Structure-based redesign of lysostaphin yields potent antistaphylococcal enzymes that evade immune cell surveillance

Blazanovic, Kristina; Zhao, Hongfeng; Choi, Yoonjoo; Li, Wen; Salvat, Regina; Osipovitch, Daniel C.; Fields, Jennifer; Moise, Leonard; Berwin, Brent; Fiering, Steven; Bailey‐Kellogg, Chris; Griswold, Karl E.

doi:10.1038/mtm.2015.21

Cited by 35 publications

(22 citation statements)

References 62 publications

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“…The methods are illustrated with case study application to a domain from a therapeutic protein that we have been developing [24,35,25]: the cell wall binding domain (CWBD) of Staphylococcus simulans lysostaphin (LST). Lysostaphin is a potent anti-staphylococcal enzyme, effective even against drug-resistant S. aureus strains [36].…”

Section: Methodsmentioning

confidence: 99%

EpiSweep: Computationally Driven Reengineering of Therapeutic Proteins to Reduce Immunogenicity While Maintaining Function

Choi

Verma

Griswold

et al. 2016

Methods in Molecular Biology

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Therapeutic proteins are yielding ever more advanced and efficacious new drugs, but the biological origins of these highly effective therapeutics renders them subject to immune surveillance within the patient’s body. When recognized by the immune system as a foreign agent, protein drugs elicit a coordinated response that can manifest a range of clinical complications including rapid drug clearance, loss of functionality and efficacy, delayed infusion-like allergic reactions, more serious anaphylactic shock, and even induced auto-immunity. It is thus often necessary to deimmunize an exogenous protein in order to enable its clinical application; critically, the deimmunization process must also maintain the desired therapeutic activity. To meet the growing need for effective, efficient, and broadly applicable protein deimmunization technologies, we have developed the EpiSweep suite of protein design algorithms. EpiSweep seamlessly integrates computational prediction of immunogenic T cell epitopes with sequence- or structure- based assessment of the impacts of mutations on protein stability and function, in order to select combinations of mutations that make Pareto optimal trade-offs between the competing goals of low immunogenicity and high-level function. The methods are applicable both to the design of individual functionally deimmunized variants as well as the design of combinatorial libraries enriched in functionally deimmunized variants. After validating EpiSweep in a series of retrospective case studies providing comparisons to conventional approaches to T cell epitope deletion, we have experimentally demonstrated it to be highly effective in prospective application to deimmunization of a number of different therapeutic candidates. We conclude that our broadly applicable computational protein design algorithms guide the engineer towards the most promising deimmunized therapeutic candidates, and thereby have the potential to accelerate development of new protein drugs by shortening time frames and improving hit rates.

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Section: Methodsmentioning

confidence: 99%

EpiSweep: Computationally Driven Reengineering of Therapeutic Proteins to Reduce Immunogenicity While Maintaining Function

Choi

Verma

Griswold

et al. 2016

Methods in Molecular Biology

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“…Nevertheless, observations made with the intact lysostaphin molecule only bear partial relevance for the lysostaphin lysibody, as this molecule only contains the lysostaphin cell wall binding domain. In fact, recent studies suggest that the catalytic domain of lysostaphin is the major driver of immunogenicity, while the binding domain is far less immunogenic (69). The molecule could be further deimmunized through elimination of T effector epitopes (70).…”

Section: Figmentioning

confidence: 99%

Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

Raz

Serrano

Thaker

et al. 2018

Antimicrob Agents Chemother

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The cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate structures that are highly conserved. While these properties make surface carbohydrates ideal targets for immunotherapy, carbohydrates elicit a poor immune response that results primarily in low-affinity IgM antibodies. In a previous publication, we introduced the lysibody approach to address this shortcoming. Lysibodies are engineered molecules that combine a high-affinity carbohydrate-binding domain of bacterial or bacteriophage origin and an Fc effector portion of a human IgG antibody, thus directing effective immunity to conserved bacterial surface carbohydrates. Here, we describe the first example of a lysibody containing the binding domain from a bacteriocin, lysostaphin. We also describe the creation of five lysibodies with binding domains derived from phage lysins, directed against The lysostaphin and LysK lysibodies showed the most promise and were further characterized. Both lysibodies bound a range of clinically important staphylococcal strains, fixed complement on the staphylococcal surface, and induced phagocytosis of by macrophages and human neutrophils. The lysostaphin lysibody had superior activity compared to that of the LysK lysibody, as well as that of the previously characterized ClyS lysibody, and it effectively protected mice in a kidney abscess/bacteremia model. These results further demonstrate that the lysibody approach is a reproducible means of creating antibacterial antibodies that cannot be produced by conventional means. Lysibodies therefore are a promising solution for opsonic antibodies that may be used passively to both treat and prevent infection by drug-resistant pathogens.

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“…Indeed, this is akin to a strategy we and others use to address the challenge of biologic drug immunogenicity. 51–53 While the goal for biologics is to reduce anti-drug antibodies, in contrast with objective of vaccination, sequence modifications that delete CD4 + T cell epitopes have been successfully balanced with maintaining biologic structure and activity to improve drug safety and efficacy.…”

Section: Ha Has a High Tolerance For Mutationsmentioning

confidence: 99%

T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

Moise

Biron

Boyle

et al. 2018

Human Vaccines & Immunotherapeutics

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The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, speed and capacity have been achieved but vaccine effectiveness remains a significant challenge. Here, we describe a novel vaccine design strategy called immune engineering in the context of H7N9 influenza vaccine development. The approach combines immunoinformatic and structure modeling methods to promote protective antibody responses against H7N9 hemagglutinin (HA) by engineering whole antigens to carry seasonal influenza HA memory CD4+ T cell epitopes – without perturbing native antigen structure – by galvanizing HA-specific memory helper T cells that support sustained antibody development against the native target HA. The premise for this vaccine concept rests on (i) the significance of CD4+ T cell memory to influenza immunity, (ii) the essential role CD4+ T cells play in development of neutralizing antibodies, (iii) linked specificity of HA-derived CD4+ T cell epitopes to antibody responses, (iv) the structural plasticity of HA and (v) an illustration of improved antibody response to a prototype engineered recombinant H7-HA vaccine. Immune engineering can be applied to development of vaccines against pandemic concerns, including avian influenza, as well as other difficult targets.

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Structure-based redesign of lysostaphin yields potent antistaphylococcal enzymes that evade immune cell surveillance

Cited by 35 publications

References 62 publications

EpiSweep: Computationally Driven Reengineering of Therapeutic Proteins to Reduce Immunogenicity While Maintaining Function

EpiSweep: Computationally Driven Reengineering of Therapeutic Proteins to Reduce Immunogenicity While Maintaining Function

Lysostaphin Lysibody Leads to Effective Opsonization and Killing of Methicillin-Resistant Staphylococcus aureus in a Murine Model

T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

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