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You are here: Home / Archives for New articles

Most read from mAbs

July 11, 2018 by The Antibody Society

The Antibody Society is pleased and proud to be affiliated with mAbs, a multi-disciplinary journal dedicated to advancing the art and science of antibody research and development. We hope you enjoy these brief summaries based on the abstracts of the most read papers published in recent issues. All the articles are open access; PDFs can be downloaded by following the links below.

Issue 10.5 (July 2018)

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. In this new review, Pereira et al. discuss the relevance of antibody core fucosylation to antibody-dependent cell-mediated cytotoxicity, and different strategies to produce afucosylated antibodies, and provide an update of afucosylated antibody drugs currently undergoing clinical trials, as well as those that have been approved.

A long non-coding SINEUP RNA boosts semi-stable production of fully human monoclonal antibodies in HEK293E cells. Sasso et al. report the results of their study of SINEUP technology applied to semi-stable production of monoclonal antibodies in HEK293E cells. SINEUP RNAs are long non-coding transcripts, possessing the ability to enhance translation of selected mRNAs. The authors propose SINEUP technology as a valuable tool to enhance semi-stable antibody production in human cell lines.

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC. Figueroa et al. present a practical approach that uses limited pharmacokinetic (PK) and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. Their findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach. In this report, Betts et al. used population-pharmacokinetic (popPK) modeling to determine a single set of ‘typical’ popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

Issue 10.4 (May/June 2018)

When monoclonal antibodies are not monospecific: Hybridomas frequently express additional functional variable regions. Bradbury et al. discuss results of their study, which analyzed 185 random hybridomas, in a large multicenter dataset, to determine the genetic diversity in antibody heavy chain and light chain genes found within individual hybridomas. Of the hybridomas evaluated, 126 (68.1%) contained no additional productive chains, while the remaining 59 (31.9%) contained one or more additional productive heavy or light chains. The expression of additional chains degraded properties of the antibodies, including specificity, binding signal and/or signal-to-noise ratio, as determined by enzyme-linked immunosorbent assay and immunohistochemistry. Their findings, reflecting the current state of hybridomas used in research, reiterate the importance of using sequence-defined recombinant antibodies for research or diagnostic use.

Evaluation of analytical similarity between trastuzumab biosimilar CT-P6 and reference product using statistical analyses. In this report, Lee et al. evaluated analytical similarity of CT-P6, a biosimilar product of trastuzumab, with the reference products (EU-Herceptin® or US-Herceptin®) following risk-based statistical approaches recommended in a recent US Food and Drug Administration guideline for the risk-based statistical approaches recommended by the US Food and Drug Administration. Various quality attributes of trastuzumab were first ranked based on the clinical impact of each attribute and subsequently adjusted to one of three tiers (Tier 1, Tier 2 and Tier 3) considering the characteristics of the assay, the level of attribute present and the feasibility of statistical analysis. Analytical similarity assessment analyzed by the three tiers clearly demonstrated that CT-P6 exhibits highly similar structural and physicochemical properties, as well as functional activities, compared with the reference products.

Analytical and functional similarity of Amgen biosimilar ABP 215 to bevacizumab. Seo et al. report the results of their analytical similarity assessment, which was designed to assess the structural and functional similarity of ABP 215 and bevacizumab sourced from both the United States (US) and the European Union (EU). Similarity assessment was also made between the US- and EU-sourced bevacizumab to assess the similarity between the two products. More than 20 batches of bevacizumab (US) and bevacizumab (EU), and 13 batches of ABP 215 representing unique drug substance lots were assessed for similarity. The large dataset allows meaningful comparisons and garners confidence in the overall conclusion for the analytical similarity assessment of ABP 215 to both US- and EU-sourced bevacizumab. The structural and purity attributes, and biological properties of ABP 215 are demonstrated to be highly similar to those of bevacizumab.

 

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Filed Under: Ab news, New articles Tagged With: antibody therapeutics, biosimilar, mAbs

Drop it and run

August 25, 2017 by Zita Schneider

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

Filed Under: Antibody discovery, New articles Tagged With: antibodies, antibody therapeutics, FcRn, neonatal Fc receptor, pH-dependent

Importance of isoelectric point (pI) of antibodies

June 28, 2017 by Zita Schneider

One important characteristic of monoclonal antibodies (mAbs) is their isoelectric point (pI), which essentially is the pH at which the antibody has no net electrical charge, and its value depends on the charged amino acids the antibody contains. If the pH of the surrounding environment is below the antibody’s pI, then the molecule carries a net positive charge, whereas the antibody will carry a net negative charge when the pH is above the pI.

When assessing pharmacokinetic (PK) properties of therapeutic antibodies not only the target-mediated drug disposition (TMDD) but also non-target-related mechanisms influence overall PK behavior and pI can be an important factor of the latter. Since the surface of most cells is negatively charged, antibodies need to be positively charged for efficient fluid-phase endocytosis (pinocytosis), therefore the environmental pH needs to be below the pI of the antibody. Therapeutic antibodies with pI values in the range of 8-9 are taken up adequately after administration since the physiological pH is 7.4, however, in some cases antibodies have a pI outside of this range or have been manipulated to achieve increased or decreased pI values (cationization or anionization, respectively). It is generally observed that increases in net positive charge of antibodies result in increased blood clearance and increased tissue retention with shorter half-life, whereas antibodies with lower pI generally have decreased tissue uptake and longer half-life (1-3), although observations can be conflicting regarding correlation between mAb clearance and pI (4). Even subtle manipulation such as molecular surface remodeling to disrupt positive patch regions can influence PK properties (5). In summary, pI of mAbs is known to have a substantial effect on PK behavior independent of recycling mediated by the neonatal Fc receptor, FcRn. Small changes of pI during the routine manufacturing of mAb charge variants, however, are not expected to result in dramatic changes and may not require extensive analyses (6). In any case, it is encouraged that pI values are reported in studies as an important factor influencing antibody behavior. Furthermore, since selecting the best candidates during early preclinical phases of product development can substantially decrease time and cost of development, it is of great importance to consider de-risk strategies and tools during drug discovery and development, including antibody variable region charge and antibody pI analyses (7-9). A new analytical platform has been recently described and validated on seven mAbs to rapidly assess and rank mAb charge variants during early stage development, which can be a useful screening technique during early stage development (10).

References:

1 Boswell et al, Bioconjug Chem. 2010 Dec 15;21(12):2153-63.
2 Igawa et al, Protein Eng Des Sel. 2010 May;23(5):385-92.
3, Li et al, MAbs. 2014;6(5):1255-64.
4, Hötzel et al, MAbs. 2012 Nov-Dec;4(6):753-60.
5, Datta-Mannan et al, MAbs. 2015;7(3):483-93.
6, Khawli et al, mAbs, 2010;(2)6:613-624.
7, Bumbaca Yadav et al, J Biol Chem. 2015 Dec 11;290(50):29732-41.
8, Dostalek et al, MAbs. 2017 May 2:1-11.
9, Jarasch et al, J Pharm Sci. 2015 Jun;104(6):1885-98.
10, Wagner-Rousset, J Chromatogr A. 2017 May 19;1498:147-154.

Filed Under: New articles Tagged With: antibodies, isoelectric point

FcRn: are we done yet?

March 1, 2017 by Zita Schneider

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.

Filed Under: New articles Tagged With: neonatal Fc receptor

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

January 31, 2017 by Janice Reichert

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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Filed Under: New articles Tagged With: antibody therapeutics, neonatal Fc receptor

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