Homology modeling and structure-based design improve hydrophobic interaction chromatography behavior of integrin binding antibodies.

Abstract:

:Monoclonal antibody (mAb) candidates from high-throughput screening or binding affinity optimization often contain mutations leading to liabilities for further development of the antibody, such as aggregation-prone regions and lack of solubility. In this work, we optimized a candidate integrin α11-binding mAb for developability using molecular modeling, rational design, and hydrophobic interaction chromatography (HIC). A homology model of the parental mAb Fv region was built, and this revealed hydrophobic patches on the surface of the complementarity-determining region loops. A series of 97 variants of the residues primarily responsible for the hydrophobic patches were expressed and their HIC retention times (RT) were measured. As intended, many of the computationally designed variants reduced the HIC RT compared to the parental mAb, and mutating residues that contributed most to hydrophobic patches had the greatest effect on HIC RT. A retrospective analysis was then performed where 3-dimentional protein property descriptors were evaluated for their ability to predict HIC RT using the current series of mAbs. The same descriptors were used to train a simple multi-parameter protein quantitative structure-property relationship model on this data, producing an improved correlation. We also extended this analysis to recently published HIC data for 137 clinical mAb candidates as well as 31 adnectin variants, and found that the surface area of hydrophobic patches averaged over a molecular dynamics sample consistently correlated to the experimental data across a diverse set of biotherapeutics.

journal_name

MAbs

journal_title

mAbs

authors

Jetha A,Thorsteinson N,Jmeian Y,Jeganathan A,Giblin P,Fransson J

doi

10.1080/19420862.2018.1475871

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

890-900

issue

6

eissn

1942-0862

issn

1942-0870

journal_volume

10

pub_type

杂志文章

相关文献

mAbs文献大全
  • Phage display-based generation of novel internalizing antibody fragments for immunotoxin-based treatment of acute myeloid leukemia.

    abstract::The current standard treatment for acute myeloid leukemia (AML) is chemotherapy based on cytarabine and daunorubicine (7 + 3), but it discriminates poorly between malignant and benign cells. Dose-limiting off‑target effects and intrinsic drug resistance result in the inefficient eradication of leukemic blast cells and...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2015.1007818

    authors: Fitting J,Blume T,Ten Haaf A,Blau W,Gattenlöhner S,Tur MK,Barth S

    更新日期:2015-01-01 00:00:00

  • Red colored IgG4 caused by vitamin B12 from cell culture media combined with disulfide reduction at harvest.

    abstract::While many antibody therapeutics are formulated at low concentration (~10-20 mg/mL) for intravenous administration, high concentration (> 100 mg/mL) formulations may be required for subcutaneous delivery in certain clinical indications. For such high concentration formulations, product color is more apparent due to th...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.28257

    authors: Derfus GE,Dizon-Maspat J,Broddrick JT,Velayo AC,Toschi JD,Santuray RT,Hsu SK,Winter CM,Krishnan R,Amanullah A

    更新日期:2014-05-01 00:00:00

  • Improved in vitro and in vivo activity against CD303-expressing targets of the chimeric 122A2 antibody selected for specific glycosylation pattern.

    abstract::Plasmacytoid dendritic cells (pDCs) play a central role for both innate and adaptive antiviral responses, as they direct immune responses through their unique ability to produce substantial concentrations of type I interferon (IFNs) upon viral encounter while also activating multiple immune cells, including macrophage...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2018.1451283

    authors: Fournier N,Jacque E,Fontayne A,Derache D,Dupont G,Verhaeghe L,Baptista L,Dehenne A,Dezetter AS,Terrier A,Longue A,Pochet-Beghin V,Beghin C,Chtourou S,de Romeuf C

    更新日期:2018-05-01 00:00:00

  • Bridging the gap: facilities and technologies for development of early stage therapeutic mAb candidates.

    abstract::Therapeutic monoclonal antibodies (mAbs) currently dominate the biologics marketplace. Development of a new therapeutic mAb candidate is a complex, multistep process and early stages of development typically begin in an academic research environment. Recently, a number of facilities and initiatives have been launched ...

    journal_title:mAbs

    pub_type: 杂志文章,评审

    doi:10.4161/mabs.3.5.16968

    authors: Munro TP,Mahler SM,Huang EP,Chin DY,Gray PP

    更新日期:2011-09-01 00:00:00

  • Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis.

