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Biological Impact of Fc Receptor Engagement

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Please join us at the Society’s annual meeting, Antibody Engineering & Therapeutics, on December 11-15, 2017 at the Manchester Grand Hyatt, San Diego, CA! In this summary, session organizers Trudi Veldman (Senior Director Biologics, AbbVie Bioresearch Center) and Chung-Ming Hsieh (Executive Director, Biologics Discovery Boston, Merck & Co.) discuss what you will learn at their session ‘Biological Impact of Fc Receptor Engagement’, which will be chaired by Chung-Ming Hsieh on Thursday December 14.

Antibodies are both binding proteins to their cognate targets and bridging molecules to downstream biological pathways via interaction with the various Fc receptors (e.g., FcγR and FcRn), complement, and lectins.  While our efforts in understanding the biology of therapeutic antibodies are often initially focused on the variable domain and target engagement, e.g., binding kinetics, potency, epitopes, it is crucial that we also gain understanding of the biology of the constant region of a therapeutic antibody and its impact on efficacy and safety.

This session aims to strengthen our current understandings on the biological impact of Fc receptor engagement.  The first presentation by Kenta Haraya (Chugai) will discuss the generation and characterization of a novel IgG1 Fc variant with optimized binding to FcRn that does not have increased binding by rheumatoid factors.  This Fc variant has been incorporated into a recycling antibody being developed for complement-mediated diseases.

The next three presentations will focus on the impact of FcγR engagement on antitumor activities of protein therapeutics.  Rony Dahan (Rockefeller) will present the finding that the antitumor activity of a human CD40 agonistic antibody is dependent on FcγRIIb engagement and is inhibited by FcγRIIa engagement, highlighting the importance of Fc domain optimization for improved efficacy.  Moving beyond antibodies, Daniel Christ (Garvan Institute of Medical Research) will present data indicating that the potent antitumor activity of interleukin-2-Fc fusion protein requires Fc-mediated depletion of regulatory T-cells.  Lastly, Frederick Arce Vargas (University College London Cancer Institute) will present the depletion of tumor-infiltrating regulatory T cells by an Fc-optimized anti-CD25 in synergy with PD-1 blockade to eradicate established tumors.

The field also continues to make progress in engineering Fc for modulating antibody effector functions, FcγR or complement engagement, and circulating half-life.  To this end, James Ernst (Genentech) will present effector function-attenuating mutations that maintain antibody stability and reduce toxicity.  George Georgiou (University of Texas at Austin) will present a set of novel engineered Fcs for half-life extension and for highly selective engagement of a single FcγR or C1q.

The full agenda for the meeting can be found here.

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Drop it and run

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Therapeutic antibodies have been successfully used for decades to treat various diseases. For antibodies targeting soluble antigens, however, a so-called “antibody buffering” effect, which can prolong the persistence of the target in the blood instead of clearing it, was observed. When a conventional IgG is injected into the body and binds to its corresponding antigen, the immune complexes are taken up into the cell where a certain amount of the antigen dissociates from the antibody in the endosomal compartments. The dissociated antigen is directed to the lysosomes for degradation, but the remaining amount of antigen (still bound to the IgG molecules) is recycled out of the cell by the neonatal Fc receptor (FcRn), and this can lead to an extension rather than a decrease of the antigen half-life in the bloodstream (1-5).

To overcome this buffering effect, antibodies with pH-dependent antigen binding characteristics were developed. These IgGs bind the soluble target molecules at physiological pH, but release antigen at the acidic pH in the endosomes. Antigen will then be directed into lysosomes for degradation and free antibodies will be recycled out of the cell, available for consecutive rounds of antigen binding and intracellular delivery. This method has been successfully applied to target different soluble antigens, demonstrating enhanced antigen clearance from the bloodstream compared to a conventional IgG with no pH-dependent antigen binding characteristics (6-9). Furthermore, to facilitate even more efficient antigen elimination, pH-dependent antibodies with additional modifications were generated. By increasing the antibody affinity for FcRn or FcyRIIb, soluble antigen bound to the engineered antibodies will enter the cell much more efficiently than by fluid-phase uptake. The combined effects of increased uptake and pH-dependent antigen dissociation resulted in a remarkable decrease of antigen levels following injection of engineered “sweeping” antibodies, opening possibilities for improved therapeutic applications in the future (10-13). We look forward to receiving further news about pH-dependent antibodies already in development (9, 14-15).

