Preclinical development of therapeutic biologics

: Infections caused by Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., Entamoeba histolytica, Giardia lamblia, Plasmodium spp., and Trichomonas vaginalis, are part of a large list of human parasitic diseases. Together, they cause more than 500 million infections per year. These protozoa parasites affect both low- and high-income countries and their pharmacological treatment is limited. Therefore, new and more effective drugs in preclinical development could improve overall therapy for parasitic infections even when their mechanisms of action are unknown. In this review, a number of heterocyclic compounds (diamidine, guanidine, quinoline, benzimidazole, thiazole, diazanaphthalene, and their derivatives) reported as antiprotozoal agents are discussed as options for developing new pharmacological treatments for parasitic diseases.

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Quantitative relations between structure and antiinflammatory activity of aryloxoalkanoic acids

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19881862 ◽

1988 ◽

Vol 53 (8) ◽

pp. 1862-1872 ◽

Cited By ~ 11

Author(s):

Miroslav Kuchař ◽

Eva Maturová ◽

Bohumila Brunová ◽

Jaroslava Grimová ◽

Hana Tomková ◽

...

Keyword(s):

Regression Analysis ◽

Structural Changes ◽

Antiinflammatory Activity ◽

Structural Parameters ◽

Considerable Effect ◽

Antiinflammatory Effect ◽

Prolonged Action ◽

Preclinical Development ◽

Indicator Variables ◽

Inhibitory Activities

The antiinflammatory effect of a series of aryloxoalkanoic acids II and of their biphenyl derivatives III was examined by measuring the inhibition of the development of carageenan- and adjuvant-induced edemas. The quantitative relations between the antiinflammatory effect and physicochemical and structural parameters of the compounds tested were evaluated. The equations obtained by the method of regression analysis showed a significant linear dependence of both inhibitory activities on the lipophilicity of the compounds and a considerable effect of some structural changes as expressed by indicator variables. The antiinflammatory effect is especially enhanced in both tests by the presence of a cyclic substituent at the aromatic ring. The high antiinflammatory effect of biphenylyl derivatives III is paralleled by their prolonged action. The prolongation of the effect is most likely a result of a suitable biotransformation of acid III to an efficient metabolite. The structural requirements which resulted from both the regression analysis and from the hypothesis of biotransformation of acids III were utilized in the synthesis of suitably substituted biphenylyloxoalkanoic acids. By this approach derivatives IIIe-i were obtained some of which showed a high antiinflammatory and also protracted effect. 4-(2',4'-Difluorbiphenylyl)-4-oxo-2-methylbutanoic acid (VÚFB-16 066, Flobufen) was chosen for further preclinical development.

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Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing

International Journal of Molecular Sciences ◽

10.3390/ijms22020477 ◽

2021 ◽

Vol 22 (2) ◽

pp. 477

Author(s):

Guendalina Froechlich ◽

Chiara Gentile ◽

Luigia Infante ◽

Carmen Caiazza ◽

Pasqualina Pagano ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Reproductive System ◽

Tumor Cell Line ◽

Breast Tumors ◽

Oncolytic Viruses ◽

Female Reproductive System ◽

Viral Glycoprotein ◽

Preclinical Development ◽

Biological Drugs

Background: HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. The availability of MSLN-retargeted oncolytic viruses may complement the current immunotherapeutic panel of biological drugs against HER2-negative breast and non-breast tumors. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Recombineering technology was used to replace an essential moiety of the viral glycoprotein D with antibody fragments derived from clinically validated MSLN monoclonal antibodies, and to allow IL12 cargo expression in infected cells. Panels of breast and female reproductive system cell lines were used to verify the oncolytic potential of the viral constructs. A platform for production of the retargeted viruses was developed in HEK 293 cells, providing stable expression of a suitable chimeric receptor. Results: We demonstrated the selectivity of viral infection and cytotoxicity by MSLN-retargeted viruses in a panel of mesothelin-positive cancer cells, originating from breast and female reproductive system tumors. We also developed a second-generation oncolytic MSLN-THV, encoding IL12, to enhance the immunotherapeutic potential of the viral backbone. A non-tumor cell line expressing a chimeric MSLN/Nectin-1 receptor, de-sensitized from antiviral responses by genetic inactivation of the Stimulator of Interferon Genes (STING)-dependent pathway was engineered, to optimize viral yields. Conclusions: Our proof-of-concept study proposes MSLN-retargeted herpesviruses as potential cancer immunotherapeutics for assessments in preclinical models of MSLN-positive tumors, complementing the available panel of oncolytic viruses to HER2-negative breast tumors.

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Discovery and Optimization of Selective Inhibitors of Meprin α (Part I)

Pharmaceuticals ◽

10.3390/ph14030203 ◽

2021 ◽

Vol 14 (3) ◽

pp. 203 ◽

Cited By ~ 1

Author(s):

Shurong Hou ◽

Juan Diez ◽

Chao Wang ◽

Christoph Becker-Pauly ◽

Gregg B. Fields ◽

...

Keyword(s):

Inhibitory Activity ◽

De Novo ◽

Selective Inhibitors ◽

Preclinical Development ◽

Starting Point ◽

Good Starting Point ◽

Parallel Screening ◽

Low Cytotoxicity

Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer’s. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization.

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The era of gene therapy: From preclinical development to clinical application

Drug Discovery Today ◽

10.1016/j.drudis.2021.03.021 ◽

2021 ◽

Author(s):

Nabil A. Alhakamy ◽

David T. Curiel ◽

Cory J. Berkland

Keyword(s):

Gene Therapy ◽

Clinical Application ◽

Preclinical Development

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Intrapulmonary vaccination with delta-inulin adjuvant stimulates non-polarised chemotactic signalling and diverse cellular interaction

Mucosal Immunology ◽

10.1038/s41385-021-00379-6 ◽

2021 ◽

Author(s):

Kia C. Ferrell ◽

Erica L. Stewart ◽

Claudio Counoupas ◽

Thomas M. Ashhurst ◽

Warwick J. Britton ◽

...

Keyword(s):

Γδ T Cells ◽

Mucosal Vaccine ◽

Cellular Interaction ◽

Respiratory Pathogens ◽

Preclinical Development ◽

Cell Recruitment ◽

Mait Cells ◽

Attractive Option ◽

Early Inflammatory Response ◽

Chemotactic Factors

AbstractThere is an urgent need for novel vaccination strategies to combat respiratory pathogens. Mucosal vaccine delivery is an attractive option as it directly targets the site of infection; however, preclinical development has been hindered by a lack of suitable mucosal adjuvants and a limited understanding of their immune effects in the lung environment. Herein, we define the early immune events following the intrapulmonary delivery of a vaccine incorporating the adjuvant delta-inulin. Analysis of the early inflammatory response showed vaccine-induced innate cell recruitment to lungs and local lymph nodes (LN) was transient and non-polarised, correlating with an increase in pulmonary chemotactic factors. Use of fluorescently labelled adjuvant revealed widespread tissue dissemination of adjuvant particles, coupled with broad cellular uptake and transit to the lung-draining LN by a range of innate immune cells. Mass cytometric analysis revealed extensive phenotypic changes in innate and adaptive cell subsets induced by vaccination; this included identification of unconventional lymphocytes such as γδ-T cells and MAIT cells that increased following vaccination and displayed an activated phenotype. This study details a comprehensive view of the immune response to intrapulmonary adjuvant administration and provides pre-clinical evidence to support delta-inulin as a suitable adjuvant for pulmonary vaccines.

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