Bispecific antibodies for cancer therapy

Chames, Patrick; Baty, Daniel

doi:10.4161/mabs.1.6.10015

Cited by 281 publications

(146 citation statements)

References 58 publications

(60 reference statements)

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“…An alternative strategy could involve the use of bispecific antibody to combine tissue targeting with therapeutic function. To date, no bispecific antibody has been clinically evaluated for use in RA; however, 2 antibodies, catumaxomab and blinatumomab, have been recently approved for cancer treatment, and several constructs are currently in clinical trials 33.…”

Section: Discussionmentioning

confidence: 99%

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Onuoha

Ferrari

Sblattero

et al. 2015

Arthritis & Rheumatology

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ObjectiveBiologic drugs, such as the anti–tumor necrosis factor (anti‐TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies.MethodsActivatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM‐1), which is up‐regulated at sites of inflammation, and anti‐TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM‐1 and an internal arm that comprises the therapeutic domain of an anti‐TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)–cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets.ResultsIntact aDVD constructs demonstrated significantly reduced binding and anti‐TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti‐TNF inhibitory capacities as the parent molecules.ConclusionThe design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off‐target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Onuoha

Ferrari

Sblattero

et al. 2015

Arthritis & Rheumatology

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“…Although the in vitro and in vivo antitumor efficiencies of bsAbs have been largely shown over the last two decades, their development has been severely hindered by different factors, including immunogenicity and the difficulty to efficiently produce large amounts of active molecules (18). With the development of antibody engineering, several innovative recombinant formats have been proposed, including diabodies, tandem single-chain variable fragments (scFvs), and minibodies (17,19,20), and some of these molecules are being tested in the clinics (21). However, most described recombinant bsAbs heavily rely on the use of peptide linkers.…”

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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“…This heterogeneity is one of the main reasons why antibodies containing two distinct binding specificities, i.e., bispecific antibodies (bsAbs), are thought to have great potential as dual-targeting therapeutic agents, as also illustrated by the expanding number of bsAb-based formats in development (1). However, the general application of most of these formats for therapeutic use has been hampered by shortcomings with respect to physicochemical stability, pharmacokinetic properties, immunogenicity, and scalability of manufacturing and purification (2)(3)(4). Furthermore, the inherent design of most bsAb-based formats precludes efficient screening of large numbers of bispecific combinations or requires reengineering on final candidate selection (5).…”

mentioning

confidence: 99%

Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange

Labrijn

Meesters

Goeij

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

273

298

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The promise of bispecific antibodies (bsAbs) to yield more effective therapeutics is well recognized; however, the generation of bsAbs in a practical and cost-effective manner has been a formidable challenge. Here we present a technology for the efficient generation of bsAbs with normal IgG structures that is amenable to both antibody drug discovery and development. The process involves separate expression of two parental antibodies, each containing single matched point mutations in the CH3 domains. The parental antibodies are mixed and subjected to controlled reducing conditions in vitro that separate the antibodies into HL half-molecules and allow reassembly and reoxidation to form highly pure bsAbs. The technology is compatible with standard large-scale antibody manufacturing and ensures bsAbs with Fcmediated effector functions and in vivo stability typical of IgG1 antibodies. Proof-of-concept studies with HER2×CD3 (T-cell recruitment) and HER2×HER2 (dual epitope targeting) bsAbs demonstrate superior in vivo activity compared with parental antibody pairs.immunotherapy | pharmacokinetics | anti-tumor

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Bispecific antibodies for cancer therapy

Cited by 281 publications

References 58 publications

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation

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

Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange

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