    abstract::Much data support a role for central nervous system antigen-specific antibodies in the pathogenesis of multiple sclerosis (MS). The effects of inducing a decrease in (auto)antibody levels on MS or experimental autoimmune encephalomyelitis (EAE) through specific blockade of FcRn, however, remain unexplored. We recently...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.25439

    authors: Challa DK,Bussmeyer U,Khan T,Montoyo HP,Bansal P,Ober RJ,Ward ES

    更新日期:2013-09-01 00:00:00

  • Pharmacokinetic properties of IgG and various Fc fusion proteins in mice.

    abstract::Fusion to an IgG Fc region is an established strategy to extend the half-life of therapeutic proteins. Most Fc fusion proteins, however, do not achieve the long half-life of IgGs. Based on findings that scFv-Fc fusion proteins exhibit a shorter half-life than the corresponding IgG molecules, we performed a comparative...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2015.1113360

    authors: Unverdorben F,Richter F,Hutt M,Seifert O,Malinge P,Fischer N,Kontermann RE

    更新日期:2016-01-01 00:00:00

  • Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge.

    abstract::Pharmacokinetic (PK) testing of a humanized (κI, VH3 framework) and affinity matured anti-hepatitis C virus E2-glycoprotein (HCV-E2) antibody (hu5B3.κ1VH3.v3) in rats revealed unexpected fast clearance (34.9 mL/day/kg). This antibody binds to the rat recycling receptor FcRn as expected for a human IgG1 antibody and do...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.29809

    authors: Li B,Tesar D,Boswell CA,Cahaya HS,Wong A,Zhang J,Meng YG,Eigenbrot C,Pantua H,Diao J,Kapadia SB,Deng R,Kelley RF

    更新日期:2014-01-01 00:00:00

  • In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes.

    abstract::Vedolizumab (VDZ) is a humanized monoclonal antibody in development for the treatment of inflammatory bowel disease. VDZ binds to the α4β7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues. To understand w...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.26392

    authors: Wyant T,Yang L,Fedyk E

    更新日期:2013-11-01 00:00:00

  • Rational identification of an optimal antibody mixture for targeting the epidermal growth factor receptor.

    abstract::The epidermal growth factor receptor (EGFR) is frequently dysregulated in human malignancies and a validated target for cancer therapy. Two monoclonal anti-EGFR antibodies (cetuximab and panitumumab) are approved for clinical use. However, the percentage of patients responding to treatment is low and many patients exp...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.3.6.17955

    authors: Koefoed K,Steinaa L,Søderberg JN,Kjær I,Jacobsen HJ,Meijer PJ,Haurum JS,Jensen A,Kragh M,Andersen PS,Pedersen MW

    更新日期:2011-11-01 00:00:00

  • Differences in N-glycan structures found on recombinant IgA1 and IgA2 produced in murine myeloma and CHO cell lines.

    abstract::The development and production of recombinant monoclonal antibodies is well established. Although most of these are IgGs, there is also great interest in producing recombinant IgAs since this isotype plays a critical role in providing immunologic protection at mucosal surfaces. The choice of expression system for prod...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.2.3.11802

    authors: Yoo EM,Yu LJ,Wims LA,Goldberg D,Morrison SL

    更新日期:2010-05-01 00:00:00

  • Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use.

    abstract::Ch-mAb7F9, a human-mouse chimeric monoclonal antibody (mAb) designed to bind (+)-methamphetamine (METH) with high affinity and specificity, was produced as a treatment medication for METH abuse. In these studies, we present the preclinical characterization that provided predictive evidence that ch-mAb7F9 may be safe a...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.27620

    authors: Stevens MW,Tawney RL,West CM,Kight AD,Henry RL,Owens SM,Gentry WB

    更新日期:2014-03-01 00:00:00

  • Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments.

    abstract::Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the instability of the anti...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2016.1248012

    authors: Egan TJ,Diem D,Weldon R,Neumann T,Meyer S,Urech DM

    更新日期:2017-01-01 00:00:00

  • A chemical and computational approach to comprehensive glycation characterization on antibodies.

    abstract::Non-enzymatic glycation is a challenging post-translational modification to characterize due to the structural heterogeneity it generates in proteins. Glycation has become increasingly recognized as an important product quality attribute to monitor, particularly for the biotechnology sector, which produces recombinant...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2015.1046663

    authors: Saleem RA,Affholter BR,Deng S,Campbell PC,Matthies K,Eakin CM,Wallace A

    更新日期:2015-01-01 00:00:00

  • Antibody Fc engineering for enhanced neonatal Fc receptor binding and prolonged circulation half-life.

