Through the barricades: overcoming the barriers to effective antibody-based cancer therapeutics.

Abstract:

:Since the turn of the century, cancer therapy has undergone a transformation in terms of new treatment modalities and renewed optimism in achieving long-lived tumor control and even cure. This is, in large part, thanks to the widespread incorporation of monoclonal antibodies (mAbs) into standard treatment regimens. These new therapies have, across many settings, significantly contributed to improved clinical responses, patient quality of life and survival. Moreover, the flexibility of the antibody platform has led to the development of a wide range of innovative and combinatorial therapies that continue to augment the clinician's armory. Despite these successes, there is a growing awareness that in many cases mAb therapy remains suboptimal, primarily due to inherent limitations imposed by the immune system's own homeostatic controls and the immunosuppressive tumor microenvironment. Here, we discuss the principal barriers that act to constrain the tumor-killing activity of antibody-based therapeutics, particularly those involving antibody glycans, using illustrative examples from both pre-clinical and market approved mAbs. We also discuss strategies that have been, or are in development to overcome these obstacles. Finally, we outline how the growing understanding of the biological terrain in which mAbs function is shaping innovation and regulation in cancer therapeutics.

journal_name

Glycobiology

journal_title

Glycobiology

authors

Dalziel M,Beers SA,Cragg MS,Crispin M

doi

10.1093/glycob/cwy043

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

697-712

issue

9

eissn

0959-6658

issn

1460-2423

pii

5003042

journal_volume

28

pub_type

杂志文章,评审
  • A novel antibody for human induced pluripotent stem cells and embryonic stem cells recognizes a type of keratan sulfate lacking oversulfated structures.

    abstract::We have generated a monoclonal antibody (R-10G) specific to human induced pluripotent stem (hiPS)/embryonic stem (hES) cells by using hiPS cells (Tic) as an antigen, followed by differential screening of mouse hybridomas with hiPS and human embryonal carcinoma (hEC) cells. Upon western blotting with R-10G, hiPS/ES cel...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cws159

    authors: Kawabe K,Tateyama D,Toyoda H,Kawasaki N,Hashii N,Nakao H,Matsumoto S,Nonaka M,Matsumura H,Hirose Y,Morita A,Katayama M,Sakuma M,Kawasaki N,Furue MK,Kawasaki T

    更新日期:2013-03-01 00:00:00

  • Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter.

    abstract::Cryptococcus neoformans, an opportunistic fungal pathogen, produces a glycan capsule to evade the immune system during infection. This definitive virulence factor is composed mainly of complex polysaccharides, which are made in the secretory pathway by reactions that utilize activated nucleotide sugar precursors. Alth...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cww078

    authors: Li LX,Ashikov A,Liu H,Griffith CL,Bakker H,Doering TL

    更新日期:2017-01-01 00:00:00

  • Circulating blood and platelets supply glycosyltransferases that enable extrinsic extracellular glycosylation.

    abstract::Glycosyltransferases, usually residing within the intracellular secretory apparatus, also circulate in the blood. Many of these blood-borne glycosyltransferases are associated with pathological states, including malignancies and inflammatory conditions. Despite the potential for dynamic modifications of glycans on dis...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cww108

    authors: Lee-Sundlov MM,Ashline DJ,Hanneman AJ,Grozovsky R,Reinhold VN,Hoffmeister KM,Lau JT

    更新日期:2017-01-01 00:00:00

  • The DXD motif is required for GM2 synthase activity but is not critical for nucleotide binding.

    abstract::We tested the importance of the aspartate-any residue-aspartate (DXD) motif for the enzymatic activity and nucleotide binding capacity of the Golgi glycosyltransferase GM2 synthase. We prepared point mutations of the motif, which is found in the sequence 352-VLWVDDDFV, and analyzed cells that stably expressed the muta...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/11.3.217

    authors: Li J,Rancour DM,Allende ML,Worth CA,Darling DS,Gilbert JB,Menon AK,Young WW Jr

