes other potential myeloid checkpoints that could be explored to enhanceimmunotherapy. IgA is being explored as an alternative isotype instead of IgG for anti-cancer antibodies. As IgA antibodies predominantly engage PolymorphonuclearLeukocytes (PMNs) as effector cells, the authors also discuss the potential advantage offrontiersin.org01Boross et al. 10.3389/fimmu.2022.1126966combining IgA antibody therapy with myeloid checkpointblockade. Baumann et al. show in vitro anti-tumor activitywith an IgA2 version of the anti-CD38 antibody daratumumab(Dara) in in vitro antibody-dependent cell-mediated cytotoxicity(ADCC) and ADCP assays. The activity of the IgA Dara variantcould be further boosted by the inhibition of myeloidcheckpoints CD47-SIRPa axis.Zeller et al. analyzed whether dual checkpoint inhibition ofthe CD47-SIRPa and HLAI/LILRB1 axes in combination withCD20-directed antibodies is a suitable approach to further boostantibody-dependent cellular phagocytosis (ADCP) oflymphoma cells. Analysis of lymphoma cell lines revealed thatthe ratio of CD20 to HLA class I cell surface moleculesdetermined the sensitivity to ADCP by the combination ofrituximab and CD47 antibody. LILRB1 blockade promotedserial engulfment of lymphoma cells and potentiated ADCPbut required CD47 co-blockade and the presence of the CD20antibody. These data provide first in vitro evidence that dualcheckpoint blockade of CD47 and LILRB1 may be promising toimprove antibody therapy of lymphoma patients throughenhancing ADCP by macrophages.Agonistic antibodies that engage co-stimulatory receptors,such as anti-CD40 antibodies, have great promise but theirclinical use is complicated by the small therapeutic window.The challenge is to separate the mechanisms that lead to anti-tumor response from those that result in unwanted toxicity.Salomon and Dahan provide an overview of the next generationof anti-CD40 antibodies. These strategies may include Fcengineering for enhanced FcgRIIB binding, intratumoraladministration but also the use of bispecific antibodies torestrict CD40 agonism exclusively at the tumor site orspecifically to dendritic cells.For a number of agonistic therapeutic antibodies the IgG Fcpart has been shown to be important for therapeutic activity butalso play a role in the induction of unwanted side effects. Some ofthese antibodies are of the IgG4 isotype which is expected tohave mild interactions with human FcgRs. Using adeglycosylated version of urelumab, an anti-CD137 antibody,Reitinger et al. showed that abrogating residual FcgR interactionsby glycan removal maintains T cell stimulatory activity whileameliorating toxicity. These results suggest that glyco-engineering of IgG4 is an interesting strategy to explore.Furthermore, their data highlights the importance of dosing inorder to separate beneficial effects from toxic side effects.Protein engineering of the IgG Fc is an attractive strategy toenhance or to ameliorate IgG effector functions. Gehlert et al.used the anti-CD19 antibody tafasitamab in which the Fcdomain has been modified by two mutations (S239D/I332E)that result in enhanced ADCP and ADCC. The authors haveintroduced a third mutation, E345K that improves Fc-Fcinteractions and increases hexamer formation on the cellFrontiers in Immunology 02membrane resulting in improved complement activation. Thismutation was functional, and resulted in improvedComplement-dependent Cytotoxicity (CDC) when effectorfunctions were studied in isolation. Importantly, however, inwhole blood assays when all effector functions were available,stronger complement activation negatively impacted FcRengagement, highlighting the need for experimental systemswhere all effector functions can be studies simultaneously.IgG1 contains one N-linked glycosylation site (Asn-297) andthe glycan structure on the IgG has profound functional effects. Inparticular the presence of core fucose is of high importance, asantibodies with low core fucose are able to trigger stronger FcgR-mediated effector functions. Golay et al. provided a comprehensiveoverview of the literature on the biological effects of the IgG corefucosylation both in the context of therapeutic antibodies where itcan be explored to modulate antibody effector functions and inphysiological polyclonal IgG response.IgG antibodies lacking the penultimate fucose residue arewell known to bind with increased affinity to FcgRIIIa. Hatfieldet al. now show that in afucosylated sugar moieties galactoseresidues play an important role in this enhanced binding. Byusing an enzymatic transglycosylation approach allowingaddition of add defined sugar moieties to IgG, theydemonstrate that