Developing inhaled protein therapeutics for lung diseases

Matthews, Abigail Ann; Ee, Pui Lai Rachel; Ge, Ruowen

doi:10.1186/s43556-020-00014-z

Cited by 54 publications

(56 citation statements)

References 101 publications

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“…To benchmark the newly implemented CVS-STEOM-CCSD method's accuracy, we have used the small molecule test set of Mathews 82 for which EOM-CCSDT results have been reported. The test set consists of five molecules H2O, CO, NH3, HCN, and C2H4, with a total of 28 core excited states.…”

Section: Resultsmentioning

confidence: 99%

A Core–Valence Separated Similarity Transformed EOM-CCSD Method for Core-Excitation Spectra

Ranga

Dutta

2021

J. Chem. Theory Comput.

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We present the theory and implementation of a core-valence separated similarity transformed EOM-CCSD (STEOM-CCSD) method for K-edge core excitation spectra. The method can select an appropriate active space using CIS natural orbitals and near 'black box' to use. The second similarity transformation Hamiltonian is diagonalized in the space of single excitation. Therefore, the final diagonalization step is free from the convergence problem arising because of the coupling of the core-excited states with the continuum of doubly excited states. Convergence trouble can appear for the preceding core-ionized states calculation in STEOM-CCSD. A core-valence separation scheme (CVS) compatible with the natural orbital based active space selection has been implemented to overcome the problem. The CVS-STEOM-CCSD has similar accuracy as that of the standard CVS-EOM-CCSD method but comes with a lower computational cost. The modification required for the CVS scheme because of the use of CIS natural orbital is highlighted. The suitability of CVS-STEOM-CCSD for chemical application is demonstrated by simulating the K-edge spectra of glycine and thymine.

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Section: Resultsmentioning

confidence: 99%

A Core–Valence Separated Similarity Transformed EOM-CCSD Method for Core-Excitation Spectra

Ranga

Dutta

2021

J. Chem. Theory Comput.

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“…Generally, DARPin molecules demonstrate excellent temperature stability, which might enable alternative routes of administration, such as inhalation described for other highly stable protein scaffolds( 47,48 ). The simple molecular architecture of multivalent DARPin molecules allows manufacturing in bacterial expression systems at very high yields which leads to cost-effective and scalable production of antiviral biologicals at industrial quantities (supplementary Table 5).…”

Section: Discussionmentioning

confidence: 99%

Highly potent anti-SARS-CoV-2 multivalent DARPin therapeutic candidates

Walser

Rothenberger

Hurdiss

et al. 2020

Preprint

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Globally accessible preventive and therapeutic molecules against SARS-CoV-2 are urgently needed. DARPin molecules are an emerging class of novel therapeutics based on naturally occurring repeat proteins (∼15 kDa in size) and can be rapidly produced in bacteria in large quantities. Here, we report the identification of 380 DARPin molecules specifically targeting the SARS-CoV-2 spike protein selected from a naïve library of 1012 DARPin molecules. Using extensive biophysical and biochemical characterization, (pseudo)virus neutralization assays and cryo-EM analysis, 11 mono-DARPin molecules targeting either the receptor binding domain (RBD), the S1 N-terminal-domain (NTD) or the S2 domain of the SARS-CoV-2 spike protein were chosen. Based on these 11 mono-DARPin molecules, 31 anti-SARS-CoV-2 multi-DARPin molecules were constructed which can broadly be grouped into 2 types; multi-paratopic RBD-neutralizing DARPin molecules and multi-mode DARPin molecules targeting simultaneously RBD, NTD and the S2 domain. Each of these multi-DARPin molecules acts by binding with 3 DARPin modules to the SARS-CoV-2 spike protein, leading to potent inhibition of SARS-CoV-2 infection down to 1 ng/ml (12 pM) and potentially providing protection against viral escape mutations. Additionally, 2 DARPin modules binding serum albumin, conferring an expected half-life of about 3 weeks in humans, were included in the multi-DARPin molecules. The protective efficacy of one multi-DARPin molecule was studied in a Golden Syrian hamster SARS-CoV-2 infection model, resulting in a significant reduction in viral load and pathogenesis. In conclusion, the multi-DARPin molecules reported here display very high antiviral potency, high-production yield, and a long systemic half-life, and thereby have the potential for single-dose use for prevention and treatment of COVID-19.

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“…The use of nanoparticles as delivery systems allows for a reduction in antibody dosing, increases area of coverage, reduces immunogenicity, and controlled release (Sousa et al 2017 ). However, the half-life of inhaled Abs in humans is approximately 16–24 h (~ 1 day) (Koussoroplis et al 2014 ; Matthews et al 2020 ). The encapsulation of antibodies in nanoparticles allows for the slow release of these antibodies, resulting in an increase in their overall bioavailability.…”

Section: Challenges and Advancements Associated With Antibody-based Prevention And Therapeutic Approaches For Inhaled Deliverymentioning

confidence: 99%

“…Gai et al ( 2020 ) have shown that a nanobody developed against the nCOV-19 showed high stability post-nebulisation. To increase antibody retention in respiratory mucosa, Zhang et al ( 2020 ) engineered a human antibody that recognises SARS-CoV-2 S1 spike protein with a higher affinity for mucin and was found to be effective in both nasal and lung areas 7 days after viral exposure in a mouse model (Matthews et al 2020 ). Other concerns include the possibility of immunogenicity of antibodies used in the nasal spray due to the anticipated long-term frequent use as prophylaxis.…”

Section: Challenges and Advancements Associated With Antibody-based Prevention And Therapeutic Approaches For Inhaled Deliverymentioning

confidence: 99%

Inhalation monoclonal antibody therapy: a new way to treat and manage respiratory infections

Parray

Shukla

Perween

et al. 2021

Appl Microbiol Biotechnol

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The route of administration of a therapeutic agent has a substantial impact on its success. Therapeutic antibodies are usually administered systemically, either directly by intravenous route, or indirectly by intramuscular or subcutaneous injection. However, treatment of diseases contained within a specific tissue necessitates a better alternate route of administration for targeting localised infections. Inhalation is a promising non-invasive strategy for antibody delivery to treat respiratory maladies because it provides higher concentrations of antibody in the respiratory airways overcoming the constraints of entry through systemic circulation and uncertainity in the amount reaching the target tissue. The nasal drug delivery route is one of the extensively researched modes of administration, and nasal sprays for molecular drugs are deemed successful and are presently commercially marketed. This review highlights the current state and future prospects of inhaled therapies, with an emphasis on the use of monoclonal antibodies for the treatment of respiratory infections, as well as an overview of their importance, practical challenges, and clinical trial outcomes. Key points • Immunologic strategies for preventing mucosal transmission of respiratory pathogens. • Mucosal-mediated immunoprophylaxis could play a major role in COVID-19 prevention. • Applications of monoclonal antibodies in passive immunisation.

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Developing inhaled protein therapeutics for lung diseases

Cited by 54 publications

References 101 publications

A Core–Valence Separated Similarity Transformed EOM-CCSD Method for Core-Excitation Spectra

A Core–Valence Separated Similarity Transformed EOM-CCSD Method for Core-Excitation Spectra

Highly potent anti-SARS-CoV-2 multivalent DARPin therapeutic candidates

Inhalation monoclonal antibody therapy: a new way to treat and manage respiratory infections

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