    更新日期:2001-03-01 00:00:00

  • Studies on the binding site of the galactose-specific agglutinin PA-IL from Pseudomonas aeruginosa.

    abstract::The binding properties of Pseudomonas aeruginosa agglutinin-I (PA-IL) with glycoproteins (gps) and polysaccharides were studied by both the biotin/avidin-mediated microtiter plate lectin-binding assay and the inhibition of agglutinin-glycan interaction with sugar ligands. Among 36 glycans tested for binding, PA-IL rea...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/8.1.7

    authors: Chen CP,Song SC,Gilboa-Garber N,Chang KS,Wu AM

    更新日期:1998-01-01 00:00:00

  • Effects of the sugar headgroup of a glycoglycerolipid on the phase behavior of phospholipid model membranes in the dry state.

    abstract::Glycolipids are important components of almost all biological membranes. They possess unique properties that have only been incompletely characterized so far. The plant glycolipid digalactosyldiacylglycerol (DGDG) strongly influences the physical behavior of phospholipid model membranes in both the dry and hydrated st...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwj001

    authors: Popova AV,Hincha DK

    更新日期:2005-11-01 00:00:00

  • Biosynthesis of 3-O-sulfated heparan sulfate: unique substrate specificity of heparan sulfate 3-O-sulfotransferase isoform 5.

    abstract::Heparan sulfate 3-O-sulfotransferase transfers sulfate to the 3-OH position of a glucosamine to generate 3-O-sulfated heparan sulfate (HS), which is a rare component in HS from natural sources. We previously reported that 3-O- sulfotransferase isoform 5 (3-OST-5) generates both an antithrombin-binding site to exhibit ...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwg101

    authors: Chen J,Duncan MB,Carrick K,Pope RM,Liu J

    更新日期:2003-11-01 00:00:00

  • Glycosylation profiling of dog serum reveals differences compared to human serum.

    abstract::Glycosylation is the most common post-translational modification of serum proteins, and changes in the type and abundance of glycans in human serum have been correlated with a growing number of human diseases. While the glycosylation pattern of human serum is well studied, little is known about the profiles of other m...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwy070

    authors: Behrens AJ,Duke RM,Petralia LM,Harvey DJ,Lehoux S,Magnelli PE,Taron CH,Foster JM

    更新日期:2018-11-01 00:00:00

  • Identification of a 175 kDa protein as the ligand-binding subunit of the rat liver sinusoidal endothelial cell hyaluronan receptor.

    abstract::The rat liver sinusoidal endothelial cell (LEC) hyaluronan (HA) receptor was previously identified using a photoaffinity HA derivative (J. Biol. Chem., 267, 20451-20456, 1992). Two polypeptides with M(r) = 175,000 and 166,000, were consistently crosslinked, suggesting that the LEC HA receptor is an oligomer. Whether o...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/7.1.15

    authors: Yannariello-Brown J,Zhou B,Weigel PH

    更新日期:1997-02-01 00:00:00

  • Addition of beta1-6 GlcNAc branching to the oligosaccharide attached to Asn 772 in the serine protease domain of matriptase plays a pivotal role in its stability and resistance against trypsin.

    abstract::beta1-6 GlcNAc branching, a product of N-acetylglucosaminyltransferase V (GnT-V), is a key structure that is associated with malignant transformations and cancer metastasis. Although a number of reports concerning tumor metastasis-related glycoproteins that contain beta1-6 GlcNAc branching have appeared, the precise f...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwh013

    authors: Ihara S,Miyoshi E,Nakahara S,Sakiyama H,Ihara H,Akinaga A,Honke K,Dickson RB,Lin CY,Taniguchi N

    更新日期:2004-02-01 00:00:00

  • Modulation of hepatocyte sialylation drives spontaneous fatty liver disease and inflammation.