galactosylation at the a6 but not the a3antennae was responsible for this enhanced binding. Theauthors further validate their finding by demonstrating thatthese IgG glycovariants have an enhanced ADCC activity.In addition to the impact of the sugar moiety attached to theFc-domain of antibodies it is well established that glycosylation ofFcgRs may also impact the IgG-FcgR interaction. For example aspecific sugar moiety in FcgRIIIa is critical for detecting IgGglycovariants with low fucose with higher affinity (2). It remainedunclear, however, which sugar residues in IgG or FcgRIIIaassociated sugar domains have a major impact on thisinteraction. Van Coillie et al. addressed this important questionby generating well-defined libraries of IgG and FcgRIIIaglycosylation variants and demonstrate that afucosylated IgG1has the highest affinity for oligomannose containing sugarmoieties attached to the Asn162 site on FcgRIIIa. Of note, thisFcgRIIIa glycovariant seems to be present predominantly on NKcells and much less on monocytes.Antibodies have become an essential therapeutic tool to treatautoimmune diseases. Thus, antibodies in the form of cytotoxicor immunomodulatory antibodies have become part ofestablished or experimental treatments. Mariottini et al.discuss which antibody-based treatment options are availablefor patients with multiple sclerosis (MS) and which antibody-dependent effector mechanisms contribute to the therapeuticeffect. In addition, they include an in depth comparison ofantibody-based versus other treatment options, such asautologous hematopoietic stem cell transplantation.frontiersin.orgBoross et al. 10.3389/fimmu.2022.1126966de Vor et al. studied the potential of monoclonal antibodiesagainst S. epidermidis to induce phagocytic killing by humanneutrophils. Different mAbs recognizing Staphylococcal surfacecomponents were characterized. To study the immune-activating potential of selected clones, bacteria were opsonizedwith mAbs in the presence or absence of complement.Activation of the complement system was essential to induceefficient phagocytosis of S. epidermidis. Similar to the study ofGehlert et al. in the context of cancer, complement activationand phagocytic killing of S. epidermidis could be enhanced byFc-mutations that improve IgG1 hexamerization on cellularsurfaces. The authors were able to show that mAbs couldgreatly enhance phagocytosis of S. epidermidis in neonatalplasma and provide insights that are crucial for optimizinganti-S. epidermidis mAbs as prophylactic agents for neonatalCentral line associated bloodstream infections (CLABSI).Taken together, a collection of original papers, Reviews andPerspective published in this Research Topic highlight recentinsights and extend our understanding of the effector functionsof human antibodies. We hope that the new insights willcontribute to the better understanding of antibody biology andhelp translate this knowledge into even more effectivetherapeutic interventions.Author contributionsAll three Guest-Editors of this Research Topic; PB, FN andMP contributed to the preparation to the present EditorialFrontiers in Immunology 03article. All authors contributed to the article and approved thesubmitted version.FundingFunding was provided by the German Research Foundation(TRR305-B02, CRC1181-A07, CRC1526-A07 to F.N.)Conflict of interestPB is an employee and holds warrants and shares at GenmabB.V. a company that is investigating the application of Antibodyeffector functions for drug therapy.The remaining authors declare that the research wasconducted in the absence of any commercial or financialrelationships that could be construed as a potential conflictof interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteedor endorsed by the publisher.References1. Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-engineering for modulatedeffector functions-improving antibodies for cancer treatment. Antibodies (Basel) 9(2020) 7;9(4):64. doi: 10.3390/antib90400642. Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, et al.Unique carbohydrate-carbohydrate interactions are required for high affinitybinding between FcgammaRIII and antibodies lacking core fucose. Proc NatlAcad Sci U.S.A. (2011) 108:12669–74. doi: 10.1073/pnas.1108455108frontiersin.org

Editorial: Effector functions of therapeutic antibodies

Boross, Peter

Peipp, Matthias

Nimmerjahn, Falk

PubMed Central

http://dx.doi.org/10.3389/fimmu.2022.1126966

Editorial: Effector functions of therapeutic antibodies

Abstract

Similar works

Full text

Available Versions

OPEN FAU Online-Publikationssystem der Friedrich-Alexander-Universität Erlangen-Nürnberg

PubMed Central