    abstract::The neonatal Fc receptor (FcRn) promotes antibody recycling through rescue from normal lysosomal degradation. The binding interaction is pH-dependent with high affinity at low pH, but not under physiological pH conditions. Here, we combined rational design and saturation mutagenesis to generate novel antibody variants...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2019.1633883

    authors: Mackness BC,Jaworski JA,Boudanova E,Park A,Valente D,Mauriac C,Pasquier O,Schmidt T,Kabiri M,Kandira A,Radošević K,Qiu H

    更新日期:2019-10-01 00:00:00

  • EFab domain substitution as a solution to the light-chain pairing problem of bispecific antibodies.

    abstract::Bispecific antibody therapeutics can expand the functionality of a conventional monoclonal antibody drug because they can bind multiple antigens. However, their great potential is counterbalanced by the challenges faced in their production. The classic asymmetric bispecific containing an Fc requires the expression of ...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2018.1519631

    authors: Cooke HA,Arndt J,Quan C,Shapiro RI,Wen D,Foley S,Vecchi MM,Preyer M

    更新日期:2018-11-01 00:00:00

  • Lepidopteran cells, an alternative for the production of recombinant antibodies?

    abstract::Monoclonal antibodies are used with great success in many different therapeutic domains. In order to satisfy the growing demand and to lower the production cost of these molecules, many alternative systems have been explored. Among them, the baculovirus/insect cells system is a good candidate. This system is very safe...

    journal_title:mAbs

    pub_type: 杂志文章,评审

    doi:10.4161/mabs.19942

    authors: Cérutti M,Golay J

    更新日期:2012-05-01 00:00:00

  • Cysteinylation of a monoclonal antibody leads to its inactivation.

    abstract::Post-translational modifications can have a signification effect on antibody stability. A comprehensive approach is often required to best understand the underlying reasons the modification affects the antibody's potency or aggregation state. Monoclonal antibody 001 displayed significant variation in terms of potency,...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2016.1160179

    authors: McSherry T,McSherry J,Ozaeta P,Longenecker K,Ramsay C,Fishpaugh J,Allen S

    更新日期:2016-05-01 00:00:00

  • Antibodies to watch in 2010.

    abstract::Monoclonal antibodies (mAbs) are a burgeoning class of therapeutics, with more than 25 approved in countries worldwide. Novel molecules are entering clinical study at a rate of nearly 40 per year, and the commercial pipeline includes approximately 240 mAb therapeutics in clinical studies that have not yet progressed t...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.2.1.10677

    authors: Reichert JM

    更新日期:2010-01-01 00:00:00

  • Site-specific antibody-drug conjugate heterogeneity characterization and heterogeneity root cause analysis.

    abstract::Site-specific antibody-drug conjugates (ADCs) are designed to overcome the heterogeneity observed with first-generation ADCs that use random conjugation to surface-exposed lysine residues or conjugation to interchain disulfide bonds. Despite significantly enhanced homogeneity, however, the production of site-specific ...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2019.1624127

    authors: Cao M,De Mel N,Jiao Y,Howard J,Parthemore C,Korman S,Thompson C,Wendeler M,Liu D

    更新日期:2019-08-01 00:00:00

  • Effective binding to protein antigens by antibodies from antibody libraries designed with enhanced protein recognition propensities.

    abstract::Antibodies provide immune protection by recognizing antigens of diverse chemical properties, but elucidating the amino acid sequence-function relationships underlying the specificity and affinity of antibody-antigen interactions remains challenging. We designed and constructed phage-displayed synthetic antibody librar...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2018.1550320

    authors: Jian JW,Chen HS,Chiu YK,Peng HP,Tung CP,Chen IC,Yu CM,Tsou YL,Kuo WY,Hsu HJ,Yang AS

    更新日期:2019-02-01 00:00:00

  • Improved monovalent TNF receptor 1-selective inhibitor with novel heterodimerizing Fc.

    abstract::The development of alternative therapeutic strategies to tumor necrosis factor (TNF)-blocking antibodies for the treatment of inflammatory diseases has generated increasing interest. In particular, selective inhibition of TNF receptor 1 (TNFR1) promises a more precise intervention, tackling only the pro-inflammatory r...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2019.1596512

    authors: Richter F,Seifert O,Herrmann A,Pfizenmaier K,Kontermann RE

    更新日期:2019-05-01 00:00:00

  • Cell culture processes for monoclonal antibody production.

    abstract::Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology. A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both...