    abstract::Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins relea...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwz096

    authors: Oswald DM,Jones MB,Cobb BA

    更新日期:2020-04-20 00:00:00

  • Identification of an endo-beta-N-acetylglucosaminidase gene in Caenorhabditis elegans and its expression in Escherichia coli.

    abstract::We report the identification, molecular cloning, and characterization of an endo-beta-N-acetylglucosaminidase from the nematode Caenorhabditis elegans. A search of the C. elegans genome database revealed the existence of a gene exhibiting 34% identity to Mucor hiemalis (a fungus) endo-beta-N-acetylglucosaminidase (End...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwf073

    authors: Kato T,Fujita K,Takeuchi M,Kobayashi K,Natsuka S,Ikura K,Kumagai H,Yamamoto K

    更新日期:2002-10-01 00:00:00

  • Hexosamine biosynthesis in keratinocytes: roles of GFAT and GNPDA enzymes in the maintenance of UDP-GlcNAc content and hyaluronan synthesis.

    abstract::UDP-N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a key substrate for the synthesis of glycoconjugates like hyaluronan, and as a metabolic sensor that controls cell functions through O-GlcNAc modification of intracellular proteins. However, little is known about the regulation of h...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cww019

    authors: Oikari S,Makkonen K,Deen AJ,Tyni I,Kärnä R,Tammi RH,Tammi MI

    更新日期:2016-07-01 00:00:00

  • Glycoprofiling with micro-arrays of glycoconjugates and lectins.

    abstract::To facilitate deciphering the information content in the glycome, thin film-coated photoactivatable surfaces were applied for covalent immobilization of glycans, glycoconjugates, or lectins in microarray formats. Light-induced immobilization of a series of bacterial exopolysaccharides on photoactivatable dextran-coate...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwh143

    authors: Angeloni S,Ridet JL,Kusy N,Gao H,Crevoisier F,Guinchard S,Kochhar S,Sigrist H,Sprenger N

    更新日期:2005-01-01 00:00:00

  • Structural studies of the O-antigen polysaccharide from Escherichia coli O115 and biosynthetic aspects thereof.

    abstract::The structure of the O-antigen polysaccharide (PS) of Escherichia coli O115 has been investigated using a combination of component analysis and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy experiments. The repeating unit of the O-antigen was elucidated using the O-deacetylated PS and has the following branc...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cws161

    authors: Fontana C,Ramström K,Weintraub A,Widmalm G

    更新日期:2013-03-01 00:00:00

  • Advances in the use of biotinylated diaminopyridine (BAP) as a versatile fluorescent tag for oligosaccharides.

    abstract::We recently described a novel fluorescent compound, 2-amino,6-amidobiotinyl-pyridine (BAP), that allows the tagging of oligosaccharides, their fractionation by reversed-phase HPLC with picomole scale detection, and the formation of functional neoglycoprotein equivalents with (strept) avidin for the detection of recept...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/4.5.653

    authors: Toomre DK,Varki A

    更新日期:1994-10-01 00:00:00

  • Impact of human galectin-1 binding to saccharide ligands on dimer dissociation kinetics and structure.

    abstract::Endogenous lectins can control critical biological responses, including cell communication, signaling, angiogenesis and immunity by decoding glycan-containing information on a variety of cellular receptors and the extracellular matrix. Galectin-1 (Gal-1), a prototype member of the galectin family, displays only one ca...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cww052

    authors: Romero JM,Trujillo M,Estrin DA,Rabinovich GA,Di Lella S

    更新日期:2016-12-01 00:00:00

  • Beta1,4-N-Acetylglucosaminyltransferase III down-regulates neurite outgrowth induced by costimulation of epidermal growth factor and integrins through the Ras/ERK signaling pathway in PC12 cells.

