BIOCHEMISTRY, BIOMEDICINE & PHARMACEUTICS

In this original research article, Dobnik et al. used the molecular biology technique and the transmission electron microscopy technique to characterize and quantitate the viral vectors used for clinical trials. Accurate Quantification and Characterization of Adeno-Associated Viral Vectors David Dobni, et al 2019. Frontier in Microbiology One of the main challenges in the gene therapy viral vector development is to establish an optimized process for its large scale production. This requires optimization for upstream and downstream processes as well as methods that enable the step-by step analytical characterization of the virus, the results of which inform the iterative refinement of production for yield, purity and potency. The biggest problem here is a plethora of viral vector formulations, many of which interfere with analytical techniques. We took adeno-associated virus (AAV) as an example and showed benefits of combined use of molecular methods and transmission electron mic...

In this review article, Fontana et al. discuss the strategies for reducing immunogenicity for therapeutic proteins using various immunomodulatory regimens. These immunomodulatory strategies may reduce the deleterious effect of the immune response evoked against the therapeutic proteins, and improve the safety and efficacy of therapeutic proteins. The strategies include agents that reduce B-cell proliferation, immune tolerization etc. Approaches to Mitigate the Unwanted Immunogenicity of Therapeutic Proteins during Drug Development Laura I. Salazar-Fontana et al. (AAPS 2017: 19(2):377-385) Abstract All biotherapeutics have the potential to induce an immune response. This immunological response is complex and, in addition to antibody formation, involves T cell activation and innate immune responses that could contribute to adverse effects. Integrated immunogenicity data analysis is crucial to understanding the possible clinical consequences of anti-drug antibody (ADA) responses....

Taking immunogenicity assessment of therapeutic proteins to the next level Büttel IC et al, Biologicals. 2011 Mar;39(2):100-9 Abstract Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g. the physiological hormone). Regulatory guidance on immunogenicity assessment needs to take into consideration a great diversity of products, indications and patient populations as well as constantly advancing manufacturing technologies. Such guidance needs to be sufficiently specific while, at the same time, allowing interactive discussion and adjusted benefit-risk weighing of each product on a case-by-case basis, e.g. for a unique treatment of a life threatening disease acceptable t...

Immunogenicity of biotherapeutics in the context of developing biosimilars and biobetters.  Barbosa MD. Drug Discov Today. 2011 Apr;16(7-8):345-53. Abstract Issues concerning the approval of biosimilars are currently being addressed by the US Food and Drug Administration and the European Medicines Agency. There appears to be a consensus that immunogenicity impacts comparability studies and the interchangeability of biosimilars. In addition, preclinical immunogenicity assessment and mitigation, if validated in clinical studies, might impact patient safety and development costs, and also facilitate the development of 'biobetters' and other protein therapeutics. This review addresses recent advances in the field of biosimilars and focuses on predictive immunology, with an emphasis on preclinical immunogenicity assessments of protein therapeutics other than vaccines and their corresponding clinical outcomes. Click here to read full text

Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility. Wadhwa M, Knezevic I, Kang HN, Thorpe R. Biologicals. 2015 Sep;43(5):298-306.   Biotherapeutic products (BTPs) are the fastest growing medicines in the pharmaceutical market. Despite their clinical success, the immunogenicity of BTPs continues to be a major concern. Assessment of immunogenicity as well as appropriate interpretation of immunogenicity data is therefore, of critical importance for defining safety profile of these products for the purpose of their licensure and use. In the past decade, much progress has been made towards how immunogenicity should be studied. This article reflects the content of the brief presentation on principles of methods used for immunogenicity assessment and their merits and limitations given at the first World Health Organization (WHO) implementation workshop on rDNA derived biotherapeutic products held in the Republic of Korea in May 2014...

Recommendations for the characterization of immunogenicity response to multiple domain biotherapeutics. Gorovits B, Wakshull E, Pillutla R, Xu Y, Manning MS, Goyal J J Immunol Methods. 2014 Jun;408:1-12 Abstract Many biotherapeutics currently in development have complex mechanisms of action and contain more than one domain, each with a specific role or function. Examples include antibody-drug conjugates (ADC), PEGylated, fusion proteins and bi-specific antibodies. As with any biotherapeutic molecule, a multi-domain biotherapeutic (MDB) can elicit immune responses resulting in the production of specific anti-drug antibodies (ADA) when administered to patients. As it is beneficial to align industry standards for evaluating immunogenicity of MDBs, this paper highlights pertinent immunogenicity risk factors and describes steps involved in the design of a testing strategy to detect and characterize binding (non-neutralizing and neutralizing, NAb) ADAs. In a common tier based appro...

A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs.  Shankar G, Pendley C, Stein KE. Nat Biotechnol. 2007 May;25(5):555-61. Bioanalytical assessments of anti-drug antibodies (ADAs) provide an understanding of the immunogenicity of biological drug molecules. The potential to induce ADAs after treatment with biologics is a safety issue that has become an important consideration in the development of biologics and a critical aspect of regulatory filings. US and European regulatory agencies are recommending that sponsors study immunogenicity using a risk-based approach, encouraging sponsors to formulate and implement their own risk management plans and to conduct discussions with the agencies when necessary. It follows from this that the greater the safety risks of ADAs, the more diligently one should clarify the immunogenicity of the product. Here we propose a general strategy to broadly assign immunogenicity risk levels...