Characterization of an Oncolytic Herpes Simplex Virus Drug Candidate

Kumru, Ozan S.; Joshi, Sangeeta B.; Thapa, Prem; Pheasey, Nigel; Bullock, Paul S.; Bashiri, Houman; Siska, Christine S.; Kerwin, Bruce A.; He, Feng; Volkin, David B.; Middaugh, C. Russell

doi:10.1002/jps.24211

Cited by 16 publications

(9 citation statements)

References 35 publications

(73 reference statements)

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“…Radar chart analysis is a data visualization tool that has been used to summarize and compare large biophysical data sets to study the effect of various stresses (e.g., pH, temperature) on physical stability of a wide variety of macromolecules including vaccine and protein drug candidates. 34,[51][52][53][54][55][56][57] Radar chart analysis in this work showed the structural integrity and conformational stability of 3 NRRV antigens as a function of pH and temperature. P [8] was the most stable, followed by P [4], and P [6] was least stable.…”

Section: Size Higher-order Structure and Physical Stability Profilementioning

confidence: 99%

Recombinant Subunit Rotavirus Trivalent Vaccine Candidate: Physicochemical Comparisons and Stability Evaluations of Three Protein Antigens

Hickey

Sahni

Toth

et al. 2020

Journal of Pharmaceutical Sciences

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a b s t r a c tAlthough live attenuated Rotavirus (RV) vaccines are available globally to provide protection against enteric RV disease, efficacy is substantially lower in low-to middle-income settings leading to interest in alternative vaccines. One promising candidate is a trivalent nonreplicating RV vaccine, comprising 3 truncated RV VP8 subunit proteins fused to the P2 CD4 þ epitope from tetanus toxin (P2-VP8-P[4/6/8]). A wide variety of analytical techniques were used to compare the physicochemical properties of these 3 recombinant fusion proteins. Various environmental stresses were used to evaluate antigen stability and elucidate degradation pathways. P2-VP8-P[4] and P2-VP8-P[6] displayed similar physical stability profiles as function of pH and temperature while P2-VP8-P[8] was relatively more stable. Forced degradation studies revealed similar chemical stability profiles with Met 1 most susceptible to oxidation, the single Cys residue (at position 173/172) forming intermolecular disulfide bonds (P2-VP8-P[6] was most susceptible), and Asn 7 undergoing the highest levels of deamidation. These results are visualized in a structural model of the nonreplicating RV antigens. The establishment of key structural attributes of each antigen, along with corresponding stability-indicating methods, have been applied to vaccine formulation development efforts (see companion paper), and will be utilized in future analytical comparability assessments.

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Section: Size Higher-order Structure and Physical Stability Profilementioning

confidence: 99%

Recombinant Subunit Rotavirus Trivalent Vaccine Candidate: Physicochemical Comparisons and Stability Evaluations of Three Protein Antigens

Hickey

Sahni

Toth

et al. 2020

Journal of Pharmaceutical Sciences

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“…13,14 Since 1950, many viruses such as herpes simplex virus, poliovirus, poxvirus, adenovirus and measles viruses have been characterized for their oncolytic property. [15][16][17][18][19] Virotherapy has emerged as a new field of therapeutics for a broad range of human cancers. The oncolytic potential of NDV was examined for the first time in 1965.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of an apoptotic strain of Newcastle disease virus isolated from an outbreak in India

Kumar

2015

Cancer Gene Ther

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Newcastle disease (ND) is a highly contagious disease of poultry. The ND virus (NDV) encodes an error-prone RNA-dependent RNA polymerase which can cause high mutation rate leading to the emergence of its new antigenic variants. Antigenic difference of NDV strains may result in massive outbreak in vaccinated and unvaccinated poultry flocks around the globe. Apart from its pathogenic potential NDV has been explored as an oncolytic agent for a broad range of human cancers. In the present study, we isolated a novel NDV strain from an outbreak in chicken flock from the eastern part of India. Molecular characterization showed the NDV strain to be virulent in nature. The complete genome sequence analysis of the newly isolated strains belongs to genotype XIII. Moreover, the newly isolated strain of NDV showed positive results in various apoptotic assays in human breast cancer cells, MCF-7. The study will be useful to explore the possibility of using a newly isolated strain of NDV for virotherapy.

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“…There is growing interest in developing live, attenuated viruses not only as vaccine candidates themselves, but as engineered vectors for vaccination against other viral diseases and as “live drugs” including therapeutic oncolytic agents. For example, engineered versions of herpes simplex virus, vesicular stomatitis virus, Newcastle disease virus, adenovirus, and poxvirus haven been used in oncolytic virotherapy [28], [29]. In addition, a live, adenoviral associated virus vector based drug, LUXTURNA™ was recently approved for treatment of retinal dystrophy [30].…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, other viruses display different stability profiles when ionic strength is varied demonstrating unique aspects of the stability profile of each live viral vaccine/vector candidate [40], [41], [42]. For example, aggregation of the HSV-1 virions contributes to viral infectivity losses due to freeze-thaw in the absence of cryoprotectants [29]. Mechanistically, freeze-thaw mediated inactivation may result not only from viral particle aggregation, but also osmotic shock [36].…”

Section: Discussionmentioning

confidence: 99%

Stabilization and formulation of a recombinant Human Cytomegalovirus vector for use as a candidate HIV-1 vaccine

Kumru

Saleh-Birdjandi

Antúnez

et al. 2019

Vaccine

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Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials.

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Characterization of an Oncolytic Herpes Simplex Virus Drug Candidate

Cited by 16 publications

References 35 publications

Recombinant Subunit Rotavirus Trivalent Vaccine Candidate: Physicochemical Comparisons and Stability Evaluations of Three Protein Antigens

Recombinant Subunit Rotavirus Trivalent Vaccine Candidate: Physicochemical Comparisons and Stability Evaluations of Three Protein Antigens

Molecular characterization of an apoptotic strain of Newcastle disease virus isolated from an outbreak in India

Stabilization and formulation of a recombinant Human Cytomegalovirus vector for use as a candidate HIV-1 vaccine

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