    abstract::A rat pheochromocytoma cell line (PC12), when transfected with beta1,4-N-acetylglucosaminyltransferase III (GnT-III), which catalyzes the formation of a bisecting GlcNAc structure in N-glycans, resulted in the suppression of neurite outgrowth induced by costimulation of epidermal growth factor (EGF) and integrins. The...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwh016

    authors: Gu J,Zhao Y,Isaji T,Shibukawa Y,Ihara H,Takahashi M,Ikeda Y,Miyoshi E,Honke K,Taniguchi N

    更新日期:2004-02-01 00:00:00

  • Galectin-8: a matricellular lectin with key roles in angiogenesis.

    abstract::Galectin-8 (gal-8) is a "tandem-repeat"-type galectin, containing two carbohydrate recognition domains connected by a linker peptide. gal-8 is expressed both in the cytoplasm and nucleus in vascular endothelial cells (ECs) from normal and tumor-associated blood vessels, and in lymphatic endothelial cells. Herein, we d...

    journal_title:Glycobiology

    pub_type: 杂志文章,评审

    doi:10.1093/glycob/cwu054

    authors: Troncoso MF,Ferragut F,Bacigalupo ML,Cárdenas Delgado VM,Nugnes LG,Gentilini L,Laderach D,Wolfenstein-Todel C,Compagno D,Rabinovich GA,Elola MT

    更新日期:2014-10-01 00:00:00

  • Mouse anti-ceramide antiserum: a specific tool for the detection of endogenous ceramide.

    abstract::Ceramide is a pivotal molecule in signal transduction and an essential structural component of the epidermal permeability barrier. The epidermis is marked by a high concentration of ceramide and by a unique spectrum of ceramide species: Besides the two ceramide structures commonly found in mammalian tissue, N-acylsphi...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/11.6.451

    authors: Vielhaber G,Brade L,Lindner B,Pfeiffer S,Wepf R,Hintze U,Wittern KP,Brade H

    更新日期:2001-06-01 00:00:00

  • Microarray analyses of closely related glycoforms reveal different accessibilities of glycan determinants on N-glycan branches.

    abstract::Glycans mediate a wide variety of biological roles via recognition by glycan-binding proteins (GBPs). Comprehensive knowledge of such interaction is thus fundamental to glycobiology. While the primary binding feature of GBPs can be easily uncovered by using a simple glycan microarray harboring limited numbers of glyca...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwz100

    authors: Li L,Guan W,Zhang G,Wu Z,Yu H,Chen X,Wang PG

    更新日期:2020-04-20 00:00:00

  • Carbohydrate-binding properties of human neo-CRP and its relationship to phosphorylcholine-binding site.

    abstract::Binding characteristics of two types of ligands for human neo-C-reactive protein (neo-CRP), which is a conformationally altered but physiologically relevant form of CRP, were studied fluorometrically by probing CRP immobilized on a polystyrene surface with europium-labeled ligands. Two Eu-ligands used were bovine seru...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwg002

    authors: Lee RT,Lee YC

    更新日期:2003-01-01 00:00:00

  • Simultaneous quantification of glucosylceramide and galactosylceramide by normal-phase HPLC using O-phtalaldehyde derivatives prepared with sphingolipid ceramide N-deacylase.

    abstract::We report here a method of simultaneously quantifying glucosylceramide (GlcCer) and galactosylceramide (GalCer) by normal-phase HPLC using O-phtalaldehyde derivatives. Treatment with sphingolipid ceramide N-deacylase which converts the cerebrosides in the sample to their lyso-forms was followed by the quantitative lab...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwp047

    authors: Zama K,Hayashi Y,Ito S,Hirabayashi Y,Inoue T,Ohno K,Okino N,Ito M

    更新日期:2009-07-01 00:00:00

  • α-L-fucosidase from Paenibacillus thiaminolyticus: its hydrolytic and transglycosylation abilities.