References:
1, Finkelman et al, J Immunol. 1993 Aug 1;151(3):1235-44.
2, O’Hear and Foote, Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):40-4.
3, Phelan et al, J Immunol. 2008 Jan 1;180(1):44-8.
4, Davda and Hansen, MAbs. 2010 Sep-Oct;2(5):576-88. doi: 10.4161/mabs.2.5.12833.
5, Xiao et al, AAPS J. 2010 Dec;12(4):646-57. doi: 10.1208/s12248-010-9222-0.
6, Igawa et al, Nat Biotechnol. 2010 Nov;28(11):1203-7. doi: 10.1038/nbt.1691.
7, Chaparro-Riggers et al, J Biol Chem. 2012 Mar 30;287(14):11090-7. doi: 10.1074/jbc.M111.319764.
8, Devanaboyina et al, MAbs. 2013 Nov-Dec;5(6):851-9. doi: 10.4161/mabs.26389.
9, Fukuzawa et al, Sci Rep. 2017 Apr 24;7(1):1080. doi: 10.1038/s41598-017-01087-7.
10, Igawa et al, PLoS One. 2013 May 7;8(5):e63236. doi: 10.1371/journal.pone.0063236.
11, Iwayanagi et al, J Immunol. 2015 Oct 1;195(7):3198-205. doi: 10.4049/jimmunol.1401470.
12, Igawa et al, Immunol Rev. 2016 Mar;270(1):132-51. doi: 10.1111/imr.12392.
13, Yang et al, accepted manuscript, MAbs. 2017 Aug 8:0. doi: 10.1080/19420862.2017.1359455.
14, ALXN1210, https://clinicaltrials.gov/ct2/show/NCT02946463
15, SA237, https://clinicaltrials.gov/ct2/show/NCT02028884

FcRn: are we done yet?

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The story of the neonatal Fc receptor (FcRn) started as a hypothesis made by F. W. Rogers Brambell more than half a century ago, when he predicted the existence of a saturable receptor responsible for protecting IgG molecules from degradation and the same or a similar system involved in IgG transport from mother to newborns. After its initial identification in neonatal rat intestine, FcRn indeed turned out to be the receptor responsible for these functions, but its further roles in albumin homeostasis and antigen presentation were also subsequently discovered (1-6).

While these properties have been widely exploited in the development of therapeutic and diagnostic reagents, the possible functions of FcRn are even broader. For example, further investigation of the immune functions of FcRn has revealed a role in anti-tumor responses. Intestinal dendritic cells expressing FcRn were shown to cross-present antigen derived from immune complexes, thereby activating tumor-specific T cells and eliciting immunity against colorectal cancer (7). More recently, it was also demonstrated that the presence of FcRn-expressing immune cells (macrophages and dendritic cells) in tumor samples was associated with a better prognosis in non-small cell lung cancer patients (8). A role for FcRn in cellular metabolism through its ability to recycle albumin has also been recently described. Specifically, low FcRn levels in tumor cell lines were associated with intracellular albumin accumulation and growth increase of tumor xenografts, whereas enforced expression of FcRn had the reverse effect (9). Despite these new results, FcRn likely has even more interesting features waiting to be revealed by enterprising scientists.


1, Rath et al, J Clin Immunol. 2013 Jan;33 Suppl 1:S9-17.
2, Challa et al, Curr Top Microbiol Immunol. 2014;382:249-72.
3, Sand et al, Front Immunol. 2015 Jan 26;5:682.
4, Pyzik et al, J Immunol. 2015 May 15;194(10):4595-603.
5, Stapleton et al, Immunol Rev. 2015 Nov;268(1):253-68.
6, Cervenak et al, Immunol Rev. 2015 Nov;268(1):269-87.
7, Baker et al, Immunity. 2013 Dec 12;39(6):1095-107.
8, Dalloneau et al, Oncotarget. 2016 Aug 23;7(34):54415-54429.
9, Swiercz et al, Oncotarget. 2017 Jan 10;8(2):3528-3541.

Free virtual issue featuring articles on neonatal Fc receptor is online now

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In a special issue of mAbs, Guest Editor Zita Schneider, D.V.M., Ph.D., Texas A&M Health Science Center, has compiled 12 articles describing recent results obtained about the neonatal Fc receptor, FcRn. All articles can be freely downloaded for a limited time. As a regulator of immunoglobulin G (IgG) and albumin homeostasis and a modulator of immune functions, this receptor has been attracting the interest of the scientific community and has become an unavoidable factor for consideration in the development of IgG- and albumin-based diagnostic and therapeutic reagents.

Burvenich et al. identified important amino acids playing a role in FcRn-IgG interaction, whereas Hironiwa et al. showed efficient antigen drop-off and IgG recycling utilizing calcium-dependent antigen-antibody binding. Ying and colleagues provided a tool to increase the transcytosis and half-life of engineered antibody domains through an FcRn-binding motif, whereas Meyer et al. utilized the albumin-binding characteristics of FcRn to generate IgA molecules with elongated half-life. Adams et al. used an anti-albumin Fv domain to extend the half-life of an Fab fragment, and Davé et al. used this domain to generate an Fab-dsFv bispecific antibody format.

FcRn can also serve as a screening tool for antibody selection as demonstrated by Souders et al. who developed a novel FcRn-binding biolayer interferometry assay, while Fan and colleagues used online peptide immune-affinity chromatography coupled with high resolution mass spectrometry to determine human FcRn expression levels in transgenic (Tg) mice and Avery et al. characterized these human FcRn Tg mice with respect to mAb pharmacokinetics (PK) prediction. Unverdorben et al. provided details of the PK of various Fc fusions compared to IgG molecules, Kelly et al. proved that FcRn-independent antigen-independent nonspecific interactions can also play a role in antibody PK, and Datta-Mannan et al. investigated several properties of mAbs in order to optimize PK parameters.

These articles provide valuable details to explore the possibilities offered by utilizing the functions of FcRn.

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