An update on antibody-based immunotherapies for &lt;em&gt;Clostridium difficile&lt;/em&gt; infection

Hussack, Greg; Tanha, Jamshid

doi:10.2147/ceg.s84017

Cited by 21 publications

(11 citation statements)

References 161 publications

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“…difficile infection were estimated to exceed a staggering $4.5 billion annually in the US alone [1]. Despite the introduction of therapies that include new antibiotic modalities, fecal transplantation and antibody-based immunotherapy, efficacy limitations remain which necessitate the continuous search for more potent therapeutic agents [2,3,4].…”

Section: Introductionmentioning

confidence: 99%

“…difficile -associated disease [5]. With respect to antibodies a number of anti-toxin formats have been explored, including intravenous immunoglobulin therapy, IgG, IgA, IgY, single-chain fragment variable (scFv) and single-domain antibodies (sdAbs) [2,7]. Recently, the anti-TcdB monoclonal antibody (mAb) bezlotoxumab was FDA-approved for the treatment of recurrent C .…”

Section: Introductionmentioning

confidence: 99%

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Neutralization of Clostridium difficile toxin B with VHH-Fc fusions targeting the delivery and CROPs domains

et al. 2018

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An increasing number of antibody-based therapies are being considered for controlling bacterial infections, including Clostridium difficile by targeting toxins A and B. In an effort to develop novel C. difficile immunotherapeutics, we previously isolated several single-domain antibodies (VHHs) capable of toxin A neutralization through recognition of the extreme C-terminal combined repetitive oligopeptides (CROPs) domain, but failed at identifying neutralizing VHHs that bound a similar region on toxin B. Here we report the isolation of a panel of 29 VHHs targeting at least seven unique epitopes on a toxin B immunogen composed of a portion of the central delivery domain and the entire CROPs domain. Despite monovalent affinities as high as KD = 70 pM, none of the VHHs tested were capable of toxin B neutralization; however, modest toxin B inhibition was observed with VHH-VHH dimers and to a much greater extent with VHH-Fc fusions, reaching the neutralizing potency of the recently approved anti-toxin B monoclonal antibody bezlotoxumab in in vitro assays. Epitope binning revealed that several VHH-Fcs bound toxin B at sites distinct from the region recognized by bezlotoxumab, while other VHH-Fcs partially competed with bezlotoxumab for toxin binding. Therefore, the VHHs described here are effective at toxin B neutralization when formatted as bivalent VHH-Fc fusions by targeting toxin B at regions both similar and distinct from the bezlotoxumab binding site.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neutralization of Clostridium difficile toxin B with VHH-Fc fusions targeting the delivery and CROPs domains

et al. 2018

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“…The large-scale production of highly toxic antigens can be a challenging and costly process. Vaccines based on non-toxic fragments of genetically engineered versions of the toxins alleviate some of these concerns including issues of safety 78,79. Karczewski et al investigated the potential of a recombinant vaccine composed of 2 separate fragments of toxin B against C. difficile 80.…”

Section: Recombinant Vaccines (Rv)mentioning

confidence: 99%

<p>Recent advances in the treatment of <em>C. difficile</em> using biotherapeutic agents</p>

Giau

Lee

et al. 2019

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Clostridium difficile ( C. difficile ) is rapidly becoming one of the most prevalent health care–associated bacterial infections in the developed world. The emergence of new, more virulent strains has led to greater morbidity and resistance to standard therapies. The bacterium is readily transmitted between people where it can asymptomatically colonize the gut environment, and clinical manifestations ranging from frequent watery diarrhea to toxic megacolon can arise depending on the age of the individual or their state of gut dysbiosis. Several inexpensive approaches are shown to be effective against virulent C. difficile in research settings such as probiotics, fecal microbiota transfer and immunotherapies. This review aims to highlight the current advantages and limitations of the aforementioned approaches with an emphasis on recent studies.

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“…The production of fully human monoclonal antibodies was achieved with the development of phage display platforms, and also with the advancements in transgenic mouse platforms [46]. mAbs are the most successful antibodies, being approved and used as a therapy for cancer, autoimmune disorders, cholesterol, and infectious diseases, with the majority of these approved mAbs being chimeric or humanized [46][47][48].…”

Section: Conventional Mammalian Monoclonal Antibodiesmentioning

confidence: 99%

Antibody-Based Immunotherapies as a Tool for Tackling Multidrug-Resistant Bacterial Infections

2022

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The discovery of antimicrobials is an outstanding achievement of mankind that led to the development of modern medicine. However, increasing antimicrobial resistance observed worldwide is rendering commercially available antimicrobials ineffective. This problem results from the bacterial ability to adapt to selective pressure, leading to the development or acquisition of multiple types of resistance mechanisms that can severely affect the efficacy of antimicrobials. The misuse, over-prescription, and poor treatment adherence by patients are factors strongly aggravating this issue, with an epidemic of infections untreatable by first-line therapies occurring over decades. Alternatives are required to tackle this problem, and immunotherapies are emerging as pathogen-specific and nonresistance-generating alternatives to antimicrobials. In this work, four types of antibody formats and their potential for the development of antibody-based immunotherapies against bacteria are discussed. These antibody isotypes include conventional mammalian polyclonal antibodies that are used for the neutralization of toxins; conventional mammalian monoclonal antibodies that currently have 100 IgG mAbs approved for therapeutic use; immunoglobulin Y found in birds and an excellent source of high-quality polyclonal antibodies able to be purified noninvasively from egg yolks; and single domain antibodies (also known as nanobodies), a recently discovered antibody format (found in camelids and nurse sharks) that allows for a low-cost synthesis in microbial systems, access to hidden or hard-to-reach epitopes, and exhibits a high modularity for the development of complex structures.

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An update on antibody-based immunotherapies for <em>Clostridium difficile</em> infection

Cited by 21 publications

References 161 publications

Neutralization of Clostridium difficile toxin B with VHH-Fc fusions targeting the delivery and CROPs domains

Neutralization of Clostridium difficile toxin B with VHH-Fc fusions targeting the delivery and CROPs domains

<p>Recent advances in the treatment of <em>C. difficile</em> using biotherapeutic agents</p>

Antibody-Based Immunotherapies as a Tool for Tackling Multidrug-Resistant Bacterial Infections

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