Assess manufacturability and immunogenicity to reduce candidate risk


Our Developability Assessment Toolbox is a suite of in silico tools and applied protein structure expertise. The platform includes Manufacturability and Immunogenicity Assessment Services applicable to customers in both discovery and early stage biological protein and antibody drug development.

  • Manufacturability Assessment Service analyzes chemical degradation pathways, post translational modifications including deamidation, oxidation and glycosylation, and potential physical stability issues, most notably, protein aggregation.
  • Immunogenicity Assessment Service uses our proprietary Epibase® in silico screening tool to identify T cell epitopes that may trigger potential immune reactions.
  • This service is applicable for all protein types whether derived from mammalian or microbial expression systems.

The benefits of early risk assessment include:

  • Reduction in development costs and time
  • Acceleration of the lead candidate selection process
  • Increase the chance of a candidates success
  • Potential optimization of the process before problems arise in development
  • Improved chance of successful manufacturing scale-up

The post assessment deliverables include full reports highlighting the predictions and analyses from the services listed above. If high-risk issues are identified in the initial assessment, our experts have an extensive range of protein engineering capabilities that have the potential to improve the structure, biological activity and the manufacturing properties of your drug candidate.


  • Manufacturability Assessment

    Make informed decisions

    Many biological therapeutics being developed today are at risk from potential Post Translational Modifications (PTMs) and chemical and physical stability issues. These structural modifications are considered relevant to determining a candidate’s overall long-term stability.

    To proactively minimize potential clinical failure, we offer a set of proprietary in silico tools for a comprehensive Manufacturability Assessment of your target candidates. This assessment is applicable for all protein types whether derived from mammalian or microbial expression systems.

    Our Manufacturability Assessment includes the analysis of post translational modifications/chemical stability and physical stability.

    • PTMs can affect binding affinity, function and safety of your potential drug. They can often impact your molecule's bioactivity and stability and can result in the production of different isoforms of your desired product.

      While not all PTMs will result in high risk issues, many have the potential to affect the manufacturability of your biologic. Our Assessment Services will identify potential PTMs and chemical issues and highlight those that are of the highest risk. Our assessment can evaluate:

      • Deamidation sites
      • Aspartate isomerization sites
      • Oxidation sites (Methionine and Tryptophan)
      • Free-Cysteine Thiol groups
      • N & O-Glycosylation sites
      • Lysine Glycation

       

    • Monitoring physical stability and aggregation of biopharmaceuticals can be a major challenge for drug developers. This is due in part to the fact that aggregation can occur at very different stages in the biomanufacturing and development processes and can also manifest itself in very different ways. Low host viability, low productivity, the presence of inclusion bodies and the development of opalescent solutions or precipitates are clear indications of stability issues.

      With these challenges in mind, we have developed a proprietary suite of predictive models designed to assess the aggregation potential of your monoclonal antibody. Our in silico aggregation assessment tool uses sequence and structural algorithms to identify motifs with a potential for aggregation. The tool will rank candidates based on a high/low risk scale and will allow you to profile your library and select the best leads using a high throughput approach (Ref. Obrezanova et al, mAbs 2015).

      The tool is also available to be used in customers' facilities through the Sentinel APART™ platform, a highly-secure, customer-dedicated, web-based application for screening and re-engineering.

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      Below is a comparison between the in silico aggregation prediction of 6 monoclonal antibodies (wild type and variants) as compared to the experimentally determined levels. Lonza’s tool correctly predicted 6 out of 6 mAbs on the propensity to aggregate.

      Variant Predicted Aggregation Risk
      WT Low
      1 Low
      2 Low
      3 High
      4 High
      5 High

      Experimentally determined level of aggregation

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  • Save time and money with early safety assessment

    All therapeutic proteins show some level of immunogenicity. An anti-drug antibody (ADA) response to a therapeutic protein can reduce efficacy and compromise the pharmacodynamics and safety of a drug candidate. High levels of immunogenicity can lead to increased adverse events  which can be  potentially life threatening. Assessing immunogenicity during preclinical development is critical to the success of your therapeutic candidate.

    Our proprietary Epibase® in silico screening is an early assessment tool for lead selection, comparison and optimization. Epibase® in silico uses a “structural bioinformatics” approach to search for potential T cell epitopes in the target protein. Epibase® in silico incorporates the most recent experimentally generated binding affinities of peptides to the HLA receptor as well as the characteristics of the latest 3D structure of the HLA receptors. Epibase® in silico screening, in conjunction with our Manufacturability Assessment Services, allow you to rank candidate sequences quickly and efficiently to prioritize your work flow and reduce attrition rates by carrying only your best candidates forward. 

    Epibase™ in silico applications

    • T cell epitope identification
    • Immunogenicity profiling and comparison of protein leads
    • Selection of low immunogenic protein therapeutics
    • T cell epitope elimination
    • Documentation of immunogenicity risk management

  • Address predicted risks 

    We offer risk mitigation for both early and later stage development programs. Early stage mitigation strategies include proprietary in silico screening and re-engineering while later stage programs address issues through process development optimization.

    Following a complete Developability Assessment, customers will be provided with a full report outlining potential issues highlighting those that pose a high risk. The report will include mitigation options for the candidate. Our protein engineers are adept at improving the structure and the manufacturing properties of your drug candidate. In addition, we can manufacture non-GMP and GMP product for in vitro validation of findings, including immunogenicity.

    The figure below shows how a developability mitigation workflow could be structured. Early risk assessments can be utilized before committing to host development. Candidates classified as ‘low risk’ may then move directly into process development stages whereas those candidates identified as having ‘high risk’ issues can be subject to a number of risk-mitigation strategies depending on where they are in the development pipeline.

    In cases where programs are still in early stages of development, the selection of an alternative candidate – for example, from display or affinity maturation libraries – can be progressed. Alternatively, molecules can be subjected to a re-engineering program to produce new and improved variants for later-stage programs, where there is only a single candidate option, developability assessment can provide information for a proactive approach to process development in order to address the predicted issues.

    Experimentally determined level of aggregation

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    Case Study: Binding Affinity

    Re-engineered variants were analyzed for the retention of binding affinity. All variants, including those where substitutions had been made in the CDR, retained binding affinity comparable to that of wild-type.

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    Case Study: Productivity

    High aggregation is often associated with lower productivity. Re-engineered variants were monitored for productivity compared to wild-type and in all cases an increase in relative productivity was observed.

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    Case Study: Re-Engineering

    Following expression and Protein A purification the candidate sequence was shown to have a high and unacceptable level of aggregation. The selected sequence was re-engineered by targeting aggregation hotspots and other motifs involved in aggregation. Specific substitutions were made to reduce the aggregation propensity of the molecule. New variants were expressed, purified and characterized in parallel with the wild-type. Aggregation was successfully reduced in all variants by up to 80% compared to the wild type.

    Preview not available in Edit Mode

Maximize your chances of success: Avoid and mitigate risk of failure when developing biotherapeutics

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