    journal_title:mAbs

    pub_type: 杂志文章,评审

    doi:10.4161/mabs.2.5.12720

    authors: Li F,Vijayasankaran N,Shen AY,Kiss R,Amanullah A

    更新日期:2010-09-01 00:00:00

  • High throughput functional epitope mapping: revisiting phage display platform to scan target antigen surface.

    abstract::Antibody engineering must be accompanied by mapping strategies focused on identifying the epitope recognized by each antibody to define its unique functional identity. High throughput fine specificity determination remains technically challenging. We review recent experiences aimed at revisiting the oldest and most ex...

    journal_title:mAbs

    pub_type: 杂志文章,评审

    doi:10.4161/mabs.36144

    authors: Rojas G,Tundidor Y,Infante YC

    更新日期:2014-01-01 00:00:00

  • Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor.

    abstract::MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose ...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2015.1136043

    authors: Deng R,Bumbaca D,Pastuskovas CV,Boswell CA,West D,Cowan KJ,Chiu H,McBride J,Johnson C,Xin Y,Koeppen H,Leabman M,Iyer S

    更新日期:2016-01-01 00:00:00

  • Generation of human single-chain variable fragment antibodies specific to dengue virus non-structural protein 1 that interfere with the virus infectious cycle.

    abstract::Severe forms of dengue virus (DENV) infection frequently cause high case fatality rate. Currently, there is no effective vaccine against the infection. Clinical cases are given only palliative treatment as specific anti-DENV immunotherapy is not available and it is urgently required. In this study, human single-chain ...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.27874

    authors: Poungpair O,Bangphoomi K,Chaowalit P,Sawasdee N,Saokaew N,Choowongkomon K,Chaicumpa W,Yenchitsomanus PT

    更新日期:2014-03-01 00:00:00

  • Molecular characterization of the cervical and systemic B-cell repertoire: Unique, yet overlapping, immune compartments of an HIV-1 resistant individual.

    abstract::The cervical mucosa of women who are highly exposed to HIV-1, yet remain persistently seronegative (HEPS), presents a unique opportunity to study the dynamics of an immune compartment potentially capable of preventing HIV-1 infection. Herein, we provide a detailed characterization of the immunoglobulin repertoire of c...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.3.2.14858

    authors: Gaudet RG,Breden F,Plummer F,Berry JD

    更新日期:2011-03-01 00:00:00

  • Rapid identification of an antibody DNA construct rearrangement sequence variant by mass spectrometry.

    abstract::During cell line development for an IgG1 antibody candidate (mAb1), a C-terminal extension was identified in 2 product candidate clones expressed in CHO-K1 cell line. The extension was initially observed as the presence of anomalous new peaks in these clones after analysis by cation exchange chromatography (CEX-HPLC) ...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.36222

    authors: Scott RA,Rogers R,Balland A,Brady LJ

    更新日期:2014-01-01 00:00:00

  • Developability studies before initiation of process development: improving manufacturability of monoclonal antibodies.

    abstract::Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other t...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.4161/mabs.25269

    authors: Yang X,Xu W,Dukleska S,Benchaar S,Mengisen S,Antochshuk V,Cheung J,Mann L,Babadjanova Z,Rowand J,Gunawan R,McCampbell A,Beaumont M,Meininger D,Richardson D,Ambrogelly A

    更新日期:2013-09-01 00:00:00

  • A method to confer Protein L binding ability to any antibody fragment.

    abstract::Recombinant antibody single-chain variable fragments (scFv) are difficult to purify homogeneously from a protein complex mixture. The most effective, specific and fastest method of purification is an affinity chromatography on Protein L (PpL) matrix. This protein is a multi-domain bacterial surface protein that is abl...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2015.1116657

    authors: Lakhrif Z,Pugnière M,Henriquet C,di Tommaso A,Dimier-Poisson I,Billiald P,Juste MO,Aubrey N

    更新日期:2016-01-01 00:00:00

  • Development and validation of an LC-MS/MS method for simultaneous quantification of co-administered trastuzumab and pertuzumab.

    abstract::Given the increasing use of combination therapy with multiple monoclonal antibodies (mAbs), there is a clinical need for multiplexing assays. For the frequently co-administered anti-human epidermal growth factor receptor 2 (HER2) mAbs trastuzumab and pertuzumab, we developed a high-throughput and robust hybrid ligand-...

    journal_title:mAbs

    pub_type: 杂志文章

    doi:10.1080/19420862.2020.1795492

    authors: Schokker S,Fusetti F,Bonardi F,Molenaar RJ,Mathôt RAA,van Laarhoven HWM

    更新日期:2020-01-01 00:00:00