    abstract::In this work, focused on possible application of α-L-fucosidases from bacterial sources in the synthesis of α-L-fucosylated glycoconjugates, several nonpathogenic aerobic bacterial strains were screened for α-L-fucosidase activity. Among them Paenibacillus thiaminolyticus was confirmed as a potent producer of enzyme w...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwt041

    authors: Benesová E,Lipovová P,Dvoráková H,Králová B

    更新日期:2013-09-01 00:00:00

  • Mac-2: a versatile galactose-binding protein of mammalian tissues.

    abstract::Mac-2 is a member of the S-(soluble) lectin family. Its identification and isolation from a wide variety of cell types and tissues suggest a diversity of roles in various biological systems. The key points to be made are that Mac-2, and the S-lectins in general, by virtue of their recognition of a variety of carbohydr...

    journal_title:Glycobiology

    pub_type: 杂志文章,评审

    doi:10.1093/glycob/4.1.5

    authors: Hughes RC

    更新日期:1994-02-01 00:00:00

  • Digalactosylceramide is the receptor for staphylococcal enterotoxin-B in human kidney proximal tubular cells.

    abstract::We have characterized a glycosphingolipid (GSL) receptor for Staphylococcus enterotoxin-B (SEB) in cultured human kidney proximal tubular (PT) cells. Solid-phase binding of [125I]SEB to the GSL receptor was concentration dependent and was not displaceable by two structurally related toxins, such as staphylococcal ente...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/5.3.327

    authors: Chatterjee S,Khullar M,Shi WY

    更新日期:1995-05-01 00:00:00

  • β4GalT6 is involved in the synthesis of lactosylceramide with less intensity than β4GalT5.

    abstract::Glycosphingolipids are expressed on the cell membrane and act as important factors in various events that occur across the plasma membrane. Lactosylceramide (LacCer) is synthesized from glucosylceramide and is a common precursor of various glycosphingolipids existing in whole body. Based on the enzyme purification, β1...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwt054

    authors: Tokuda N,Numata S,Li X,Nomura T,Takizawa M,Kondo Y,Yamashita Y,Hashimoto N,Kiyono T,Urano T,Furukawa K,Furukawa K

    更新日期:2013-10-01 00:00:00

  • Helicobacter pylori β1,3-N-acetylglucosaminyltransferase for versatile synthesis of type 1 and type 2 poly-LacNAcs on N-linked, O-linked and I-antigen glycans.

    abstract::Poly-N-acetyllactosamine extensions on N- and O-linked glycans are increasingly recognized as biologically important structural features, but access to these structures has not been widely available. Here, we report a detailed substrate specificity and catalytic efficiency of the bacterial β3-N-acetylglucosaminyltrans...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cws101

    authors: Peng W,Pranskevich J,Nycholat C,Gilbert M,Wakarchuk W,Paulson JC,Razi N

    更新日期:2012-11-01 00:00:00

  • New oligosaccharyltransferase assay method.

    abstract::We developed a new in vitro assay for oligosaccharyltransferase (OST), which catalyzes the transfer of preassembled oligosaccharides on lipid carriers onto asparagine residues in polypeptide chains. The asparagine residues reside in the sequon, Asn-X-Thr/Ser, where X can be any amino acid residue except Pro. We demons...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwm087

    authors: Kohda D,Yamada M,Igura M,Kamishikiryo J,Maenaka K

    更新日期:2007-11-01 00:00:00

  • Incorporation of orally applied (13)C-galactose into milk lactose and oligosaccharides.

    abstract::Biosynthesis and functions of human milk oligosaccharides (HMO) are not well known. A typical housekeeping enzyme, beta1,4-galactosyltransferase, links galactose to glucose to form lactose which is then used as backbone for the assembly of HMO. We investigated whether milk lactose and HMO may be labeled in vivo by an ...

    journal_title:Glycobiology

    pub_type: 杂志文章

    doi:10.1093/glycob/cwj092

    authors: Rudloff S,Obermeier S,Borsch C,Pohlentz G,Hartmann R,Brösicke H,Lentze MJ,Kunz C

    更新日期:2006-06-01 00:00:00