Therapeutic antibodies: successes, limitations and hopes for the future

Chames, Patrick; Regenmortel, Marc van; Weiss, Étienne; Baty, Daniel

doi:10.1111/j.1476-5381.2009.00190.x

Cited by 1,191 publications

(985 citation statements)

References 83 publications

(92 reference statements)

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“…Most of these mAbs (9/15) are human immunoglobulin G1 (IgG1) that trigger various mechanisms, such as target signaling inhibition, apoptosis, activation of the classical complement pathway, and/or of immune effector cells expressing Fcg receptors (FcgR; refs. 1,2). Although it is difficult to assess the contribution of each of these mechanisms in their in vivo efficacy, clinical trial results support an important role of antibody-dependent cell-mediated cytotoxicity (ADCC) for both lymphomas and solid tumors (3).…”

Section: Introductionmentioning

confidence: 99%

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Rozan

Cornillon

Pétiard

et al. 2013

Molecular Cancer Therapeutics

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Antibody-dependent cell-mediated cytotoxicity, one of the most prominent modes of action of antitumor antibodies, suffers from important limitations due to the need for optimal interactions with Fcg receptors. In this work, we report the design of a new bispecific antibody format, compact and linker-free, based on the use of llama single-domain antibodies that are capable of circumventing most of these limitations. This bispecific antibody format was created by fusing single-domain antibodies directed against the carcinoembryonic antigen and the activating FcgRIIIa receptor to human Ck and CH1 immunoglobulin G1 domains, acting as a natural dimerization motif. In vitro and in vivo characterization of these Fab-like bispecific molecules revealed favorable features for further development as a therapeutic molecule. They are easy to produce in Escherichia coli, very stable, and elicit potent lysis of tumor cells by human natural killer cells at picomolar concentrations. Unlike conventional antibodies, they do not engage inhibitory FcgRIIb receptor, do not compete with serum immunoglobulins G for receptor binding, and their cytotoxic activity is independent of Fc glycosylation and FcgRIIIa polymorphism. As opposed to anti-CD3 bispecific antitumor antibodies, they do not engage regulatory T cells as these latter cells do not express FcgRIII. Studies in nonobese diabetic/severe combined immunodeficient gamma mice xenografted with carcinoembryonic antigen-positive tumor cells showed that Fab-like bispecific molecules in the presence of human peripheral blood mononuclear cells significantly slow down tumor growth. This new compact, linker-free bispecific antibody format offers a promising approach for optimizing antibody-based therapies.

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Section: Introductionmentioning

confidence: 99%

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Rozan

Cornillon

Pétiard

et al. 2013

Molecular Cancer Therapeutics

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“…Biopharmaceuticals are a fast growing class of therapeutics (1)(2)(3)(4). Assessment of pharmacokinetics (PK) and pharmacodynamics (PD) is an integral part of preclinical and clinical development (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Multiplexing of receptor occupancy measurements for pharmacodynamic biomarker assessment of biopharmaceuticals

Vainshtein¹,

Schneider²,

Sun³

et al. 2015

Cytometry Part B Clinical

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Background: Receptor occupancy (RO) assays measure drug target engagement, and are used as pharmacodynamic (PD) biomarkers. RO assays are commonly performed by flow cytometry and often require multiplexing for assessment of multiple PD biomarkers when specimen volumes are limited. We present multiplexed RO assays for an IGF1R-EGFR bispecific antibody (Bs-Ab) and a CTLA4-Ig recombinant fusion protein to demonstrate key considerations for accurate RO assessment.Methods: RO in cynomolgus monkeys was determined in whole blood using flow cytometry. Free and total receptors were measured using anti-receptor fluorescence-labeled detection reagents, competitive and noncompetitive to drug, respectively.Results: RO of IGF1R was examined as PD for Bs-Ab, since IGF1R was expressed on blood cells. Multiplexed measurements of free and total IGF1R showed that IGF1R expression measured by total receptor was highly variable, impacting interpretation of free-IGF1R. Normalization of free-over-total IGF1R measurements compensated for variability of receptor expression allowing for accurate RO assessment. RO of CTLA4-Ig, a recombinant fusion protein targeting CD80 and CD86 receptors, was multiplexed to simultaneously measure target engagements for both receptors. Both RO methods demonstrated specificity of receptor measurements without cross-reactivity to each other in multiplexed formats. RO methods were used for evaluation of PD activity of Bs-Ab and CTLA4-Ig in cynomolgus monkeys. In both cases, RO results showed dose-dependent target engagement, corresponding well to the pharmacokinetics.Conclusions: Multiplexed RO methods allowed accurate assessment of PD activity for Bs-Ab and CTLA4-Ig, facilitating development of these biopharmaceuticals from preclinical to clinical stages.

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“…Intense research efforts have been dedicated to predict and reduce immunogenicity 246 . In line with the huge success of monoclonal antibodies since the late 1990's 247 , the administered doses have massively multiplied 248 . On the other hand, in a study with twenty-eight single clonal CHO cell lines, correlations were identified between the antibody titer and the level of both aggregation and low-molecular species 249 .…”

Section: Introductionmentioning

confidence: 99%

Tailoring recombinant protein quality by rational media design

Brühlmann

Jordan

Hemberger³

et al. 2015

Biotechnology Progress

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Clinical efficacy and safety of recombinant proteins are closely associated with their structural characteristics. The major quality attributes comprise glycosylation, charge variants (oxidation, deamidation, and C‐ & N‐terminal modifications), aggregates, low‐molecular‐weight species (LMW), and misincorporation of amino acids in the protein backbone. Cell culture media design has a great potential to modulate these quality attributes due to the vital role of medium in mammalian cell culture. The purpose of this review is to provide an overview of the way both classical cell culture medium components and novel supplements affect the quality attributes of recombinant therapeutic proteins expressed in mammalian hosts, allowing rational and high‐throughput optimization of mammalian cell culture media. A selection of specific and/or potent inhibitors and activators of oligosaccharide processing as well as components affecting multiple quality attributes are presented. Extensive research efforts in this field show the feasibility of quality engineering through media design, allowing to significantly modulate the protein function. © 2015 American Institute of Chemical Engineers Biotechnol. Prog., 31:615–629, 2015

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Therapeutic antibodies: successes, limitations and hopes for the future

Cited by 1,191 publications

References 83 publications

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Single-Domain Antibody–Based and Linker-Free Bispecific Antibodies Targeting FcγRIII Induce Potent Antitumor Activity without Recruiting Regulatory T Cells

Multiplexing of receptor occupancy measurements for pharmacodynamic biomarker assessment of biopharmaceuticals

Tailoring recombinant protein quality by rational media design

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